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f657acaf2c82f9c10d10a29a7790bd07b0492f50 | cma | None | # INTRODUCTION
The worldwide pandemic of coronavirus disease 19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Co2) has emerged as one of the biggest public health crises in a century. Health systems in Canada face immense challenges, both to cope with the number of affected patients and the constraints imposed by containment measures such as physical distancing, quarantine, and personal protection. Stroke care across the globe and within Canada is rapidly changing to meet these challenges (see Appendix 1 in Supplementary material).
This document provides guidance on implementing evidencebased stroke care during the COVID-19 pandemic, based on expert opinion from the Canadian Stroke Best Practices Advisory Council. Despite incomplete and rapidly evolving evidence, we offer early guidance without formal recommendations and evidence grades because urgent changes are necessary. This guidance is based on expert opinion and early shared experiences with reorganizing stroke systems at the time of writing (April 13, 2020).
This document is guided by two main principles. First, stroke remains a medical emergency and should be treated as such. Second, stroke care is highly effective. Stroke best practice recommendations remain as evidence-based and relevant as ever, even though logistics and workflows need to change to accommodate the pandemic. Evidence-based stroke care reduces mortality, length of stay, improves functional outcomes, and prevents recurrence, contributing to relief of the health system. It should not be intentionally stopped or suspended, and this is universally agreed upon by stroke leaders (Appendix 1 in Supplementary material).
Across the globe, stroke centers are reporting decreased number of individuals with stroke symptoms presenting to emergency departments for care, especially those with TIA or milder symptoms. The causes behind this are not clear at this time. There is anecdotal evidence that patterns of patient engagement with health care services may be changing during the pandemic. Such decreases may raise new concerns, as individuals reluctant to seek medical care may be at a higher risk of a recurrent event with more severe and lasting physical, cognitive, and emotional impacts without timely assessment and treatment.
# STROKE AWARENESS RECOGNITION AND RESPONSE
Stroke is a medical emergency. This fact is not altered by the COVID-19 pandemic. Public awareness campaigns and existing processes in place for emergency medical system response to stroke should be maintained. Active public awareness efforts are needed to reinforce this message and reduce delays in seeking medical assistance.
# HYPERACUTE STROKE CARE
Acute stroke activations pose a risk because the stroke team must come in close contact with patients from the community, many of whom will have uncertain COVID-19 status. Patients unable to answer COVID-19 screening questions due to aphasia, cognitive issues, or encephalopathy should be treated as suspected COVID-19 positive. Personal protective equipment (PPE) should be worn, in accordance with local policies. Guidance for a "protected code stroke pathway" has been offered, emphasizing screening, appropriate use of PPE, where each team member understands their specific role, to minimize potential COVID-19 exposure. 1,4 Telemedicine can be used for acute stroke consultation to avoid exposing team members and reduce use of PPE.
Endovascular thrombectomy (EVT) is a highly effective stroke treatment indicated for severely affected ischemic stroke patients at risk for respiratory instability, vomiting, aspiration, and coughing, all of which could increase spread of viral-laden droplets. To avoid the risk of emergency intubation in the EVT angiography suite with potential viral spread, it is appropriate to make early decisions regarding the need for intubation. If needed, it should be done in an elective, controlled manner prior to transfer to the angiography suite in a negative pressure room. This does not imply the need to intubate more patients, and we continue to recommend that monitored anaesthesia is preferred unless there is a clinical indication for intubation. 5 Similarly, recent multisociety guidance agrees that intubation is not necessary for all suspected or confirmed COVID-19 patients. 11,12 The minimum possible sedation should be used in COVID-19 suspected patients, to reduce the risk that bag-mask ventilation, an aerosol-generating procedure, would be required. 11 Demand for intensive care unit (ICU) beds may exceed supply during the surge of COVID-19 patients. It is appropriate to consider predicted stroke-related mortality as one of the criteria for ICU admission. However, many patients with stroke, including hemorrhagic stroke, can be saved with intensive care and will have a lower expected mortality than similar-aged COVID-19 patients with acute respiratory distress syndrome. As recommended by ethicists, decisions on triage should be based on objective evidence for mortality risk without making presumptions about quality of life for stroke survivors. 13 Triage for ICU admission should be made only after attempting emergency procedures to reverse the patient's condition, including intravenous thrombolysis and EVT for acute ischemic stroke and treatment of hydrocephalus in hemorrhagic stroke patients.
We encourage clinicians to amend their practices but not to deviate from evidence-based care. 5 We do not suggest amending acute stroke computed tomography (CT)-angiography protocols to include CT of the chest to look for signs of COVID-19. The diagnostic value of CT chest for COVID-19, including false positive and negative rates, is not well defined at present. We also do not suggest substituting tenecteplase for alteplase for thrombolysis even though tenecteplase is more convenient to infuse, requiring shorter duration of contact with the patient. There is insufficient evidence that tenecteplase is equivalent to alteplase, and the optimal dose is not clear.
# Key Messages
- Stroke is a medical emergency irrespective of the pandemic and existing evidence-based stroke guidelines should continue to be followed. 2. There is a need to continue to raise awareness with the public that stroke is a medical emergency, and they need to seek medical attention without delay despite COVID concerns. 3. Hyperacute stroke response teams remain available to treat acute stroke. 4. Changes in workflow processes are required within a Protected Code Stroke model. 5. Intubation is not necessary for all suspected or confirmed COVID-19 patients undergoing EVT.
# INPATIENT AND STROKE UNIT CARE
Stroke unit care, defined as care by an experienced interdisciplinary team with colocation of patients on a designated inpatient unit, reduces disability and saves lives. Challenges to providing stroke unit care during the pandemic include reduced staff due to illness and redeployment and potential admission of COVID-19-positive stroke patients to general medical wards rather than stroke units.
There is already an increasing strain on health care resources in hospitals, including redeployment of highly skilled health care providers (HCP). As a result, stroke units may be staffed by nonstroke experts. Accordingly, hospitals should develop strong, team-based approaches to optimize best practice care for stroke patients using all team members' capabilities. Patients with a dual diagnosis of acute stroke and COVID-19 may be admitted to a nonstroke unit with HCP less experienced at providing stroke care and early rehabilitation. 5 In these instances, there should be processes in place for consultation with stroke experts and education on stroke best practices. 14 Particularly important is education for the recognition, assessment, and management of dysphagia, aphasia, cognitive impairment, handling and positioning of hemiplegic extremities, venous thromboembolism prevention, transfers, and fall prevention. All interdisciplinary staff should also receive basic stroke education on assessment for signs and symptoms of stroke as part of monitoring for possible stroke transformation. This should include screening tools such as FAST (Face, Arms, Speech, Time) 15 and protocols for inhospital actions to be taken if signs and symptoms of stroke are identified. Additional education and support may be required for HCP caring for patients with intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH).
After patients receive hyperacute reperfusion treatment (thrombolysis and/or EVT), care is optimally provided in an intensively monitored unit or critical care bed. Where access to critical care beds becomes limited, this care could be provided in a ward bed with appropriate supports. Broadly speaking, this would include measures for enhanced patient monitoring particularly within the first 24 h post-hyperacute treatment, education of the interdisciplinary team regarding all aspects of care for thrombolysis and EVT patients, and clear communication between team members regarding patient clinical status. Patients should be cared for in an area with high visibility from the hall and ideally with cardiac telemetry.
# Key Messages
- Stroke patients should continue to be cared for in specialized acute stroke units where possible. 2. Education and basic skills training may be required for nonstroke experts caring for stroke patients to ensure patient safety and optimizing recovery. 3. Where access to critical care beds becomes limited, this care could be provided in a ward bed with appropriate supports.
# STROKE REHABILITATION
Access to rehabilitation care has been significantly reduced during the COVID-19 pandemic. 16,17 People with stroke discharged directly to the community from acute care may have limited access to specialized stroke rehabilitation. Those who receive inpatient stroke rehabilitation may have a reduced length of stay. 1,18 It remains vital that persons with stoke continue to have access to specialized inpatient, outpatient, early supported discharge, and community stroke rehabilitation. Stroke rehabilitation is essential for people to achieve an optimal physical, cognitive, emotional, communicative, and social functional level following stroke, as well as to prevent or slow future functional decline and secondary health conditions. 19 Rehabilitation teams need to continue to follow evidencebased care for stroke patients. 19 Rehabilitation teams should be well educated on the use of PPE with strict adherence to infection control procedures for direct contact therapies, shared equipment, and spaces to ensure safe access is maintained. 17 Essential components of stroke rehabilitation care should be adapted to follow public health recommendations on physical distancing with consideration of such things as virtual team conferences.
Telerehabilitation is an effective and well-accepted method of providing outpatient and community rehabilitation services and is of particular importance during the COVID-19 pandemic. To support discharge planning, the use of telerehabilitation should be considered for family conferences, family and caregiver education and skills training, assessment of home environment, patient monitoring, and outpatient therapies. If telerehabilitation is planned for outpatient therapy, then education, skills training, and setup of the selected telerehabilitation platform for patients and family and caregivers residing with them should be provided prior to discharge. Patients should also be provided with clear discharge recommendations 19 and instructions for continued rehabilitation at home. Consideration ought to be given for earlier follow-up for patients whose lengths of stays are shortened by COVID-19 policies to allow earlier identification of potential complications or functional decline. Telemedicine can also help identify those individuals whose changing needs and health status require an in-person assessment. 23 People living in the community with chronic stroke will continue to require access to rehabilitation services. Rehabilitation professionals should ensure they have processes in place to triage referrals and address their needs to help prevent functional decline and complications during this time. Outpatient botulinum toxin injections during the COVID-19 pandemic should be considered when proper PPE is available and the individual is experiencing or is at risk of experiencing significant discomfort or pain, functional decline, or increased caregiver burden.
# Key Messages
- It is vital that persons with stoke continue to have access to specialized inpatient, outpatient, early supported discharge, and community stroke rehabilitation. 2. Essential components of stroke rehabilitation care should be adapted to follow public health recommendations on physical distancing and ensuring personal protection for staff and patient when direct contact is required. 3. Telerehabilitation is an effective and well-accepted method of providing outpatient and community rehabilitation services and is of particular importance during the COVID-19 pandemic.
# SECONDARY PREVENTION OF STROKE CARE
During the pandemic, access to specialized secondary stroke prevention services 24 may be limited. In-person outpatient assessments have been strongly discouraged in many health jurisdictions. Most stroke preventive care during the pandemic will need to be delivered by telemedicine, and evaluations should be modeled along the topics defined in the Post Stroke Checklist and core elements of stroke prevention care. 25,26 Lifestyle management issues of secondary prevention such as diet, exercise, weight, alcohol intake, and smoking should be addressed and may be impacted by public health policies that recommend staying at home. Patients, families, and caregivers should be provided with education, strategies, and resources for selfmanagement. 27 It is possible to complete some elements of a neurological exam via telemedicine with direct exam (e.g., mental status and speech), observation (e.g., portions of cranial nerve exam, extremity motor exam, coordination and gait), or with assistance of another person accompanying the patient (sensory exam). 28 This is essential when evaluating for occurrence of a new event. Patients should be asked whether they have a home blood pressure unit and glucometer (if applicable) for ongoing monitoring of secondary prevention targets.
For cases requiring in-person care, rapid assessment TIA clinics and stroke prevention clinics will need to have mechanisms in place to screen all patients for COVID-19 symptoms prior to arrival, and appropriate PPE measures and equipment should be available in these clinics. Individuals presenting within 24 hours should continue to have urgent brain and vascular imaging (e.g. CT/CTS scans) and electrocardiogram performed. It is advised that health professionals requesting urgent neuro (vascular) imaging communicate directly with a radiologist to ensure that the imaging can be completed in a timely manner as normal request workflows may be interrupted. Other investigations should be completed as soon as possible according to guidelines, acknowledging that some diagnostic services (e.g., echocardiography) may not be available during the pandemic. Individuals outside of the 24-h timeframe should have investigations completed as defined in the stroke best practice algorithm. 24 Direct admission is suggested for cases requiring hospitalization to reduce ED burden.
# Key Messages
- Secondary prevention services and follow-up must continue to be implemented to reduce recurrent stroke incidence, with revised workflows. 2. Telemedicine-enabled evaluation should be modeled on the topics defined in the Post Stroke Checklist and core elements of stroke prevention care. 25,26 3. Individuals presenting within 24 hours should continue to have urgent brain and vascular imaging (e.g. CT/CTA scans) and electrocardiogram performed.
# TELESTROKE ACROSS THE CONTINUUM
During the COVID-19 pandemic, telemedicine has been rapidly adopted by many health systems to facilitate care provision while maintaining physical distancing and reducing the risk of nosocomial viral transmission. Telestroke systems for hyperacute stroke care and support in decision-making for thrombolysis and EVT care are well established. 20 Telemedicine can provide remote access to stroke specialists, sparing the need for transfer to tertiary care centers. It preserves the stroke specialist workforce by avoiding the risk of in-person exposure and infection and reduces use of PPE. 1 In institutions without current telestroke systems, other telemedicine supports using videoconferencing software, shared imaging access, and telephone consultation may be implemented to assist in hyperacute stroke decision-making. 29,30 Toolkits based on current evidence and expert opinion are available within the Canadian Stroke Best Practice Recommendations (CSBPR) to help inform services that are switching to virtual care within short timelines. 20,31 Stroke care providers and health systems should be aware of potential barriers to access such as patients and caregivers without reliable internet services or access to devices. Barriers to use of technology in individuals with stroke and communication, cognitive, or physical impairments should also be considered. Other social determinants of health such as stable housing may also create challenges in using virtual modalities to receive health care services. Telephone visits or involvement of family members in the assessment process could address these barriers.
# Key Messages
- Telestroke systems for hyperacute stroke care and support in decision-making for thrombolysis and EVT care are well established, and implementation should be expanded to service all regions. 2. Toolkits based on current evidence and expert opinion are available within the CSBPR to help inform services that are switching to virtual care within short timelines. 3. Barriers to access and utilization should be considered and work-around solutions implemented.
# SUMMARY
The COVID-19 pandemic has drastically changed the processes of patient access and stroke care. Yet, the nature and quality of stroke care across the whole continuum has proven benefits on long-term outcomes. Standards and comprehensiveness of care for stroke patients must be preserved; otherwise, the rate of recurrent stroke and ongoing functional, cognitive, and social disabilities will rise and create a new burden on an already over-stressed system. Overall, measures to sustain best practice stroke care should be implemented within pandemic planning across the health system. Alternate care models can allow continued access to stroke care for those who need it throughout and beyond the COVID-19 pandemic.
# STATEMENT OF AUTHORSHIP
EES is first author, led the hyperacute stroke management section and contributed to all aspects of the concept, design, writing and editing of the manuscript. AM led the rehabilitation section and contributed to all aspects of the concept, design, writing and editing of the manuscript. MDH contributed to the hyperacute stroke management section and contributed to all aspects of the concept, design, writing and editing of the manuscript. THW led the prevention section and contributed to all aspects of the concept, design, writing and editing of the manuscript. DB led the telemedicine section and contributed to all aspects of the concept, design, writing and editing of the manuscript and supports digital knowledge translation resources. LKC led the inpatient stroke care section and contributed to all aspects of the concept, design, writing and editing of the manuscript. EL contributed to the inpatient stroke care section and contributed to aspects of the concept, design, writing and editing of the manuscript. NF conducted the systematic evidence reviews, and contributed to the editing and preparation of the manuscript. GG contributed to aspects of the writing and editing of the manuscript, and supports digital knowledge translation resources. AS contributed to all aspects of the concept, design and editing of the manuscript and supports digital knowledge translation resources.
MPL is senior and corresponding author, coordinated and contributed to all aspects of the concept, design, writing and editing of the manuscript, and digital knowledge translation resources.
# SUPPLEMENTARY MATERIAL
To view supplementary material for this article, please visit . | # INTRODUCTION
The worldwide pandemic of coronavirus disease 19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Co2) has emerged as one of the biggest public health crises in a century. Health systems in Canada face immense challenges, both to cope with the number of affected patients and the constraints imposed by containment measures such as physical distancing, quarantine, and personal protection. Stroke care across the globe and within Canada is rapidly changing to meet these challenges [1][2][3][4][5][6][7] (see Appendix 1 in Supplementary material).
This document provides guidance on implementing evidencebased stroke care during the COVID-19 pandemic, based on expert opinion from the Canadian Stroke Best Practices Advisory Council. Despite incomplete and rapidly evolving evidence, we offer early guidance without formal recommendations and evidence grades because urgent changes are necessary. This guidance is based on expert opinion and early shared experiences with reorganizing stroke systems at the time of writing (April 13, 2020).
This document is guided by two main principles. First, stroke remains a medical emergency and should be treated as such. Second, stroke care is highly effective. Stroke best practice recommendations remain as evidence-based and relevant as ever, even though logistics and workflows need to change to accommodate the pandemic. Evidence-based stroke care reduces mortality, length of stay, improves functional outcomes, and prevents recurrence, contributing to relief of the health system. [8][9][10] It should not be intentionally stopped or suspended, and this is universally agreed upon by stroke leaders (Appendix 1 in Supplementary material).
Across the globe, stroke centers are reporting decreased number of individuals with stroke symptoms presenting to emergency departments for care, especially those with TIA or milder symptoms. The causes behind this are not clear at this time. There is anecdotal evidence that patterns of patient engagement with health care services may be changing during the pandemic. Such decreases may raise new concerns, as individuals reluctant to seek medical care may be at a higher risk of a recurrent event with more severe and lasting physical, cognitive, and emotional impacts without timely assessment and treatment.
# STROKE AWARENESS RECOGNITION AND RESPONSE
Stroke is a medical emergency. This fact is not altered by the COVID-19 pandemic. Public awareness campaigns and existing processes in place for emergency medical system response to stroke should be maintained. Active public awareness efforts are needed to reinforce this message and reduce delays in seeking medical assistance.
# HYPERACUTE STROKE CARE
Acute stroke activations pose a risk because the stroke team must come in close contact with patients from the community, many of whom will have uncertain COVID-19 status. Patients unable to answer COVID-19 screening questions due to aphasia, cognitive issues, or encephalopathy should be treated as suspected COVID-19 positive. Personal protective equipment (PPE) should be worn, in accordance with local policies. Guidance for a "protected code stroke pathway" has been offered, emphasizing screening, appropriate use of PPE, where each team member understands their specific role, to minimize potential COVID-19 exposure. 1,4 Telemedicine can be used for acute stroke consultation to avoid exposing team members and reduce use of PPE.
Endovascular thrombectomy (EVT) is a highly effective stroke treatment indicated for severely affected ischemic stroke patients at risk for respiratory instability, vomiting, aspiration, and coughing, all of which could increase spread of viral-laden droplets. To avoid the risk of emergency intubation in the EVT angiography suite with potential viral spread, it is appropriate to make early decisions regarding the need for intubation. If needed, it should be done in an elective, controlled manner prior to transfer to the angiography suite in a negative pressure room. This does not imply the need to intubate more patients, and we continue to recommend that monitored anaesthesia is preferred unless there is a clinical indication for intubation. 5 Similarly, recent multisociety guidance agrees that intubation is not necessary for all suspected or confirmed COVID-19 patients. 11,12 The minimum possible sedation should be used in COVID-19 suspected patients, to reduce the risk that bag-mask ventilation, an aerosol-generating procedure, would be required. 11 Demand for intensive care unit (ICU) beds may exceed supply during the surge of COVID-19 patients. It is appropriate to consider predicted stroke-related mortality as one of the criteria for ICU admission. However, many patients with stroke, including hemorrhagic stroke, can be saved with intensive care and will have a lower expected mortality than similar-aged COVID-19 patients with acute respiratory distress syndrome. As recommended by ethicists, decisions on triage should be based on objective evidence for mortality risk without making presumptions about quality of life for stroke survivors. 13 Triage for ICU admission should be made only after attempting emergency procedures to reverse the patient's condition, including intravenous thrombolysis and EVT for acute ischemic stroke and treatment of hydrocephalus in hemorrhagic stroke patients.
We encourage clinicians to amend their practices but not to deviate from evidence-based care. 5 We do not suggest amending acute stroke computed tomography (CT)-angiography protocols to include CT of the chest to look for signs of COVID-19. The diagnostic value of CT chest for COVID-19, including false positive and negative rates, is not well defined at present. We also do not suggest substituting tenecteplase for alteplase for thrombolysis even though tenecteplase is more convenient to infuse, requiring shorter duration of contact with the patient. There is insufficient evidence that tenecteplase is equivalent to alteplase, and the optimal dose is not clear.
# Key Messages
1. Stroke is a medical emergency irrespective of the pandemic and existing evidence-based stroke guidelines should continue to be followed. 2. There is a need to continue to raise awareness with the public that stroke is a medical emergency, and they need to seek medical attention without delay despite COVID concerns. 3. Hyperacute stroke response teams remain available to treat acute stroke. 4. Changes in workflow processes are required within a Protected Code Stroke model. 5. Intubation is not necessary for all suspected or confirmed COVID-19 patients undergoing EVT.
# INPATIENT AND STROKE UNIT CARE
Stroke unit care, defined as care by an experienced interdisciplinary team with colocation of patients on a designated inpatient unit, reduces disability and saves lives. Challenges to providing stroke unit care during the pandemic include reduced staff due to illness and redeployment and potential admission of COVID-19-positive stroke patients to general medical wards rather than stroke units.
There is already an increasing strain on health care resources in hospitals, including redeployment of highly skilled health care providers (HCP). As a result, stroke units may be staffed by nonstroke experts. Accordingly, hospitals should develop strong, team-based approaches to optimize best practice care for stroke patients using all team members' capabilities. Patients with a dual diagnosis of acute stroke and COVID-19 may be admitted to a nonstroke unit with HCP less experienced at providing stroke care and early rehabilitation. 5 In these instances, there should be processes in place for consultation with stroke experts and education on stroke best practices. 14 Particularly important is education for the recognition, assessment, and management of dysphagia, aphasia, cognitive impairment, handling and positioning of hemiplegic extremities, venous thromboembolism prevention, transfers, and fall prevention. All interdisciplinary staff should also receive basic stroke education on assessment for signs and symptoms of stroke as part of monitoring for possible stroke transformation. This should include screening tools such as FAST (Face, Arms, Speech, Time) 15 and protocols for inhospital actions to be taken if signs and symptoms of stroke are identified. Additional education and support may be required for HCP caring for patients with intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH).
After patients receive hyperacute reperfusion treatment (thrombolysis and/or EVT), care is optimally provided in an intensively monitored unit or critical care bed. Where access to critical care beds becomes limited, this care could be provided in a ward bed with appropriate supports. Broadly speaking, this would include measures for enhanced patient monitoring particularly within the first 24 h post-hyperacute treatment, education of the interdisciplinary team regarding all aspects of care for thrombolysis and EVT patients, and clear communication between team members regarding patient clinical status. Patients should be cared for in an area with high visibility from the hall and ideally with cardiac telemetry.
# Key Messages
1. Stroke patients should continue to be cared for in specialized acute stroke units where possible. 2. Education and basic skills training may be required for nonstroke experts caring for stroke patients to ensure patient safety and optimizing recovery. 3. Where access to critical care beds becomes limited, this care could be provided in a ward bed with appropriate supports.
# STROKE REHABILITATION
Access to rehabilitation care has been significantly reduced during the COVID-19 pandemic. 16,17 People with stroke discharged directly to the community from acute care may have limited access to specialized stroke rehabilitation. Those who receive inpatient stroke rehabilitation may have a reduced length of stay. 1,18 It remains vital that persons with stoke continue to have access to specialized inpatient, outpatient, early supported discharge, and community stroke rehabilitation. Stroke rehabilitation is essential for people to achieve an optimal physical, cognitive, emotional, communicative, and social functional level following stroke, as well as to prevent or slow future functional decline and secondary health conditions. 19 Rehabilitation teams need to continue to follow evidencebased care for stroke patients. 19 Rehabilitation teams should be well educated on the use of PPE with strict adherence to infection control procedures for direct contact therapies, shared equipment, and spaces to ensure safe access is maintained. 17 Essential components of stroke rehabilitation care should be adapted to follow public health recommendations on physical distancing with consideration of such things as virtual team conferences.
Telerehabilitation is an effective and well-accepted method of providing outpatient and community rehabilitation services and is of particular importance during the COVID-19 pandemic. [20][21][22] To support discharge planning, the use of telerehabilitation should be considered for family conferences, family and caregiver education and skills training, assessment of home environment, patient monitoring, and outpatient therapies. If telerehabilitation is planned for outpatient therapy, then education, skills training, and setup of the selected telerehabilitation platform for patients and family and caregivers residing with them should be provided prior to discharge. Patients should also be provided with clear discharge recommendations 19 and instructions for continued rehabilitation at home. Consideration ought to be given for earlier follow-up for patients whose lengths of stays are shortened by COVID-19 policies to allow earlier identification of potential complications or functional decline. Telemedicine can also help identify those individuals whose changing needs and health status require an in-person assessment. 23 People living in the community with chronic stroke will continue to require access to rehabilitation services. Rehabilitation professionals should ensure they have processes in place to triage referrals and address their needs to help prevent functional decline and complications during this time. Outpatient botulinum toxin injections during the COVID-19 pandemic should be considered when proper PPE is available and the individual is experiencing or is at risk of experiencing significant discomfort or pain, functional decline, or increased caregiver burden.
# Key Messages
1. It is vital that persons with stoke continue to have access to specialized inpatient, outpatient, early supported discharge, and community stroke rehabilitation. 2. Essential components of stroke rehabilitation care should be adapted to follow public health recommendations on physical distancing and ensuring personal protection for staff and patient when direct contact is required. 3. Telerehabilitation is an effective and well-accepted method of providing outpatient and community rehabilitation services and is of particular importance during the COVID-19 pandemic.
# SECONDARY PREVENTION OF STROKE CARE
During the pandemic, access to specialized secondary stroke prevention services 24 may be limited. In-person outpatient assessments have been strongly discouraged in many health jurisdictions. Most stroke preventive care during the pandemic will need to be delivered by telemedicine, and evaluations should be modeled along the topics defined in the Post Stroke Checklist and core elements of stroke prevention care. 25,26 Lifestyle management issues of secondary prevention such as diet, exercise, weight, alcohol intake, and smoking should be addressed and may be impacted by public health policies that recommend staying at home. Patients, families, and caregivers should be provided with education, strategies, and resources for selfmanagement. 27 It is possible to complete some elements of a neurological exam via telemedicine with direct exam (e.g., mental status and speech), observation (e.g., portions of cranial nerve exam, extremity motor exam, coordination and gait), or with assistance of another person accompanying the patient (sensory exam). 28 This is essential when evaluating for occurrence of a new event. Patients should be asked whether they have a home blood pressure unit and glucometer (if applicable) for ongoing monitoring of secondary prevention targets.
For cases requiring in-person care, rapid assessment TIA clinics and stroke prevention clinics will need to have mechanisms in place to screen all patients for COVID-19 symptoms prior to arrival, and appropriate PPE measures and equipment should be available in these clinics. Individuals presenting within 24 hours should continue to have urgent brain and vascular imaging (e.g. CT/CTS scans) and electrocardiogram performed. It is advised that health professionals requesting urgent neuro (vascular) imaging communicate directly with a radiologist to ensure that the imaging can be completed in a timely manner as normal request workflows may be interrupted. Other investigations should be completed as soon as possible according to guidelines, acknowledging that some diagnostic services (e.g., echocardiography) may not be available during the pandemic. Individuals outside of the 24-h timeframe should have investigations completed as defined in the stroke best practice algorithm. 24 Direct admission is suggested for cases requiring hospitalization to reduce ED burden.
# Key Messages
1. Secondary prevention services and follow-up must continue to be implemented to reduce recurrent stroke incidence, with revised workflows. 2. Telemedicine-enabled evaluation should be modeled on the topics defined in the Post Stroke Checklist and core elements of stroke prevention care. 25,26 3. Individuals presenting within 24 hours should continue to have urgent brain and vascular imaging (e.g. CT/CTA scans) and electrocardiogram performed.
# TELESTROKE ACROSS THE CONTINUUM
During the COVID-19 pandemic, telemedicine has been rapidly adopted by many health systems to facilitate care provision while maintaining physical distancing and reducing the risk of nosocomial viral transmission. Telestroke systems for hyperacute stroke care and support in decision-making for thrombolysis and EVT care are well established. 20 Telemedicine can provide remote access to stroke specialists, sparing the need for transfer to tertiary care centers. It preserves the stroke specialist workforce by avoiding the risk of in-person exposure and infection and reduces use of PPE. 1 In institutions without current telestroke systems, other telemedicine supports using videoconferencing software, shared imaging access, and telephone consultation may be implemented to assist in hyperacute stroke decision-making. 29,30 Toolkits based on current evidence and expert opinion are available within the Canadian Stroke Best Practice Recommendations (CSBPR) to help inform services that are switching to virtual care within short timelines. 20,31 Stroke care providers and health systems should be aware of potential barriers to access such as patients and caregivers without reliable internet services or access to devices. Barriers to use of technology in individuals with stroke and communication, cognitive, or physical impairments should also be considered. Other social determinants of health such as stable housing may also create challenges in using virtual modalities to receive health care services. Telephone visits or involvement of family members in the assessment process could address these barriers.
# Key Messages
1. Telestroke systems for hyperacute stroke care and support in decision-making for thrombolysis and EVT care are well established, and implementation should be expanded to service all regions. 2. Toolkits based on current evidence and expert opinion are available within the CSBPR to help inform services that are switching to virtual care within short timelines. 3. Barriers to access and utilization should be considered and work-around solutions implemented.
# SUMMARY
The COVID-19 pandemic has drastically changed the processes of patient access and stroke care. Yet, the nature and quality of stroke care across the whole continuum has proven benefits on long-term outcomes. Standards and comprehensiveness of care for stroke patients must be preserved; otherwise, the rate of recurrent stroke and ongoing functional, cognitive, and social disabilities will rise and create a new burden on an already over-stressed system. Overall, measures to sustain best practice stroke care should be implemented within pandemic planning across the health system. Alternate care models can allow continued access to stroke care for those who need it throughout and beyond the COVID-19 pandemic.
# STATEMENT OF AUTHORSHIP
EES is first author, led the hyperacute stroke management section and contributed to all aspects of the concept, design, writing and editing of the manuscript. AM led the rehabilitation section and contributed to all aspects of the concept, design, writing and editing of the manuscript. MDH contributed to the hyperacute stroke management section and contributed to all aspects of the concept, design, writing and editing of the manuscript. THW led the prevention section and contributed to all aspects of the concept, design, writing and editing of the manuscript. DB led the telemedicine section and contributed to all aspects of the concept, design, writing and editing of the manuscript and supports digital knowledge translation resources. LKC led the inpatient stroke care section and contributed to all aspects of the concept, design, writing and editing of the manuscript. EL contributed to the inpatient stroke care section and contributed to aspects of the concept, design, writing and editing of the manuscript. NF conducted the systematic evidence reviews, and contributed to the editing and preparation of the manuscript. GG contributed to aspects of the writing and editing of the manuscript, and supports digital knowledge translation resources. AS contributed to all aspects of the concept, design and editing of the manuscript and supports digital knowledge translation resources.
MPL is senior and corresponding author, coordinated and contributed to all aspects of the concept, design, writing and editing of the manuscript, and digital knowledge translation resources.
# SUPPLEMENTARY MATERIAL
To view supplementary material for this article, please visit https://doi.org/10.1017/cjn.2020.74. | None | None |
fc5aa5928dea5849375c5247a8fe02d3ee34300f | cma | None | To assist clinicians in the management of bleeding in patients receiving a direct oral anticoagulant (DOAC).Four direct oral anticoagulants (DOACs; dabigatran, apixaban, edoxaban, and rivaroxaban) are approved for clinical use in Canada based on findings from large, randomized trials. Like all anticoagulants, bleeding is the major complication of DOAC therapy. Although the mainstay of bleeding management is supportive, a specific anticoagulant reversal agent is available for dabigatran (idarucizumab ). There are currently nonspecific reversal agents available for factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) available in Canada. The use of non-specific pro-hemostatic products (e.g. 4-factor prothrombin complex concentrate , activated PCC ) has been evaluated in small cohorts of DOAC-treated patients with major bleeding . Appropriate management in all cases of bleeding requires a systematic approach to assessing the competing risks and consequences of bleeding and thrombosis.# MANAGEMENT OF BLEEDING EPISODES:
Minor Bleeding (examples: extremity bruising, hemorrhoidal bleeding, subconjunctival bleed, self-limited epistaxis):
- Continue anticoagulant and monitor - Confirm the patient is receiving the appropriate drug and dose based on indication, age, weight, and creatinine clearance - Consider measuring hemoglobin, platelet count, creatinine, and liver function tests - Review concomitant medications which may contribute to bleeding (e.g. antiplatelet therapies, NSAIDs)
# Clinically Relevant Nonmajor Bleeding
# Apixaban/Edoxaban/Rivaroxaban
- If apixaban/edoxaban/rivaroxaban is likely still present (as per time of last dose and creatinine clearance), give PCC. PCCs are not selective reversal agents, and their effect is debatable. If specific drug levels are rapidly available and less than 30-50 ng/mL, no treatment is required. - Inform patients/families regarding potential thrombotic risk in this setting due to interruption of anticoagulation, activation of coagulation to stop bleeding, and administration of PCC (e.g. stroke, myocardial infarction, and venous thromboembolism), but highlight that consequences of uncontrolled bleeding likely exceed this risk. - Consider adjunctive therapy with tranexamic acid for uncontrolled bleeding (limited data in this setting) - Note: Andexanet alfa is a specific antidote for factor Xa inhibitors but is not currently available in Canada. - >30 ng/mL = likely significant anticoagulant effect 1
- <30 ng/mL = likely no significant anticoagulant effect 1
- >30 ng/mL = likely significant anticoagulant effect 1 1 There are no data to establish a hemostatic threshold below which drug levels are unlikely to affect hemostasis. These estimates are extrapolated from observations in clinical trials and are in agreement with other guidelines.
Rule out other causes of increased PT/INR/PTT (e.g. DIC, coagulopathy of liver disease, vitamin K deficiency, warfarin, a coagulation factor inhibitor, or a factor deficiency). Notes regarding pro-hemostatic therapies (PCC, FEIBA®, recombinant factor VIIa) for DOAC-associated severe/life-threatening bleeding:
- Supportive clinical data for pro-hemostatic agents (PCC, FEIBA®, rVIIa) are limited and based on the results of several small observational cohorts of DOAC-treated bleeding patients, in vitro studies, animal models, and studies in human volunteers evaluating coagulation markers. - PCC (Octaplex®, Beriplex®) and activated PCC (FEIBA®) are coagulation factor concentrates, not DOAC antidotes. They do not affect the inhibitory effect of DOACs on coagulation factors IIa (thrombin) and Xa, and they do not affect DOAC drug levels. These agents may reduce DOACassociated bleeding by providing large amounts of exogenous factors II and X. They may be associated with a small increased prothrombotic risk. - The use of antifibrinolytic agents such as tranexamic acid (Cyclokapron®) and aminocaproic acid (Amicar®) has no direct supporting evidence of benefit in patients with DOAC-associated bleeding. However, early use of tranexamic acid has benefit in traumatic bleeding, postpartum bleeding, and cardiac surgery and it has a good safety profile. Therefore, it may be considered as an adjunct for the treatment of DOAC-associated bleeding although specific data in this setting are lacking. - Recombinant factor VIIa (rFVIIa; NovoSeven®, Niastase®) is generally not recommended because of a lack of benefit in animal and in vitro studies and is associated with prothrombotic risk.
# WHEN BLEEDING HAS RESOLVED
- Assess patients for resumption of anticoagulation when hemostasis is achieved with consideration of patient values and preferences. Confirm ongoing indication for anticoagulation. 2. Estimate the risks of recurrent bleeding and thrombosis (and their clinical sequelae) with multidisciplinary input. 3. Assess baseline laboratory tests (hemoglobin, platelet count, creatinine, liver function tests) and current patient's weight.
- Review concomitant medications and reassess the need for medications which may contribute to bleeding (e.g. antiplatelet therapies, NSAIDs). 5. Confirm the appropriateness of the type and dose of anticoagulant based on clinical characteristics such as indication, age, weight, and creatinine clearance. 6. Provide education and counselling regarding bleeding complications and when to seek medical attention. 7. Ensure routine follow-up and reassessment of #1 to #6 at regular intervals.
# SPECIAL CONSIDERATIONS:
# Pediatrics
There are no studies evaluating the management of bleeding in children receiving DOACs.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Apixaban (Eliquis®) - Dabigatran (Pradaxa®)
# Date of version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To assist clinicians in the management of bleeding in patients receiving a direct oral anticoagulant (DOAC).Four direct oral anticoagulants (DOACs; dabigatran, apixaban, edoxaban, and rivaroxaban) are approved for clinical use in Canada based on findings from large, randomized trials. Like all anticoagulants, bleeding is the major complication of DOAC therapy. Although the mainstay of bleeding management is supportive, a specific anticoagulant reversal agent is available for dabigatran (idarucizumab [Praxbind®]). There are currently nonspecific reversal agents available for factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) available in Canada. The use of non-specific pro-hemostatic products (e.g. 4-factor prothrombin complex concentrate [PCC; Beriplex®, Octaplex®], activated PCC [aPCC; FEIBA®]) has been evaluated in small cohorts of DOAC-treated patients with major bleeding . Appropriate management in all cases of bleeding requires a systematic approach to assessing the competing risks and consequences of bleeding and thrombosis.# MANAGEMENT OF BLEEDING EPISODES:
Minor Bleeding (examples: extremity bruising, hemorrhoidal bleeding, subconjunctival bleed, self-limited epistaxis):
• Continue anticoagulant and monitor • Confirm the patient is receiving the appropriate drug and dose based on indication, age, weight, and creatinine clearance • Consider measuring hemoglobin, platelet count, creatinine, and liver function tests • Review concomitant medications which may contribute to bleeding (e.g. antiplatelet therapies, NSAIDs)
# Clinically Relevant Nonmajor Bleeding
# Apixaban/Edoxaban/Rivaroxaban
• If apixaban/edoxaban/rivaroxaban is likely still present (as per time of last dose and creatinine clearance), give PCC. PCCs are not selective reversal agents, and their effect is debatable. If specific drug levels are rapidly available and less than 30-50 ng/mL, no treatment is required. • Inform patients/families regarding potential thrombotic risk in this setting due to interruption of anticoagulation, activation of coagulation to stop bleeding, and administration of PCC (e.g. stroke, myocardial infarction, and venous thromboembolism), but highlight that consequences of uncontrolled bleeding likely exceed this risk. • Consider adjunctive therapy with tranexamic acid for uncontrolled bleeding (limited data in this setting) • Note: Andexanet alfa is a specific antidote for factor Xa inhibitors but is not currently available in Canada. • >30 ng/mL = likely significant anticoagulant effect 1
• <30 ng/mL = likely no significant anticoagulant effect 1
• >30 ng/mL = likely significant anticoagulant effect 1 1 There are no data to establish a hemostatic threshold below which drug levels are unlikely to affect hemostasis. These estimates are extrapolated from observations in clinical trials and are in agreement with other guidelines.
# 2
Rule out other causes of increased PT/INR/PTT (e.g. DIC, coagulopathy of liver disease, vitamin K deficiency, warfarin, a coagulation factor inhibitor, or a factor deficiency). Notes regarding pro-hemostatic therapies (PCC, FEIBA®, recombinant factor VIIa) for DOAC-associated severe/life-threatening bleeding:
• Supportive clinical data for pro-hemostatic agents (PCC, FEIBA®, rVIIa) are limited and based on the results of several small observational cohorts of DOAC-treated bleeding patients, in vitro studies, animal models, and studies in human volunteers evaluating coagulation markers. • PCC (Octaplex®, Beriplex®) and activated PCC (FEIBA®) are coagulation factor concentrates, not DOAC antidotes. They do not affect the inhibitory effect of DOACs on coagulation factors IIa (thrombin) and Xa, and they do not affect DOAC drug levels. These agents may reduce DOACassociated bleeding by providing large amounts of exogenous factors II and X. They may be associated with a small increased prothrombotic risk. • The use of antifibrinolytic agents such as tranexamic acid (Cyclokapron®) and aminocaproic acid (Amicar®) has no direct supporting evidence of benefit in patients with DOAC-associated bleeding. However, early use of tranexamic acid has benefit in traumatic bleeding, postpartum bleeding, and cardiac surgery and it has a good safety profile. Therefore, it may be considered as an adjunct for the treatment of DOAC-associated bleeding although specific data in this setting are lacking. • Recombinant factor VIIa (rFVIIa; NovoSeven®, Niastase®) is generally not recommended because of a lack of benefit in animal and in vitro studies and is associated with prothrombotic risk.
# WHEN BLEEDING HAS RESOLVED
1. Assess patients for resumption of anticoagulation when hemostasis is achieved with consideration of patient values and preferences. Confirm ongoing indication for anticoagulation. 2. Estimate the risks of recurrent bleeding and thrombosis (and their clinical sequelae) with multidisciplinary input. 3. Assess baseline laboratory tests (hemoglobin, platelet count, creatinine, liver function tests) and current patient's weight.
4. Review concomitant medications and reassess the need for medications which may contribute to bleeding (e.g. antiplatelet therapies, NSAIDs). 5. Confirm the appropriateness of the type and dose of anticoagulant based on clinical characteristics such as indication, age, weight, and creatinine clearance. 6. Provide education and counselling regarding bleeding complications and when to seek medical attention. 7. Ensure routine follow-up and reassessment of #1 to #6 at regular intervals.
# SPECIAL CONSIDERATIONS:
# Pediatrics
There are no studies evaluating the management of bleeding in children receiving DOACs.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Apixaban (Eliquis®) • Dabigatran (Pradaxa®)
# Date of version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
069ec051013ca7ceb36df37f59f07224074faa8d | cma | None | The recommendations in this document were developed based on best available evidence and with input from Ontario Health's Evusheld Clinical Working Group.- There are limitations to the evidence that is currently available. Information about Evusheld, including its effectiveness against different variants of COVID-19, is evolving rapidly. Prescribers must determine whether adopting suggested information is clinically appropriate for individual patients through a risk-benefit assessment.Ontario Health does not recommend routine use of Evusheld for pre-exposure prophylaxis for any patient group, including immunocompromised patients, due to the prevalence of variants that are resistant to Evusheld (including BA.4.6, BF.7, BQ.1, and BQ.1.1), 1,2 which are expected to comprise >55% of circulating variants in Ontario by December 7, 2022. 3 The prevalence of variants that are resistant to Evusheld is expected to continue to rise given weekly relative growth rates. 3 Evusheld will remain available to be dispensed through pharmacies for use as pre-exposure prophylaxis in exceptional circumstances where the health care provider and patient have determined that the potential benefit outweighs the risks (e.g., with consideration to regional prevalence of resistant subvariants and individual patient risk factors). Any health care provider administering Evusheld due to exceptional circumstances (as outlined above) should refer to the product monograph 5 for details on Evusheld, including information on dosing (600 mg of Evusheld, administered as two separate 3.0 mL, sequential, injections of 300 mg of tixagevimab and 300 mg of cilgavimab) and repeat dosing (every 6 months).Health care providers should communicate with patients who have received Evusheld to: 4 - Inform patients about the potential for a lack of effectiveness against certain circulating variants and that if they have received Evusheld in the past, they cannot rely on it for protection.#
- Advise patients of the importance of immunization as the best method to remain protected against COVID-19. - Advise patients to continue to limit potential exposure to COVID-19 through public health measures such as masking and limiting contacts. - Advise patients to immediately seek medical advice if signs or symptoms of COVID-19 occur. Ontario Health's Evusheld patient handout has been revised to support communications with patients as outlined above.
# Treatment
Ontario Health does not recommend use of Evusheld for treatment of COVID-19 due to the risk of treatment failure against currently circulating variants in Ontario 1,2,3 and the availability of more effective treatments (e.g., Paxlovid). | The recommendations in this document were developed based on best available evidence and with input from Ontario Health's Evusheld Clinical Working Group.* There are limitations to the evidence that is currently available. Information about Evusheld, including its effectiveness against different variants of COVID-19, is evolving rapidly. Prescribers must determine whether adopting suggested information is clinically appropriate for individual patients through a risk-benefit assessment.Ontario Health does not recommend routine use of Evusheld for pre-exposure prophylaxis for any patient group, including immunocompromised patients, due to the prevalence of variants that are resistant to Evusheld (including BA.4.6, BF.7, BQ.1, and BQ.1.1), 1,2 which are expected to comprise >55% of circulating variants in Ontario by December 7, 2022. 3 The prevalence of variants that are resistant to Evusheld is expected to continue to rise given weekly relative growth rates. 3 Evusheld will remain available to be dispensed through pharmacies for use as pre-exposure prophylaxis in exceptional circumstances where the health care provider and patient have determined that the potential benefit outweighs the risks (e.g., with consideration to regional prevalence of resistant subvariants and individual patient risk factors). Any health care provider administering Evusheld due to exceptional circumstances (as outlined above) should refer to the product monograph 5 for details on Evusheld, including information on dosing (600 mg of Evusheld, administered as two separate 3.0 mL, sequential, injections of 300 mg of tixagevimab and 300 mg of cilgavimab) and repeat dosing (every 6 months).Health care providers should communicate with patients who have received Evusheld to: 4 • Inform patients about the potential for a lack of effectiveness against certain circulating variants and that if they have received Evusheld in the past, they cannot rely on it for protection.#
• Advise patients of the importance of immunization as the best method to remain protected against COVID-19. • Advise patients to continue to limit potential exposure to COVID-19 through public health measures such as masking and limiting contacts. • Advise patients to immediately seek medical advice if signs or symptoms of COVID-19 occur. Ontario Health's Evusheld patient handout has been revised to support communications with patients as outlined above.
# Treatment
Ontario Health does not recommend use of Evusheld for treatment of COVID-19 due to the risk of treatment failure against currently circulating variants in Ontario 1,2,3 and the availability of more effective treatments (e.g., Paxlovid). | None | None |
a3a111f2a45e561eae5732fee680f9efaf39c9d6 | cma | None | Purpose Since the last Canadian Airway Focus Group (CAFG) guidelines were published in 2013, the literature on airway management has expanded substantially. The CAFG therefore re-convened to examine this literature and update practice recommendations. This first of two articles addresses difficulty encountered with airway management in an unconscious patient. Source Canadian Airway Focus Group members, including anesthesia, emergency medicine, and critical care physicians, were assigned topics to search. Searches were run in the Medline, EMBASE, Cochrane Central The members of the Canadian Airway Focus Group are listed in Appendix.# Register of
Controlled Trials, and CINAHL databases. Results were presented to the group and discussed during video conferences every two weeks from April 2018 to July 2020. These CAFG recommendations are based on the best available published evidence. Where high-quality evidence was lacking, statements are based on group consensus. Findings and key recommendations Most studies comparing video laryngoscopy (VL) with direct laryngoscopy indicate a higher first attempt and overall success rate with VL, and lower complication rates. Thus, resources allowing, the CAFG now recommends use of VL with appropriately selected blade type to facilitate all tracheal intubations. If a first attempt at tracheal intubation or supraglottic airway (SGA) placement is unsuccessful, further attempts can be made as long as patient ventilation and oxygenation is maintained. Nevertheless, total attempts should be limited (to three or fewer) before declaring failure and pausing to consider ''exit strategy'' options. For failed intubation, exit strategy options in the still-oxygenated patient include awakening (if feasible), temporizing with an SGA, a single further attempt at tracheal intubation using a different technique, or front-of-neck airway access (FONA). Failure of tracheal intubation, face-mask ventilation, and SGA ventilation together with current or imminent hypoxemia defines a ''cannot ventilate, cannot oxygenate'' emergency. Neuromuscular blockade should be confirmed or established, and a single final attempt at face-mask ventilation, SGA placement, or tracheal intubation with hyper-angulated blade VL can be made, if it had not already been attempted. If ventilation remains impossible, emergency FONA should occur without delay using a scalpel-bougie-tube technique (in the adult patient). The CAFG recommends all institutions designate an individual as ''airway lead'' to help institute difficult airway protocols, ensure adequate training and equipment, and help with airway-related quality reviews.
# Résumé
Objectif Depuis la dernie`re publication des lignes directrices du Canadian Airway Focus Group (CAFG) en 2013, la litte´rature sur la prise en charge des voies ae´riennes s'est conside´rablement e´toffe´e. Le CAFG s'est donc re´uni a`nouveau pour examiner la litte´rature et mettre a`jour ses recommandations de pratique. Ce premier article de deux traite de la prise en charge des voies ae´riennes difficiles chez un patient inconscient. Sources Des sujets de recherche ont e´te´assigne´s aux membres du Canadian Airway Focus Group, qui compte des me´decins anesthe´sistes, urgentologues et intensivistes. Les recherches ont e´te´mene´es dans les bases de donne´es Medline, EMBASE, Cochrane Central Register of Controlled Trials et CINAHL. Les re´sultats ont e´teṕ re´sente´s au groupe et discute´s lors de vide´oconfe´rences toutes les deux semaines entre avril 2018 et juillet 2020. Les recommandations du CAFG sont fonde´es sur les meilleures donne´es probantes publie´es. Si les donne´es probantes de haute qualite´manquaient, les e´nonce´s se fondent alors sur le consensus du groupe.
Constatations et recommandations clés La plupart des e´tudes comparant la vide´olaryngoscopie a`la laryngoscopie directe indiquent un taux de re´ussite plus e´leve´a`la premie`re tentative et globalement avec la vide´olaryngoscopie, ainsi que des taux de complication infe´rieurs. Ainsi, les ressources le permettant, le CAFG recommande dore´navant l'utilisation de vide´olaryngoscopes avec le type de lame convenablement se´lectionne´pour faciliter toutes les intubations trache´ales. En cas d'e´chec de la premie`re tentative d'intubation trache´ale ou d'e´chec de positionnement du dispositif supraglottique (DSG), d'autres tentatives peuvent eˆtre entreprises tant que la ventilation et l'oxyge´nation du patient le permettent. Ne´anmoins, le nombre total de tentatives devrait eˆtre limite´, à trois ou moins, avant de de´clarer un e´chec et de conside´rer les options de « strate´gie de retrait ». En cas d'e´chec de l'intubation, les options de strate´gie de retrait chez un patient toujours oxyge´ne´comprennent l'e´veil (si possible), la temporisation avec un DSG, une dernie`re tentative d'intubation trache´ale a`l'aide d'une technique diffe´rente, ou une cricothyroı¨dotomie. L'e´chec de l'intubation trache´ale, de la ventilation au masque facial et de la ventilation via un DSG accompagne´d'une hypoxe´mie pre´sente ou imminente, de´finit une urgence « impossible de ventiler, impossible d'oxyge´ner ». Le bloc neuromusculaire doit alors eˆtre confirme´ou mis en place, et une tentative finale de ventilation au masque, de positionnement du DSG ou d'intubation trache´ale avec une lame de vide´olaryngoscopie hyper-angule´e peut eˆtre re´alise´e, si cette approche n'a pas encore e´te´essaye´e. Si la ventilation demeure impossible, une cricothyroı¨dotomie d'urgence devrait eˆtre re´alise´e sans de´lai utilisant une technique de scalpel-bougie-tube (chez le patient adulte). Le CAFG recommande a`toutes les institutions de de´signer une personne comme « leader des voies ae´riennes » afin d'assister a`la mise en place de protocoles pour les voies ae´riennes difficiles, d'assurer une formation et un e´quipement ade´quats et d'aider aux examens de la qualite´en rapport avec les voies ae´riennes.
# Introduction
Morbidity related to airway management continues to be reported in closed legal claims 1,2 and practice audits. 3,4 When such adverse airway outcomes are subject to peer review and analysis, patterns of care are often found to be suboptimal. Common themes include persistence with one technique when tracheal intubation proves difficult; failure to recognize an evolving ''cannot ventilate, cannot oxygenate'' (CVCO) scenario and failure to perform timely emergency front-of-neck airway access (eFONA) when indicated. Failure of non-technical skills such as effective communication and good team dynamics have often also contributed to airway-related morbidity. With previous guidelines published in 1998 5 and 2013, 6,7 this update to Canadian airway management recommendations reflects new evidence and opinion appearing in the literature. It applies to difficulty encountered with airway management in an unconscious and often apneic patient.
Significant difficulty with airway management in the unconscious patient can often be avoided by careful airway evaluation before the induction of general anesthesia. In part 2 of these updated recommendations, 8 we have addressed decision-making and implementation of the planned airway strategy for the patient with an anticipated difficult airway. Recommendations in both articles are meant to be broadly applicable to all specialties involved in airway management.
# Methods
The Canadian Airway Focus Group (CAFG) comprises 17 members (see Appendix), with representation from across Canada as well as one member each from New Zealand and Australia.
The CAFG membership includes anesthesiologists, emergency physicians, and critical care physicians. Topics for review were divided among the members, with most assigned to two members. Members reviewed the literature published from 2011 onwards.
A medical librarian helped design and conduct the literature searches. Though not constituting a formal systematic review, databases searched included Medline, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL. Non-English and non-French, animal, manikin, and cadaver studies were excluded, as were case reports, editorials, and letters. Nevertheless, team members had discretion to include such material where relevant.
The CAFG met every two weeks via videoconference from April 2018 to July 2020 to review findings and arrive at consensus regarding recommendations. Similar to other airway management guidelines, we did not assign levels of evidence or strength of recommendation. This follows from a lack of what is considered high-level evidence seen in other medical fields. Randomized controlled trials of airway devices typically address efficacy (often in a population of low-risk elective surgical patients) but when critical events are uncommon (as with airway management), they are unable to evaluate the safety of techniques or decision-making. 13 Information gleaned from large database studies is better able to capture uncommon events, 13 but analysis is limited to association rather than causation, and the population studied may not represent all practice environments. Thus, although evidence-based to the extent possible, some of the recommendations that follow are based largely on expert consensus.
After review by the CAFG, draft documents were sent to several international airway experts (see Acknowledgments) for informal review and comment.
# Definitions
The following definitions are used throughout the manuscript:
- Difficult airway. A difficult airway exists when an experienced airway manager anticipates or encounters difficulty with any or all of laryngoscopy or tracheal intubation, face-mask ventilation (FMV), supraglottic airway (SGA) use, or eFONA. The airway extends from the nostrils and lips to the alveoli, and anatomical variation or pathological distortion anywhere along its length may cause difficulty. Physiologic or contextual issues may compound difficulty with airway management. - Difficult and failed face-mask ventilation. Difficulty with or the failure of FMV can be described according to the four-grade scale presented in Table 1. 14,15 Grades 3 and 4 correspond to difficult and failed ventilation, respectively. The CAFG does not include the number of hands used for a mask seal (i.e., 1 vs 2) in its definition of difficulty, recognizing that the use of two hands may simply reflect clinician preference or the need to optimize a seal to minimize patient exhalation/air leak to the environment. - Difficult and failed supraglottic airway use.
Supraglottic airway use is difficult when more than one attempt at insertion is required, or the resulting ventilation is inadequate. Failed use of an SGA is defined by inadequate ventilation and oxygenation after a maximum of three attempts. As with FMV, this will be reflected by an absent or severely attenuated capnography trace. - Difficult and failed direct or video laryngoscopy. The view obtained during direct laryngoscopy (DL) or video laryngoscopy (VL) is typically quantified using the Cormack-Lehane 16 grade or one of its modifications 17,18 (Table 2 given that the physiologic endpoints of ventilation and oxygenation are the more important goals. Historically, this might have led to persistence with multiple futile attempts at tracheal intubation in the imminently or already hypoxemic patient and may have failed to prompt an attempt at ventilation using an SGA. Secondly, it acknowledges that the absent or severely attenuated waveform capnography that accompanies each of failed tracheal intubation, FMV, and SGA use (i.e., cannot ventilate) will sometimes precede significant oxygen desaturation, especially in the well pre-oxygenated patient (or possibly, when apneic oxygenation is in use). This window of imminent hypoxemia, between the recognition of the ''cannot ventilate'' situation and the onset of severe hypoxemia offers the best opportunity for a good patient outcome by promptly performing eFONA. - Emergency front-of-neck airway access. This refers to emergency access to the trachea via the front of the neck by either cricothyrotomy or tracheotomy. In the hands of non-surgeons, eFONA most often occurs in the adult patient by cricothyrotomy and is considered difficult if it requires more than one attempt.
# Incidence of difficult and failed airway management
Table 3 outlines data from studies in various contexts reporting the frequency of difficult and/or failed FMV, SGA use, tracheal intubation, and eFONA. The studies from which these data are taken are heterogeneous, with inconsistent variables such as patient population, airway manager experience, definitions of difficulty or failure, and the use of neuromuscular blockade. This is likely to explain some of the table's wide-ranging numbers.
6 Response to difficulty with airway management in the unconscious patient Airway managers should be ready with a pre-planned, stepwise approach to managing difficulty with FMV, SGA use, or tracheal intubation.
# Response to difficult FMV
Difficult FMV is challenging to reliably predict, 19 and is often indicated by an attenuated waveform capnography trace. 15,71 Options for responding to difficult FMV are presented in Table 4.
# Response to difficult SGA insertion or ventilation
Although SGAs are used as the intended primary airway technique in many elective surgical procedures, they also play a vital rescue role when a difficult or failed tracheal intubation is encountered in any context. An SGA can also serve as a conduit to facilitate flexible bronchoscope (FB)- PPV = positive pressure ventilation; SpO 2 = peripheral oxygen saturation by pulse oximetry guided tracheal intubation, either in a rescue capacity or as the intended primary technique. Second-generation SGAs are defined by the presence of an esophageal drainage port and cuff design to help maximize seal. They may or may not also be designed to support FB-guided tracheal intubation. Second-generation devices have some benefit over first-generation devices with respect to addressing aspiration risk, but clinically significant aspiration events are rare so this potential advantage has yet to be proven. Nevertheless, given the potential benefits of second-generation SGAs 81 and with no reported disadvantages, the CAFG recommends the routine use of second-generation devices whenever an SGA is needed. Recommended options for SGA insertion troubleshooting appear in Table 5.
# Response to difficult tracheal intubation facilitated by direct or video laryngoscopy
Tracheal intubation facilitated by DL or VL comprises two separate actions: visualizing the glottis, followed by intubating the trachea. Difficulty may occur with either or both component(s). 30% 24 6.6%-9.5% 25,26 Approx. 15% 27 17% 28 Failed or impossible FMV 0.03-0.2% 19,21,29 14% 23 9% 24 No data 7-18% 30,31 No data Difficult FMV combined with difficult laryngoscopy/ intubation 0.3-0.4% 19,22 No data 12.5% 26 No data 27% 28 Difficult tracheal intubation 3-8% 19,22,32,33 1.6-5.7% 23, 0.2-5.5% 25,26,38,39 1-11% 27,40-44 5-23% 28,33, Failed tracheal intubation 0.006-0.4 19,48,49 Options for responding to difficult face-mask ventilation
- Ensure adequate depth of anesthesia.
- Use an oropharyngeal airway (routine use is recommended for all emergency airway management). A nasopharyngeal airway is an alternative if the mouth cannot be accessed. - Use a two-handed mask hold with exaggerated jaw lift; 72,73 positive pressure ventilation can be performed by an assistant or a ventilator set to pressure control ventilation at C 15-cm H 2 O. 74,75 - Use a thenar eminence (''V-E'') grip for two-handed mask seal/jaw lift. 72,76 - Ensure neuromuscular blockade. 63,77 - Consider an alternate size or type of face mask to improve the airway seal.
- Perform additional head extension 72 or lateral head rotation 78 (if not contraindicated).
- Release any applied cricoid pressure. 79 - Consider head-up patient positioning (hemodynamics permitting).
- Consider gastric decompression via an orogastric tube if significant gastric distention is suspected.
- Exclude presence of a physical obstruction or compression (e.g., foreign body, tumour, or stenosis) in the upper airway or trachea.
- Progress to an alternate mode of ventilation, e.g., SGA or tracheal intubation. 22,80 SGA = supraglottic airway The terms ''direct'' and ''video'' laryngoscopy encompass a variety of devices. For the purposes of the following discussion, we categorize laryngoscopy as follows:
- Direct laryngoscopy refers to use of non-video enabled laryngoscopes, typically with Macintosh or Miller blades. Glottic visualization occurs by direct eye-toglottis sighting. - Video laryngoscopy refers chiefly to use of laryngoscopes with a camera in the blade that delivers an image to an external video screen.
Originally designed with a hyper-angulated blade (HA-VL), video laryngoscopes are now available with varying blade geometries, including Macintosh-shaped video laryngoscopy (Mac-VL). Further details appear in Table 6.
Responses to difficulty with glottic exposure or difficulty with tracheal intubation using DL and Mac-VL appear in Table 7. Unless the glottis is obscured by pathology, 122 fogging, blood or secretions/emesis in the pharynx, difficult laryngoscopy is unusual when using HA-VL, provided the blade can be inserted and placed within the oropharynx. Instead, difficulty with HA-VL facilitated tracheal intubation often relates to difficulty with ''around the corner'' delivery of the tracheal tube to and through the glottis. Recommended measures to help address difficulty with tracheal tube delivery when using HA-VL are presented in Table 8.
# Primary use of video laryngoscopy
The CAFG studied whether a recommendation could be made for the routine primary use of VL (as opposed to DL) to facilitate tracheal intubation. Unfortunately, the currently available literature comparing Macintosh DL with VL is difficult to interpret. While plentiful, most systematic reviews and meta-analyses comparing DL with VL combine various VL blade types (HA-VL and Mac-VL), patient populations, clinical contexts, airway manager experience, and measured outcomes. 141 Nevertheless, compared with DL, the first-attempt and overall success rates of tracheal intubation using VL (Mac-VL or HA-VL) are rarely worse, and are often better. 105,113,114, The use of a Mac-VL, 106,154 HA-VL, 48,155 or VL of unspecified blade type 37 have all been shown to facilitate successful tracheal intubation after failed DL. In addition, there may be lower complication rates with VL, including fewer occurrences of esophageal intubation. 52,113, The use of VL also enables a ''shared mental model'', helping to increase engagement of all airway team members. On balance, and resources allowing, the CAFG recommends the routine primary use of VL with an appropriate blade type for all tracheal intubations. If difficulty is predicted with glottic exposure using DL or Mac-VL, first-attempt use of HA-VL to facilitate tracheal intubation should be strongly considered. For the patient at risk of upper airway soiling (e.g., blood, emesis), consider using Mac-VL so that direct, eye-toglottis visualization can occur should the video camera become obscured. Intermediate geometry blade VL (e.g., McGrath Mac) or DL are alternatives in this situation.
# Response to an unsuccessful first (or subsequent) attempt at the intended airway technique
The following sections address difficulty and failure encountered with attempted tracheal intubation. The response to difficulty and failure with an SGA is discussed in section 8.
Table 5 Recommended options for responding to difficult supraglottic airway insertion
Options for responding to difficult supraglottic airway (SGA) insertion
- Ensure an adequate depth of general anesthesia for SGA insertion.
- Unless contraindicated, use a ''sniff'' position for SGA insertion, with lower neck flexion and head extension. 82,83 - Consider rotating the SGA 90°during advancement around the tongue. - Use an alternate size 88,89 or design of SGA, including one with a different cuff material. 90 - In the context of failed tracheal intubation, release any applied cricoid pressure for SGA insertion. - Consider neuromuscular blockade (evidence regarding benefit during SGA use is conflicting; however, no harm is reported). - Consider SGA insertion facilitated by direct or video laryngoscopy. 89,90, With a second-generation SGA, a tracheal tube introducer (''bougie'') placed through the SGA's esophageal drainage port can first be advanced into the esophagus to subsequently help guide the SGA into position. 103,104 - Progress to an alternate mode of ventilation, e.g., tracheal intubation or FMV.
FMV = face-mask ventilation; SGA = supraglottic airway Using similar technique and optimizing maneuvers as DL, Macintosh geometry VL (Mac-VL) enables laryngeal visualization to occur by direct eye-to-glottis sighting or indirect, on-screen videoscopic sighting. The videoscopic view may be better than that afforded by standard direct laryngoscopy and may or may not 112 be significantly better than that afforded by direct eye-to-glottis viewing with the same video laryngoscope. Higher firstpass 105,113 and overall 105,114 success rates have been reported with Mac-VL than with DL. As with DL, once a view of the glottis is obtained, tracheal tube delivery tends to be straightforward.
- C-MACÒ with Macintosh blade A - GlideScopeÒ DVM B
Hyper-angulated or hyper-curved blade video laryngoscopy (HA-VL)
Hyper-angulated blade VL (HA-VL) allows ''around the corner'' viewing of the glottis by indirect, videoscopic viewing only. The view with HA-VL is often superior to that obtained by DL or Mac-VL. 117 First pass tracheal intubation success with HA-VL is frequently higher than with DL. 113 Tracheal intubation with HA-VL requires use of a stylet 118 or other adjunct and for the inexperienced airway manager, may be more challenging or take longer than with DL. 119,120 This can occur despite good glottic visualization. 121,122 It is important to maintain direct (i.e., non-videoscopic) intraoral visual contact with the advancing styleted tube until its tip is past the soft palate, to avoid inadvertent soft-tissue injuries. 123,124 In this regard, a malleable stylet is preferred and equally effective 118 to a rigid stylet. Some HA-VLs feature an integrated channel in the blade to help safely guide the tracheal tube to the glottis.
Non-channelled - Apply external laryngeal manipulation (not cricoid pressure).
- C-MACÒ D-blade - GlideScopeÒ LoPro
- Ensure the Macintosh blade is inserted sufficiently deep into the vallecula to engage the hyoepiglottic ligament.
- Consider directly lifting the epiglottis (applies to both Macintosh and straight blades).
- Exaggerate head lift and ''sniff'' positions, if not contraindicated.
- Release any applied cricoid pressure. 130 - If using Mac-VL, switch to indirect, videoscopic viewing if direct eye-to-glottis viewing is suboptimal.
- For continued difficulty with glottic exposure, if the patient remains well-oxygenated, strongly consider progressing to HA-VL. 48 Options for response to difficulty with tracheal tube passage during DL or Mac-VL
- Use a tracheal tube introducer (''bougie''). The bougie is an effective adjunct when Mac-VL or DL results in a limited (e.g., Cormack-Lehane 2b or 3a) view. 40,131 The CAFG endorses the immediate availability of a bougie in all airway management locations. - If not using a bougie, use a stylet to optimally shape the tracheal tube.
- If difficulty with tube passage has occurred in the context of a suboptimal glottic view, consider progressing to HA-VL 48 if the patient remains well-oxygenated. DL = direct laryngoscopy; HA-VL = hyper-angulated blade video laryngoscopy; Mac-VL = Macintosh geometry blade video laryngoscopy 7.1 The hazards of multiple attempts at tracheal intubation Airway managers are susceptible to a variety of cognitive biases 160 that may negatively affect patient care 161 . One of the most concerning is perseveration, defined in the 2019 American Society of Anesthesiologists (ASA) closed claims publication as the ''consistent application of any airway management technique or tool more than twice without deviation or change of technique, or the return to a technique or tool that had previously been unsuccessful''. 1 Perseveration with multiple tracheal intubation attempts appears to be particularly prevalent in otherwise healthy adults 1 and in children where no difficulty was anticipated. 39 Most airway managers recognize that failure of an optimized attempt using one device should mean that another device, technique or operator should be employed during subsequent attempts. Yet even with the substitution of a different device, multiple attempts are correlated with adverse events. Thus, first-attempt success at the intended technique should always be a goal. Adverse outcomes associated with multiple attempts at tracheal intubation include hypoxemia, esophageal intubation, airway trauma, and cardiac arrest. This association exists in pre-hospital care (if tracheal intubation is used), 162,163 pediatric settings, critical care, emergency medicine, 43,44, and in the operating room (OR) 38,39 (Table 9). Similar evidence exists regarding multiple attempts at SGA insertion. 38,166 As a result, virtually all national airway management guidelines in adults, 6,9,10,12,71,173-180 obstetrics, 181,182 and pediatrics agree that a maximum of two to four optimized attempts (collectively, by all airway managers involved) at tracheal intubation occur before pausing to consider an alternate (''exit'') strategy, with the goal of returning the patient to a point of safety.
# Unsuccessful first or subsequent attempt at tracheal intubation with oxygen saturation in a safe range
The following narrative should be read in conjunction with the flow diagram depicted in the Figure . If a first attempt at tracheal intubation is unsuccessful, further attempts at tracheal intubation can be made according to the following guiding principles:
- Further intubation attempts should only be made if the peripheral oxygen saturation (SpO 2 ) remains in, or has been returned to, a safe range for the patient (e.g., C 90%). This may occur by FMV or SGA ventilation, the effectiveness of which can be seen by waveform capnography. It also includes the situation where the patient is not ventilated after an unsuccessful first intubation attempt, but the SpO 2 is maintained in a safe range because of pre-oxygenation and/or the use of apneic oxygenation. - For a further attempt at tracheal intubation, if not already applied, apneic oxygenation should be considered. This can be administered by via conventional nasal prongs at 5-15 LÁmin -1 or a high- - Partially withdraw the HA-VL blade during laryngoscopy, seeking to achieve no more than a limited view of the larynx (e.g., Grade 2). 132 This allows for both a wider field of view and also a straighter pathway for tube delivery. - Modify the curvature of the styleted tracheal tube to accommodate specific patient anatomy. When a semi-rigid or malleable stylet is used to facilitate HA-VL, it should generally be shaped to match the angulation or curvatureof the blade (i.e., not including the handle)-typically at angles between 60 and 90°. 118,133,134 - Centre the view of the glottis on the screen, then slide the styleted tube's tip along the undersurface of the blade to help direct it to the glottis. 135 - Withdraw the stylet by 4 cm once the tip of the tracheal tube has been passed through the glottis. By allowing the tracheal tube to reflect off the anterior tracheal wall, this facilitates its further advancement down the trachea. - For tube ''hang-up'' persisting after partial stylet withdrawal, rotation of the tube 45-90°to the right (clockwise) may help address tube impingement on the cricoid cartilage or a tracheal ring. 135 - Insertion of a styleted tube before 136 or concomitantly with 137 the videolaryngoscope blade may help with tube passage in the patient with a small mouth. Note that blind insertion of a styleted tracheal tube is contraindicated in some clinical circumstances (e.g., retropharyngeal abscess). - Changing to DL or Mac-VL may succeed if tube delivery continues to be problematic with HA-VL, 122,138,139 unless already proven unsuccessful.
# HA-VL (channelled blades)
- Slight withdrawal, caudad angulation of the blade and lifting of the scope may help better align the advancing tube with the glottic opening and trachea 140 . It is important to not use too small a tracheal tube, as it can exit the channel in an excessively caudad direction. A. Awaken the patient If feasible, when both ventilation and oxygenation are non-problematic, allowing the patient to emerge from general anesthesia after failed tracheal intubation may prevent deterioration to a CVCO scenario. Airway patency and gas exchange can be supported using FMV or an SGA until spontaneous ventilation resumes and the patient can maintain airway patency without assistance. The status of any neuromuscular blockade and sedative agents must be assessed and managed (e.g., with medications such as sugammadex, 190 naloxone, or flumazenil, as appropriate). Once a patient has emerged from general anesthesia, options include regional anesthesia, deferring elective surgery, or if the surgery is urgent, immediate awake oral/nasal tracheal intubation, or awake tracheotomy.
Awakening the patient after failed tracheal intubation in the context of a surgical emergency or critical illness (as with most emergency department or critical care intubations) might not be possible or appropriate, as the patient's clinical trajectory with deteriorating course over time may preclude a return to a functional respiratory or cognitive state. In this case, other exit strategy options should be considered.
B. Temporize with an SGA An SGA can be placed after failed tracheal intubation to temporize (e.g., pending the arrival of additional equipment or expertise) or to support the airway while the patient emerges from general anesthesia. In general, when tracheal intubation was the intended technique for an elective surgical case but has failed, proceeding with the case using only the SGA is inadvisable. 3 This follows from the trauma and swelling to the larynx that may have occurred with the preceding attempts at tracheal intubation. Also, if subsequent intraoperative SGA malfunction occurs, the fallback option of tracheal intubation has already proven to have failed. Nevertheless, in certain contexts (e.g., emergency Cesarean delivery ), the potential benefit of proceeding with a surgical procedure with an SGA after failed tracheal intubation may exceed the risk, although the risk of aspiration must be considered.
A second-generation SGA should be used (ideally one that also supports FB-guided intubation) and a plan for intraoperative SGA failure should be considered.
The critically ill non-surgical patient successfully temporized by SGA or FMV after failed tracheal intubation will likely still require timely tracheal intubation (see next section) or FONA.
C. Proceed with a further attempt at tracheal intubation Pausing to consider exit strategy options after a maximum of three attempts at tracheal intubation helps to both avoid perseveration with failed techniques and maintain situational awareness. It does not absolutely preclude another attempt at tracheal intubation. Nevertheless, a further intubation attempt should only be considered as an exit strategy option with the following provisos: 1) ventilation and oxygenation by FMV or an SGA remain non-problematic; 2) the patient has already undergone prior attempts at tracheal intubation and the larynx may have been subjected to trauma, so an exit strategy intubation should be limited to a single attempt by an airway manager experienced with the planned technique; 3) the planned technique should have a high likelihood of addressing the anatomic constraints that contributed to the earlier failure(s); and 4) a second airway manager should be present. The intubation technique is chosen according to clinical judgement. Nevertheless, if not already attempted, an FB can often prove effective, used on its own or in conjunction with another device:
- Flexible bronchoscope use on its own: When used on its own, an intubating oropharyngeal airway 48 This is an effective combination, 48, with each device working synergistically to address the limitations of the other. Once well advanced into the trachea, the FB acts as an extended flexible stylet to facilitate tracheal intubation, addressing the issue of difficult tracheal tube delivery with HA-VL used on its own. Similarly, the VL controls collapsing soft tissues in the anesthetized patient to create a patent pharyngeal conduit through which to advance the FB, and also enables visualization of tracheal tube passage through the larynx over the FB. Using both devices together may increase success more than using either device alone, but it does require practice in co-ordinating the tasks of two airway managers-i.e., one to maintain a stable VL view while another manages the FB. Apneic oxygenation should be used throughout.
A successful exit strategy tracheal intubation should prompt the airway manager to carefully consider a safe tracheal extubation strategy (see companion article). 8 Conversely, failure of an exit strategy tracheal intubation attempt should prompt re-consideration of other exit strategy options, including awakening the patient, temporizing with an SGA, or proceeding to FONA.
D. Front-of-neck (surgical) airway access Although very rarely indicated in the still-oxygenated elective surgical patient, this option may be appropriate after failed tracheal intubation of a critically ill patient, or for the patient requiring emergency surgery. Patient ventilation and oxygenation may be maintained by FMV or an SGA while FONA is performed by cricothyrotomy or tracheotomy.
# The ''cannot ventilate, cannot oxygenate'' situation
The CVCO situation is defined as the failure of tracheal intubation, face-mask-, and SGA ventilation (cannot ventilate), resulting in current or imminent hypoxemia (cannot oxygenate). Thus, in the context of tracheal intubation, this means that one or more intubation attempts has failed and, despite fallback attempts at ventilating and oxygenating the patient by optimized FMV and SGA ventilation, the patient is:
- Currently hypoxemic (e.g., SpO 2 is \ 90%) - Imminently hypoxemic (SpO 2 is currently C 90%-e.g., because of pre-oxygenation or the use of apneic oxygenation-but an absent or severely attenuated waveform capnograph for all of tracheal intubation, FMV, and SGA use has indicated a ''can't ventilate'' situation, so that hypoxemia will likely rapidly follow).
Depicted on the right-hand side of the Figure, the CVCO situation should be managed according to the following guiding principles: - Once recognized, the CVCO situation should be verbally declared (e.g., ''This is a can't ventilate, can't oxygenate situation and we need to perform a cricothyrotomy immediately'') and eFONA should proceed without delay. It is worth emphasizing that it is not desirable to allow hypoxemia to occur before transitioning to eFONA when hypoxemia is a predictable consequence of the ''cannot ventilate'' situation. Successfully performing eFONA before severe or prolonged hypoxemia has occurred in a CVCO situation will maximize the possibility of a good outcome.
- Help should be summoned.
- Equipment for eFONA should be obtained, the anterior neck quickly landmarked and the most qualified person already present should be delegated to perform eFONA.
Concurrent with the foregoing preparations for beginning eFONA, neuromuscular blockade should be confirmed or established, especially if tracheal intubation had proceeded with succinylcholine or without neuromuscular blockade. FMV generally gets easier with the onset of neuromuscular blockade or, at worst, remains unchanged. 77, It may also facilitate SGA placement and performing eFONA. In addition to neuromuscular blockade, a single attempt at any or all of the following should be made, if not yet attempted:
- Placement of an SGA. A number of reports have indicated that an attempt at SGA placement was often overlooked prior to performing eFONA. 3,68 - Two-handed FMV with an oropharyngeal airway, facilitated by neuromuscular blockade. - Video laryngoscopic tracheal intubation, if not already attempted. The CAFG is of the opinion that an attempt at tracheal intubation facilitated by HA-VL should ideally have occurred prior to eFONA. Notwithstanding, in an already hypoxemic patient, this option implies that the video laryngoscope is already present, so that the attempt will not substantively delay the onset of eFONA, if unsuccessful.
If adequate oxygenation is restored with any of the foregoing, eFONA is not immediately required and the airway manager can now consider exit strategy options (FIGURE). Conversely, if the foregoing options have failed, then eFONA should proceed without delay (see next section).
The ASA Closed Claims 1 and NAP4 3 studies describe airway manager delay in the recognition of an evolving CVCO emergency as a major contributor to brain damage and death. While some CVCO situations may be immediately evident (e.g., cannot ventilate, currently hypoxemic), others may occur over time, making their recognition more challenging for those managing the patient (''change blindness''). 200,201 Thus, all team members should be explicitly empowered to say when they believe a trigger for declaring a CVCO situation has occurred. Multidisciplinary simulation exercises can help identify and break down barriers to having any team member speak up in such situations. 202,203 Although infrequent, CVCO emergencies are often unanticipated and can occur in otherwise healthy patients (e.g., those presenting for elective surgery). Therefore, all airway managers should regularly practice their skills in eFONA to maintain competence in the procedure. While surgeons familiar with the technique may prefer to perform rapid tracheotomy in the CVCO situation, 204 in the hands of non-surgeon clinicians, and because of anatomic advantages in adult patients, eFONA should generally proceed via the cricothyroid space. For its simplicity, ease of equipment stocking, generalizability to different airway manager types, and emerging evidence of first-pass success in various settings, 205,206 the CAFG recommends a scalpelbougie-tube approach for cricothyrotomy. If feasible, the neck should be fully extended. The location of the cricothyroid membrane (CTM) itself may be difficult to identify by external palpation in some patients, 207 so the CAFG recommends beginning cricothyrotomy with an initial 4-6 cm longitudinal incision over the estimated location of the midline of the larynx in all adult patients. Identifying the laryngeal cartilage and its midline may be aided by a ''laryngeal handshake'' (i.e., moving the laryngeal cartilage from side to side while attempting to palpate the cricothyroid space). 208 Following the longitudinal incision, re-palpation within the wound will allow more accurate identification of the CTM. A transverse incision is made through the CTM, then access to the opened trachea is maintained with the airway manager's finger or the scalpel blade turned into a cephalad-caudad orientation. The bougie is passed into the trachea behind the placeholder finger or alongside the blade, then with finger or blade removed, a 6.0-mm internal diameter cuffed tube (adult patient) is advanced over the bougie. The cuff is inflated and correct tube location confirmed. The CAFG recommends stocking the following equipment at every airway management location: disposable scalpel (#10, 20, or 21 blade), a bougie, and a 6.0 tracheal tube (for adult hospitals), all packaged together. Size-based pediatric equipment should be readily available in pediatric facilities. Pediatric eFONA options are discussed in section 11.6.
False passage of a bougie or tracheal tube can occur during cricothyrotomy or tracheotomy, so correct tube placement must be confirmed by waveform capnography. A flat trace should be considered to represent a malpositioned tracheal tube until proven otherwise and must not be attributed to hypoxemic cardiac arrest. 3,209 8 Supraglottic airway use as the intended technique Similar considerations to those appearing in section 7 on tracheal intubation apply to the use of an SGA as the intended airway management technique.
# Confirmation of tracheal intubation and continuous waveform capnography
The CAFG advocates continuous waveform capnography as the gold standard for confirming correct tracheal tube placement. Waveform capnography has excellent sensitivity and specificity (Table 10) and is widely available. Pattern recognition of capnographic waveforms can easily be learned. 211 For tracheal intubation by nasal, oral or front-of-neck routes, assessment of multiple sustained amplitude waveforms 212 are required to conclude the tracheal tube is correctly positioned and to avoid false positive results (e.g., CO 2 detection with esophageal intubation). Waveform capnography should also be routinely used to confirm effective ventilation by face-mask 15,71 or SGA. 213 Capnography will generally provide earlier feedback on their effectiveness than changes in SpO 2 .
Effectiveness of chest compressions as well as return of spontaneous circulation during cardiopulmonary resuscitation can also be assessed using waveform capnography. The 2015 American Heart Association guidelines for cardiopulmonary resuscitation in adults recommends waveform capnography as ''the most reliable method of confirming and monitoring correct placement of an ETT'' during cardiac arrest. 214 After cardiac arrest, CO 2 detectable by waveform capnography is likely to persist for at least 30 min, 215 although the waveform will be attenuated. In this context, a flat capnograph must not be ascribed to the absence of pulmonary perfusion-rather, esophageal intubation or false passage must be excluded (''no trace = wrong place''). 209 Colorimetric capnometry is less specific than waveform capnography, with additional causes of a false positive result (Table 10). It may have a role if waveform capnography is not available. Other modes of tracheal tube confirmation together with their potential pitfalls, sensitivities, and specificities are presented in Table 10.
The CAFG recommends the routine use of waveform capnography with at least one other method to confirm successful tracheal intubation. To help direct the airway manager's attention to the need for objective confirmation, we recommend routinely making a verbal declaration such as ''sustained CO 2 confirmed'' or ''good trace, right place'' once success has been determined. 209,216 Finally, the CAFG recommends ongoing waveform capnography monitoring in all intubated patients, in all hospital locations, including within-hospital transportation.
# The obstetric patient-special considerations
Many studies continue to indicate a higher risk of failed tracheal intubation in the parturient than in the general surgical population, 35,37,51,249,250 although this has been challenged by other studies. 36,251 Regardless, other patient and contextual factors amplify difficulty. The parturient can be physiologically unforgiving, the need for out-ofhours emergency work common, and the obstetrical suite can be isolated from access to difficult airway equipment or additional expertise.
Obstetrical suites should be well-equipped with difficult airway equipment including, but not limited to, secondgeneration SGAs, video laryngoscopes, a FB, and equipment for cricothyrotomy. 181 As rates of regional anesthesia for CD continue to be high, 36,252 trainees and attending staff with significant exposure to obstetrical practice must make the effort to attain and maintain competence in difficult airway techniques.
Antenatal airway screening of all obstetrical patients should ideally occur with multidisciplinary consultation when indicated. 253,254 Should a parturient possess a nonreassuring airway, early epidural catheter placement and testing should occur during labour. If CD under general anesthesia is required, the airway should be re-assessed, recognizing the dynamic nature of the airway during labour. 253,255 Landmarking neck anatomy including the cricothyroid space by external palpation is particularly challenging in this population; ultrasound has proven useful. 256,257 For CD under general anesthesia, the patient should be positioned optimally and pre-oxygenation undertaken with a tightly fitting face mask with a standard flow of 15 L min -1 . Evidence for the benefit of high-flow nasal oxygen (HFNO) therapy for the obstetric patient is mixed. It is less effective than a tightly applied face mask for preoxygenation but may provide benefit during apnea 261 and laryngoscopy (provided airway patency is maintained). With potential benefit and minimal downside, apneic oxygenation with HFNO or standard nasal cannulae at flows of 5-15 L min -1 is recommended during apnea for the parturient undergoing general anesthesia. Cricoid pressure should be applied by a trained individual. After general anesthesia induction, gentle FMV (e.g., keeping positive inspiratory pressure \ 20 cm H 2 O) is recommended while awaiting the onset of neuromuscular blockade to help extend the safe apnea time during - Equipment malfunction or disconnect
- Severe bronchospasm
- Kinked or occluded tube
- Tracheal obstruction
- Tracheal tube cuff not inflated
- Obstruction of pulmonary circulation
- Failure to assess for sustained waveforms
- Tube lying in pharynx outside larynx (e.g., cuff above the cords)
- Recent extensive use of FMV or bilevel positive airway pressure non-invasive ventilation 222 - Ingestion of antacid or carbonated beverages Colorimetric capnometry 97-100% (non-arrest) 220, 69-85% (arrest) 223,225,226 91-100% (non-arrest) 220,223,224 100% (arrest) 223,226 As above, plus:
- Low cardiac output/severe hypotension
- ETCO 2 \ 2-5%
- Neonates and infants 227 As above, plus:
- Contamination of detector with acidic gastric contents; 228 - Recent instillation of medications through the tracheal tube including epinephrine, atropine, surfactant, 229 naloxone.
# Visualization of tracheal tube between cords
No data No data - Adverse patient anatomy precludes a view of any aspect of the larynx during DL or Mac-VL
- ''Glottic impersonation'': entrance to hypopharynx is misinterpreted as the larynx during excess lifting pressure on laryngoscope 230 - Inadvertent intubation of a tracheoesophageal fisutla 231,232 Tube misting 100% 237,247,248 15-71% 237,247,248 No data - The esophagus is also a moist environment.
BMI = body mass index; DL = direct laryngoscopy; ETCO 2 = end-tidal carbon dioxide; FMV = face-mask ventilation; Mac-VL = Macintosh geometry blade video laryngoscopy; SGA = supraglottic airway subsequent laryngoscopy. 181 The CAFG recommends the primary use of VL to facilitate tracheal intubation of the parturient.
# Unsuccessful first attempt at tracheal intubation in the parturient
An unsuccessful optimized attempt at tracheal intubation in the parturient should be transitioned rapidly to FMV or SGA insertion. Help should be enlisted. Cricoid pressure should be released if thought to be contributing to difficulty. If face-mask-or SGA ventilation is successful and adequate patient oxygenation is maintained, a second attempt at tracheal intubation can be made with a different device or by a more experienced airway manager. The use of VL has been reported to be effective after failed DL in the parturient. 37,262 If the second attempt is unsuccessful, a failed tracheal intubation situation should be declared and exit strategy options considered. This is one fewer attempt than might be considered for the non-parturient, reflecting the parturient's adverse physiology.
10.2 Failed tracheal intubation in the parturient with SpO 2 in a safe range-exit strategy options
Having verbally declared the failed intubation situation, the airway manager should maintain oxygenation by facemask-or SGA ventilation while considering exit strategy options. Help should be sought, if available. Further actions are predicated on the status of the mother and the fetus.
- No fetal or maternal distress: If the situation is stable without maternal or fetal emergency, the mother can be allowed to emerge from general anesthesia. Once awake, use of regional anesthesia can be revisited if not contraindicated, or awake tracheal intubation can be performed. - Fetal or maternal distress exists: If the situation is unstable with either fetal or maternal emergency, an SGA should be placed (if not already done) to enable CD or maternal resuscitation to proceed. Cricoid pressure should be released. For CD while using an SGA, a generous surgical incision should be made, minimal fundal pressure applied, and vacuum extraction considered, as necessary. 263 Early use of an SGA in a rescue scenario is accepted practice in the parturient, with success rates reported to be between 86 and 100%. 37,51,250 In a review of 45 years of obstetric airway management in the United Kingdom, there was a steady, decade-over-decade increase in continuing with CD using SGAs after failed tracheal intubation, coinciding with their increasing use as rescue devices. 51 A second-generation SGA with an esophageal drainage port should be used, optimally incorporating a widediameter conduit to support FB-aided tracheal intubation, if chosen. When feasible, a suction catheter can be advanced down the drainage port to help drain the esophagus of any gastric contents. The catheter should be removed after suctioning is completed.
Once the fetus has been delivered or the maternal emergency stabilized, whether to complete the case using the SGA or to secure the airway by tracheal intubation before proceeding should be based on the context of the patient's body mass index, fasting status, and predicted surgical complexity and duration. Currently, there is no evidence to support or refute continuing with the case with a well-functioning SGA. Use of an SGA to complete CD after failed tracheal intubation is supported by studies of the elective use of SGAs for CD under general anesthesia rather than tracheal intubation. Most such studies originate from outside North America, in countries where general anesthesia is more commonly used for CD and the population may be of lower average body mass index. 264 With most using second-generation SGAs, the studies indicate a high success rate and minimal occurrence of gastric content aspiration. 265 Notwithstanding, the CAFG does not currently espouse SGA use for elective CD. This position might change as the role of ultrasound in assessing gastric contents and aspiration risk becomes more understood. 265 10.3 ''Cannot ventilate, cannot oxygenate'' in the parturient
The CVCO scenario in the parturient is also defined as failed tracheal intubation not rescued by attempts at both face-mask-or SGA ventilation, with current or imminent hypoxemia. Maternal oxygen desaturation is likely to occur rapidly, leading to fetal compromise and precluding maternal emergence from general anesthesia. Thus, cricothyrotomy must occur without delay. Once correct placement of a cuffed tracheal tube placed via cricothyrotomy is confirmed, CD can proceed.
# Tracheal extubation and the postpartum period
Maternal mortality data from both the USA and UK indicate that many of the reported obstetric-related airway catastrophes occurred during the postpartum period-i.e., at emergence after CD, in the postanesthesia care unit, or during postpartum surgical procedures (e.g., postpartum hemorrhage). 266,267 Vigilance during these phases is thus paramount.
11 The pediatric patient-special considerations
Respiratory events are the most common cause of adverse events during pediatric anesthesia. 268 These complications are age dependent, with neonates and infants being at highest risk. Elective management of patients \ 12 months of age with a known or suspected difficult airway should occur in a specialized centre, when feasible. 269 Young children are predisposed to adverse respiratory events during airway management because of their high metabolic demand and relatively small respiratory reserve. Resulting short apnea times can lead to hypoxemia, bradycardia, and cardiac arrest. 39 Supplementary oxygen before and during tracheal intubation is recommended to reduce the risk of hypoxemia. Options include HFNO 270 or oxygen applied buccally, via a laryngoscope, or through an advancing tracheal tube.
Airway assessment tools have not been validated in small children, but micrognathia, microstomia, macroglossia, and evidence of temporomandibular joint dysfunction are suggestive of airway management difficulty. Asthma, wheezing, upper respiratory tract infections, snoring, and smoking exposure are associated with critical respiratory events regardless of the airway device used.
# Pediatric airway obstruction
Help should be summoned and poor head/neck position, nasal/oral obstruction, secretions, foreign material, atelectasis, and gastric distension should be considered and treated promptly. Pharmacologic treatment should be employed for laryngospasm, bronchospasm, opioidmediated rigidity, and light anesthesia.
# Pediatric FMV
The incidence of difficult FMV (albeit with varying definitions) in children has been reported to be between 6.6 and 9.5%. 25,26 Impossible FMV is less common, with only six occurrences reported in 1,018 pediatric difficult intubation registry cases. 39
# Pediatric SGAs
Pediatric SGAs have significantly improved in recent years. 271 Fewer adverse respiratory events have been described with SGA use for infant airway management compared with tracheal intubation. Neonatal resuscitation with SGAs can result in fewer neonatal intensive care unit admissions and superior resuscitation rates compared with FMV and tracheal intubation.
# Pediatric flexible bronchoscopy through a conduit
Performing FB intubation through an SGA is particularly useful for difficult infant airways, compared with VL. 272 Supraglottic airways for this purpose should have a wide inlet, a short ventilation tube and should facilitate a good bronchoscopic view of the glottis. They should also allow for easy withdrawal of the SGA. The air-Q ILA TM , (CookgasÒ LLC, Mercury Medical, Clearwater, FL, USA) has shown comparatively higher airway leak pressures and superior flexible bronchoscopic views of the glottis than the LMA Unique (Teleflex, Inc., Wayne, PA, USA) in pediatric patients. 273
# Pediatric tracheal intubation
In a multicentre pediatric difficult intubation registry, easy tracheal intubation by an anesthesiologist occurred in up to 99.8% of pediatric cases. 39 Of the remaining cases that proved difficult, 20% had an airway-related complication. Risk factors for complications included C two intubation attempts, weight \ 2 kg, a short thyromental distance, and multiple DL attempts. 39 The CAFG recommends limiting DL attempts to two and rapidly transitioning to a FB or VL. When used after failed DL, a FB was successful in 54% of cases and VL succeeded in 55%. Cuffed tracheal tubes are recommended for all children[3 kg, with appropriate care to avoid cuff overinflation. 274 11.6 Pediatric eFONA Employing eFONA through the CTM in a neonate or infant is not feasible or recommended. At this age, the CTM is underdeveloped and difficult to landmark; the cartilages are also fragile and susceptible to injury. An open tracheotomy is preferred if an individual with the skills is present. Needle tracheotomy is an alternative, although one animal study suggests a low success rate and significant risk of tracheal compression by the advancing needle. 275 If needle cricothyrotomy is used, ventilation should ideally proceed using a Ventrain device (Ventinova Medical, Eindhoven, Netherlands). 276,277 For older children (i.e., [8-12 yr), the scalpel-bougie technique can be used via the CTM. There is no evidence that cricothyrotomy kits are superior to a scalpel cricothyrotomy technique.
12 Tracheal extubation of the at-risk airway Tracheal extubation is an elective procedure and is addressed further in the companion article 8 .
# Human factors in airway management
The term ''difficult airway'' typically relates to patient anatomy or physiology that adversely affects ease of airway management. Difficulty can also arise from how an airway manager and the assembled team performs during challenging airway management. This can sometimes be impacted by suboptimal organizational culture. Human factor issues have been reported to be contributory in 40-100% of airway management-related adverse outcomes. 1,278 Many human factor issues occurring during airway management relate to dysfunctional team dynamics. These are characterized by poor communication, inadequate leadership, and the lack of a shared mental model. 279 In situ multidisciplinary training improves team dynamics but is still not commonly done. 280 Checklists can improve communication, help ensure equipment availability, and aid in team briefing. While the published evidence for tracheal intubation checklists has not shown decreased mortality, outcomes such as hypoxemia may be reduced. 284 Human factor issues that may impact airway management and their potential mitigation strategies are presented in Table 11. The published evidence base regarding these factors continues to evolve.
# Airway leads and quality assurance
The CAFG recommends designating an individual as departmental or hospital ''airway lead'' to help adopt or develop difficult airway protocols, recommend difficult airway equipment, and ensure equipment standardization across hospital locations. 3,288 The airway lead or a multidisciplinary airway committee can also help organize training events and assist in airway-related quality assurance by debriefing critical incidents or nearevents. Debriefing can provide opportunities to share concerns but also to help reinforce what went well. It is important that such quality assurance occurs using an objective ''just culture'' model, focusing more on organizational learning and less on the role of any one individual in the event.
# Documentation
All airway management events should be documented in the patient's paper or electronic medical record (EMR). Previously documented difficult or failed tracheal intubation is a robust predictor of subsequent difficulty. 289 In general, the airway technique used should be recorded, together with optimizing maneuvers or adjuncts used, view obtained, number of attempts, details of any challenges encountered as well as how they were resolved. Major (e.g., significant hypoxemia, hypotension, cardiac arrest) and minor (e.g., mucosal bleeding, dental injury) complications should be recorded. Suggestions for future airway management should also be recorded.
If performed, ease of FMV must always be recorded (e.g., with a mandatory field in an EMR). This is crucial information to help guide future planning for airway management.
The airway manager should personally inform the patient after a significantly difficult airway encounter and provide a written letter describing the difficulty and how it was resolved. Copies of the letter should be added to the patient's medical record and forwarded to the patient's primary care physician. The patient should be flagged as having a potentially difficult airway during subsequent hospital admissions, including use of in-hospital alert bracelets. Difficult airway information should also be submitted to local or national difficult airway databases, if available (e.g., www.medicalert.org/everybody/difficultairwayintubation-registry). In addition, using a robust incident reporting system will help address system-wide patient safety and quality of care issues. 290 In the future, it may be possible to routinely add photos or recordings of VL to the EMR, or for the patient to use secure, app-based technology to store or access their own airway-related information. 291 16 Airway management education Routine clinical practice may not be sufficient to maintain airway management skills. Performing a scalpel-bougie aided cricothyrotomy in a CVCO situation is a rare, yet high acuity event. Successfully performing such infrequently used skills requires deliberate practice, characterized by regular learning opportunities in a simulation environment that incorporates clear goals, focuses on technique, and provides timely expert feedback. This option is safe for the learner, teacher, and patient. Mistakes can be corrected through coaching, and procedures can be simulated repetitively and interrupted for immediate feedback. As competence and comfort with a skill such as cricothyrotomy increases, the airway manager is more likely to consider its use as part of a plan rather than symbolic of a failure of the plan.
Valuable lessons in airway management can also occur through experiential learning in the OR. Nevertheless, the experience that develops over years is not necessarily equivalent to expertise. Expertise is gained by exposure to difficult airways, with learners pushing themselves to manage increasingly difficult experiences. 294 Learning is Table 11 Human factor-related issues in airway management, with potential mitigating strategies Potential human factor-related issues that may occur during management of the difficult airway in the unconscious patient, with mitigation strategies
# Issue
Possible mitigation strategies: by the airway manager by the assembled team by the organization Calling for help: The airway manager might overlook calling for help when difficulty occurs.
- Have personal triggers for calling for help, e.g., (1) whenever you first contemplate it; (2) failed intubation or failed SGA insertion after a maximum of 3 attempts or (3) a CVCO situation.
- Recognize that a helper can provide hands for tasks, so that the airway manager can concentrate on the ''big picture'' and reduce their stress level.
- Consider making a habit of asking a colleague to physically stand by when inducing a patient with anticipated airway risk.
- Strongly consider physically attending any request for backup, even if phrased as a ''heads-up''.
- A helper should announce their arrival by asking ''How can I help?''
- Any team member should be empowered to call for help, bring in equipment, or call a code blue independently.
- All departments should foster a culture of calling for help.
- During team training, e.g., during in situ simulation sessions, requesting help should always be debriefed as a critical action.
Loss of ''situation awareness.'' During an airway crisis, it can be difficult to correctly receive and process incoming information. This will impair diagnosis and decision-making and may promote inappropriate fixation on a single familiar but ineffective technique (perseveration). 285 - Maintaining situation awareness involves long-term memory content, which may be difficult to access during a critical event. Help from other staff provides the airway manager with additional processing capacity for integration of basic information. 285,286 - Call for help after 3 failed attempts at the intended technique: a fresh pair of eyes will help interrupt perseveration.
Be alert for the ''change blindness'' 200,201 that can occur when a critical airway event evolves over time.
A newly arrived helper may better be able to see the obvious.
- Use difficult airway techniques in dayto-day routine practice (e.g., the combination of VL and FB) so that their use is practiced, and so that you think of them when in difficulty.
- Perform a team briefing before embarking on all airway management. Include specific mention of triggers for moving from one plan to the next and empower all team members to speak up once they feel a trigger has occurred.
- Team members should be trained in the interpretation of waveform capnography and pulse oximetry and should be empowered to declare when waveform capnography is nonreassuring or the SpO 2 is decreasing.
- Ensure all team members have been empowered to suggest using an SGA for rescue or CVCO at any time and that they know the equipment's location.
- Mandate adherence to a standard operating procedure for the difficult airway by using an algorithm or cognitive aid based on the algorithm.
- Facilitate multidisciplinary in situ team simulation to practice using the algorithm or cognitive aid for difficult airway scenarios. A major objective during such sessions is to encourage and empower all team members to speak up.
- Airway workshops should include education on non-technical as well as technical skills. Common cognitive errors should be addressed.
Fear. Faced with a hypoxemic patient, the airway manager might experience a maladaptive sympathetic response. This might include fight (e.g., arguing with team members); flight (e.g., disbelief of patient vital signs) or freeze (e.g., not performing eFONA when indicated).
- Call for help early in any evolving airway event. Not being emotionally invested, a newly arrived colleague might possess better situation awareness.
- Have a strategy (a coordinated series of plans) for encountering difficulty in all patients, whether predicted or not. Moving smoothly and deliberately through the steps of a pre-planned strategy will help keep you in control of yourself as well as the situation.
Mentally rehearse the strategy on a regular basis.
- During an airway crisis, team members must recognize that the airway manager who induced the patient is deeply emotionally invested. They might be experiencing a profound sympathetic response, compromising thinking or motor skills. Any team member should call for help if they feel it is in the best interest of the patient.
- Once qualified help arrives, the initial airway manager should consider moving to a supportive role on the team, providing information and suggestions.
- High acuity but rare events such as CVCO should be ''overlearned'' during simulation sessions. 286 This will help demystify them and make their management more routine in clinicians' minds.
Barriers to use of eFONA can include not knowing which procedure to employ (''device confusion''), lack of confidence in one's ability to perform the procedure, or a ''freeze'' response to fear. The reluctance to act may manifest by insisting a surgeon or better qualified person be called to perform eFONA.
- By training in eFONA, all airway managers must be prepared to proceed with eFONA themselves.
- Deliberately practice eFONA on a parttask trainer at least twice a year.
- When encountering difficulty, follow the department's recommended algorithm or cognitive aid.
- Team performance in rare emergencies such as CVCO benefits from in situ simulation.
- Swapping team roles during simulation sessions may reveal latent errors in communication and equipment.
- The organization should ensure that all airway managers are trained in and prepared to perform eFONA.
- Minimize choices to a single technique for high-stress procedures such as eFONA (e.g., scalpel-bougie-tube for the adult patient).
- Make task trainers easily accessible for individual clinician eFONA practice. This can include 3D-printed models of the larynx.
-ptimally achieved by assessing the trainee's background knowledge and skill before starting in the OR, establishing educational goals, and supervising performance with immediate feedback. 296 Thus, a knowledgeable teacher can optimize learning for trainees in the OR. 297,298 Making educational programs multidisciplinary can further augment benefit by creating positive relationships between disciplines.
# Summary and key recommendations
As the literature on airway management evolves, guidelines and recommendations must be updated regularly. 299 Published national airway management guidelines espouse largely consistent management principles. This invites an opportunity to develop a universal lexicon of terms to describe common airway management situations 300 and accepted principles on how to manage them. 301 When such universal guidance is published, it must still be applied to the national or local context in which the airway manager practices. In this third iteration of airway management recommendations from the CAFG, there are few guiding principles and recommendations:
- Resources allowing, VL, with appropriately selected blade type, should be used for the first attempt at tracheal intubation. - Multiple attempts at tracheal intubation and even SGA insertion are associated with adverse events; firstattempt success should be a goal. - If unsuccessful on the first attempt, further attempts can be made at the intended technique provided patient ventilation and oxygenation are maintained. A stepwise progression through different optimizing maneuvers, devices, or airway managers should occur. - Total attempts at the intended technique should be limited to three or fewer before pausing to consider exit strategy options. Patient ventilation and oxygenation should be maintained while considering and then executing the exit strategy. - Exit strategy options to consider after declaring failed tracheal intubation include awakening the patient, temporizing with an SGA, proceeding with one further controlled attempt at tracheal intubation with a different technique, or FONA. - Avoid use of vague language, such as ''we should…'', ''somebody…''
- Delegate specific tasks by name.
- Use 3-step ''closed loop'' communication: 287 (a) Transmit message to receiver, by name.
(b) Receiver to verbally acknowledge message.
(c) Transmitter verifies with the receiver that the message has been received and correctly understood.
- Listen to suggestions or observations from anyone present, regardless of (perceived) hierarchy.
- Help avoid detrimental task fixation (e.g., on tracheal intubation) by delegating an individual to monitor the overall clinical situation or to look after other aspects of a resuscitation.
- All team members should practice graded assertiveness, when indicated, e.g., by use of the ''PACE'' mnemonic:
Probe to see if others are aware of an issue the team member has identified.
Alert others of the problem.
Challenge the current action if necessary, or to seek clarification.
Emergency; give explicit instruction, e.g., ''you must do a surgical airway now''.
- Passage of time during an airway crisis can appear distorted. A team member should be tasked with keeping the rest of the team appraised.
- A flat hierarchy between colleagues or a (perceived) hierarchy between members of different professions can both be problematic. Roles should be respectfully clarified by either party.
- Avoid assumptions: the loudest voice is not necessarily the most knowledgeable.
- Train airway managers in the relevant principles of CRM.
- Train all team members to use ''PACE'' (or similar) graded assertiveness prompts during multidisciplinary simulation sessions.
- Wear name tags in locations where team members are likely to not know each other (e.g., a trauma code).
CRM = crisis resource management; CVCO = ''cannot ventilate, cannot oxygenate''; eFONA = emergency front of neck airway access; FB = flexible bronchoscope; SGA = supraglottic airway; SpO 2 = peripheral oxygen saturation by pulse oximetry; VL = video laryngoscopy
- A CVCO situation is defined by the failure of tracheal intubation, FMV, and SGA use, with imminent or current hypoxemia. Neuromuscular blockade should be ensured, and eFONA undertaken in a timely fashion. - The CAFG recommends that a scalpel-bougie-tube technique be used for adult eFONA, and that the necessary equipment for eFONA, packaged together, be stocked at every hospital airway management location. - Similar principles are broadly applicable to the parturient and to the pediatric patient. - Human factors often contribute to airway-related adverse events; efforts should be made to educate airway managers about common pitfalls. - An airway lead is recommended for all hospitals to help many aspects of airway management at an organizational level.
Without doubt, no matter how well addressed, it will always be preferable to avoid having to manage a difficult airway presenting in the unconscious patient. To this end, thorough patient airway evaluation should be made, followed by appropriate decision-making and safe implementation of the plan. These aspects of safe management of a patient with a difficult airway are addressed further in the companion article 8 , as is advice on tracheal extubation of the difficult airway patient.
Author contributions See Appendix. | Purpose Since the last Canadian Airway Focus Group (CAFG) guidelines were published in 2013, the literature on airway management has expanded substantially. The CAFG therefore re-convened to examine this literature and update practice recommendations. This first of two articles addresses difficulty encountered with airway management in an unconscious patient. Source Canadian Airway Focus Group members, including anesthesia, emergency medicine, and critical care physicians, were assigned topics to search. Searches were run in the Medline, EMBASE, Cochrane Central The members of the Canadian Airway Focus Group are listed in Appendix.# Register of
Controlled Trials, and CINAHL databases. Results were presented to the group and discussed during video conferences every two weeks from April 2018 to July 2020. These CAFG recommendations are based on the best available published evidence. Where high-quality evidence was lacking, statements are based on group consensus. Findings and key recommendations Most studies comparing video laryngoscopy (VL) with direct laryngoscopy indicate a higher first attempt and overall success rate with VL, and lower complication rates. Thus, resources allowing, the CAFG now recommends use of VL with appropriately selected blade type to facilitate all tracheal intubations. If a first attempt at tracheal intubation or supraglottic airway (SGA) placement is unsuccessful, further attempts can be made as long as patient ventilation and oxygenation is maintained. Nevertheless, total attempts should be limited (to three or fewer) before declaring failure and pausing to consider ''exit strategy'' options. For failed intubation, exit strategy options in the still-oxygenated patient include awakening (if feasible), temporizing with an SGA, a single further attempt at tracheal intubation using a different technique, or front-of-neck airway access (FONA). Failure of tracheal intubation, face-mask ventilation, and SGA ventilation together with current or imminent hypoxemia defines a ''cannot ventilate, cannot oxygenate'' emergency. Neuromuscular blockade should be confirmed or established, and a single final attempt at face-mask ventilation, SGA placement, or tracheal intubation with hyper-angulated blade VL can be made, if it had not already been attempted. If ventilation remains impossible, emergency FONA should occur without delay using a scalpel-bougie-tube technique (in the adult patient). The CAFG recommends all institutions designate an individual as ''airway lead'' to help institute difficult airway protocols, ensure adequate training and equipment, and help with airway-related quality reviews.
# Résumé
Objectif Depuis la dernie`re publication des lignes directrices du Canadian Airway Focus Group (CAFG) en 2013, la litte´rature sur la prise en charge des voies ae´riennes s'est conside´rablement e´toffe´e. Le CAFG s'est donc re´uni a`nouveau pour examiner la litte´rature et mettre a`jour ses recommandations de pratique. Ce premier article de deux traite de la prise en charge des voies ae´riennes difficiles chez un patient inconscient. Sources Des sujets de recherche ont e´te´assigne´s aux membres du Canadian Airway Focus Group, qui compte des me´decins anesthe´sistes, urgentologues et intensivistes. Les recherches ont e´te´mene´es dans les bases de donne´es Medline, EMBASE, Cochrane Central Register of Controlled Trials et CINAHL. Les re´sultats ont e´teṕ re´sente´s au groupe et discute´s lors de vide´oconfe´rences toutes les deux semaines entre avril 2018 et juillet 2020. Les recommandations du CAFG sont fonde´es sur les meilleures donne´es probantes publie´es. Si les donne´es probantes de haute qualite´manquaient, les e´nonce´s se fondent alors sur le consensus du groupe.
Constatations et recommandations clés La plupart des e´tudes comparant la vide´olaryngoscopie a`la laryngoscopie directe indiquent un taux de re´ussite plus e´leve´a`la premie`re tentative et globalement avec la vide´olaryngoscopie, ainsi que des taux de complication infe´rieurs. Ainsi, les ressources le permettant, le CAFG recommande dore´navant l'utilisation de vide´olaryngoscopes avec le type de lame convenablement se´lectionne´pour faciliter toutes les intubations trache´ales. En cas d'e´chec de la premie`re tentative d'intubation trache´ale ou d'e´chec de positionnement du dispositif supraglottique (DSG), d'autres tentatives peuvent eˆtre entreprises tant que la ventilation et l'oxyge´nation du patient le permettent. Ne´anmoins, le nombre total de tentatives devrait eˆtre limite´, à trois ou moins, avant de de´clarer un e´chec et de conside´rer les options de « strate´gie de retrait ». En cas d'e´chec de l'intubation, les options de strate´gie de retrait chez un patient toujours oxyge´ne´comprennent l'e´veil (si possible), la temporisation avec un DSG, une dernie`re tentative d'intubation trache´ale a`l'aide d'une technique diffe´rente, ou une cricothyroı¨dotomie. L'e´chec de l'intubation trache´ale, de la ventilation au masque facial et de la ventilation via un DSG accompagne´d'une hypoxe´mie pre´sente ou imminente, de´finit une urgence « impossible de ventiler, impossible d'oxyge´ner ». Le bloc neuromusculaire doit alors eˆtre confirme´ou mis en place, et une tentative finale de ventilation au masque, de positionnement du DSG ou d'intubation trache´ale avec une lame de vide´olaryngoscopie hyper-angule´e peut eˆtre re´alise´e, si cette approche n'a pas encore e´te´essaye´e. Si la ventilation demeure impossible, une cricothyroı¨dotomie d'urgence devrait eˆtre re´alise´e sans de´lai utilisant une technique de scalpel-bougie-tube (chez le patient adulte). Le CAFG recommande a`toutes les institutions de de´signer une personne comme « leader des voies ae´riennes » afin d'assister a`la mise en place de protocoles pour les voies ae´riennes difficiles, d'assurer une formation et un e´quipement ade´quats et d'aider aux examens de la qualite´en rapport avec les voies ae´riennes.
# Introduction
Morbidity related to airway management continues to be reported in closed legal claims 1,2 and practice audits. 3,4 When such adverse airway outcomes are subject to peer review and analysis, patterns of care are often found to be suboptimal. [1][2][3] Common themes include persistence with one technique when tracheal intubation proves difficult; failure to recognize an evolving ''cannot ventilate, cannot oxygenate'' (CVCO) scenario and failure to perform timely emergency front-of-neck airway access (eFONA) when indicated. Failure of non-technical skills such as effective communication and good team dynamics have often also contributed to airway-related morbidity. [1][2][3] With previous guidelines published in 1998 5 and 2013, 6,7 this update to Canadian airway management recommendations reflects new evidence and opinion appearing in the literature. It applies to difficulty encountered with airway management in an unconscious and often apneic patient.
Significant difficulty with airway management in the unconscious patient can often be avoided by careful airway evaluation before the induction of general anesthesia. In part 2 of these updated recommendations, 8 we have addressed decision-making and implementation of the planned airway strategy for the patient with an anticipated difficult airway. Recommendations in both articles are meant to be broadly applicable to all specialties involved in airway management.
# Methods
The Canadian Airway Focus Group (CAFG) comprises 17 members (see Appendix), with representation from across Canada as well as one member each from New Zealand and Australia.
The CAFG membership includes anesthesiologists, emergency physicians, and critical care physicians. Topics for review were divided among the members, with most assigned to two members. Members reviewed the literature published from 2011 onwards.
A medical librarian helped design and conduct the literature searches. Though not constituting a formal systematic review, databases searched included Medline, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL. Non-English and non-French, animal, manikin, and cadaver studies were excluded, as were case reports, editorials, and letters. Nevertheless, team members had discretion to include such material where relevant.
The CAFG met every two weeks via videoconference from April 2018 to July 2020 to review findings and arrive at consensus regarding recommendations. Similar to other airway management guidelines, [9][10][11][12] we did not assign levels of evidence or strength of recommendation. This follows from a lack of what is considered high-level evidence seen in other medical fields. Randomized controlled trials of airway devices typically address efficacy (often in a population of low-risk elective surgical patients) but when critical events are uncommon (as with airway management), they are unable to evaluate the safety of techniques or decision-making. 13 Information gleaned from large database studies is better able to capture uncommon events, 13 but analysis is limited to association rather than causation, and the population studied may not represent all practice environments. Thus, although evidence-based to the extent possible, some of the recommendations that follow are based largely on expert consensus.
After review by the CAFG, draft documents were sent to several international airway experts (see Acknowledgments) for informal review and comment.
# Definitions
The following definitions are used throughout the manuscript:
• Difficult airway. A difficult airway exists when an experienced airway manager anticipates or encounters difficulty with any or all of laryngoscopy or tracheal intubation, face-mask ventilation (FMV), supraglottic airway (SGA) use, or eFONA. The airway extends from the nostrils and lips to the alveoli, and anatomical variation or pathological distortion anywhere along its length may cause difficulty. Physiologic or contextual issues may compound difficulty with airway management. • Difficult and failed face-mask ventilation. Difficulty with or the failure of FMV can be described according to the four-grade scale presented in Table 1. 14,15 Grades 3 and 4 correspond to difficult and failed ventilation, respectively. The CAFG does not include the number of hands used for a mask seal (i.e., 1 vs 2) in its definition of difficulty, recognizing that the use of two hands may simply reflect clinician preference or the need to optimize a seal to minimize patient exhalation/air leak to the environment. • Difficult and failed supraglottic airway use.
Supraglottic airway use is difficult when more than one attempt at insertion is required, or the resulting ventilation is inadequate. Failed use of an SGA is defined by inadequate ventilation and oxygenation after a maximum of three attempts. As with FMV, this will be reflected by an absent or severely attenuated capnography trace. • Difficult and failed direct or video laryngoscopy. The view obtained during direct laryngoscopy (DL) or video laryngoscopy (VL) is typically quantified using the Cormack-Lehane 16 grade or one of its modifications 17,18 (Table 2 given that the physiologic endpoints of ventilation and oxygenation are the more important goals. Historically, this might have led to persistence with multiple futile attempts at tracheal intubation in the imminently or already hypoxemic patient and may have failed to prompt an attempt at ventilation using an SGA. Secondly, it acknowledges that the absent or severely attenuated waveform capnography that accompanies each of failed tracheal intubation, FMV, and SGA use (i.e., cannot ventilate) will sometimes precede significant oxygen desaturation, especially in the well pre-oxygenated patient (or possibly, when apneic oxygenation is in use). This window of imminent hypoxemia, between the recognition of the ''cannot ventilate'' situation and the onset of severe hypoxemia offers the best opportunity for a good patient outcome by promptly performing eFONA. • Emergency front-of-neck airway access. This refers to emergency access to the trachea via the front of the neck by either cricothyrotomy or tracheotomy. In the hands of non-surgeons, eFONA most often occurs in the adult patient by cricothyrotomy and is considered difficult if it requires more than one attempt.
# Incidence of difficult and failed airway management
Table 3 outlines data from studies in various contexts reporting the frequency of difficult and/or failed FMV, SGA use, tracheal intubation, and eFONA. The studies from which these data are taken are heterogeneous, with inconsistent variables such as patient population, airway manager experience, definitions of difficulty or failure, and the use of neuromuscular blockade. This is likely to explain some of the table's wide-ranging numbers.
6 Response to difficulty with airway management in the unconscious patient Airway managers should be ready with a pre-planned, stepwise approach to managing difficulty with FMV, SGA use, or tracheal intubation.
# Response to difficult FMV
Difficult FMV is challenging to reliably predict, 19 and is often indicated by an attenuated waveform capnography trace. 15,71 Options for responding to difficult FMV are presented in Table 4.
# Response to difficult SGA insertion or ventilation
Although SGAs are used as the intended primary airway technique in many elective surgical procedures, they also play a vital rescue role when a difficult or failed tracheal intubation is encountered in any context. An SGA can also serve as a conduit to facilitate flexible bronchoscope (FB)- PPV = positive pressure ventilation; SpO 2 = peripheral oxygen saturation by pulse oximetry guided tracheal intubation, either in a rescue capacity or as the intended primary technique. Second-generation SGAs are defined by the presence of an esophageal drainage port and cuff design to help maximize seal. They may or may not also be designed to support FB-guided tracheal intubation. Second-generation devices have some benefit over first-generation devices with respect to addressing aspiration risk, but clinically significant aspiration events are rare so this potential advantage has yet to be proven. Nevertheless, given the potential benefits of second-generation SGAs 81 and with no reported disadvantages, the CAFG recommends the routine use of second-generation devices whenever an SGA is needed. Recommended options for SGA insertion troubleshooting appear in Table 5.
# Response to difficult tracheal intubation facilitated by direct or video laryngoscopy
Tracheal intubation facilitated by DL or VL comprises two separate actions: visualizing the glottis, followed by intubating the trachea. Difficulty may occur with either or both component(s). 30% 24 6.6%-9.5% 25,26 Approx. 15% 27 17% 28 Failed or impossible FMV 0.03-0.2% 19,21,29 14% 23 9% 24 No data 7-18% 30,31 No data Difficult FMV combined with difficult laryngoscopy/ intubation 0.3-0.4% 19,22 No data 12.5% 26 No data 27% 28 Difficult tracheal intubation 3-8% 19,22,32,33 1.6-5.7% 23,[34][35][36][37] 0.2-5.5% 25,26,38,39 1-11% 27,40-44 5-23% 28,33,[45][46][47] Failed tracheal intubation 0.006-0.4 19,48,49 Options for responding to difficult face-mask ventilation
• Ensure adequate depth of anesthesia.
• Use an oropharyngeal airway (routine use is recommended for all emergency airway management). A nasopharyngeal airway is an alternative if the mouth cannot be accessed. • Use a two-handed mask hold with exaggerated jaw lift; 72,73 positive pressure ventilation can be performed by an assistant or a ventilator set to pressure control ventilation at C 15-cm H 2 O. 74,75 • Use a thenar eminence (''V-E'') grip for two-handed mask seal/jaw lift. 72,76 • Ensure neuromuscular blockade. 63,77 • Consider an alternate size or type of face mask to improve the airway seal.
• Perform additional head extension 72 or lateral head rotation 78 (if not contraindicated).
• Release any applied cricoid pressure. 79 • Consider head-up patient positioning (hemodynamics permitting).
• Consider gastric decompression via an orogastric tube if significant gastric distention is suspected.
• Exclude presence of a physical obstruction or compression (e.g., foreign body, tumour, or stenosis) in the upper airway or trachea.
• Progress to an alternate mode of ventilation, e.g., SGA or tracheal intubation. 22,80 SGA = supraglottic airway The terms ''direct'' and ''video'' laryngoscopy encompass a variety of devices. For the purposes of the following discussion, we categorize laryngoscopy as follows:
• Direct laryngoscopy refers to use of non-video enabled laryngoscopes, typically with Macintosh or Miller blades. Glottic visualization occurs by direct eye-toglottis sighting. • Video laryngoscopy refers chiefly to use of laryngoscopes with a camera in the blade that delivers an image to an external video screen.
Originally designed with a hyper-angulated blade (HA-VL), video laryngoscopes are now available with varying blade geometries, including Macintosh-shaped video laryngoscopy (Mac-VL). Further details appear in Table 6.
Responses to difficulty with glottic exposure or difficulty with tracheal intubation using DL and Mac-VL appear in Table 7. Unless the glottis is obscured by pathology, 122 fogging, blood or secretions/emesis in the pharynx, difficult laryngoscopy is unusual when using HA-VL, provided the blade can be inserted and placed within the oropharynx. Instead, difficulty with HA-VL facilitated tracheal intubation often relates to difficulty with ''around the corner'' delivery of the tracheal tube to and through the glottis. Recommended measures to help address difficulty with tracheal tube delivery when using HA-VL are presented in Table 8.
# Primary use of video laryngoscopy
The CAFG studied whether a recommendation could be made for the routine primary use of VL (as opposed to DL) to facilitate tracheal intubation. Unfortunately, the currently available literature comparing Macintosh DL with VL is difficult to interpret. While plentiful, most systematic reviews and meta-analyses comparing DL with VL combine various VL blade types (HA-VL and Mac-VL), patient populations, clinical contexts, airway manager experience, and measured outcomes. 141 Nevertheless, compared with DL, the first-attempt and overall success rates of tracheal intubation using VL (Mac-VL or HA-VL) are rarely worse, and are often better. 105,113,114,[142][143][144][145][146][147][148][149][150][151][152][153] The use of a Mac-VL, 106,154 HA-VL, 48,155 or VL of unspecified blade type 37 have all been shown to facilitate successful tracheal intubation after failed DL. In addition, there may be lower complication rates with VL, including fewer occurrences of esophageal intubation. 52,113,[144][145][146][147][156][157][158][159] The use of VL also enables a ''shared mental model'', helping to increase engagement of all airway team members. On balance, and resources allowing, the CAFG recommends the routine primary use of VL with an appropriate blade type for all tracheal intubations. If difficulty is predicted with glottic exposure using DL or Mac-VL, first-attempt use of HA-VL to facilitate tracheal intubation should be strongly considered. For the patient at risk of upper airway soiling (e.g., blood, emesis), consider using Mac-VL so that direct, eye-toglottis visualization can occur should the video camera become obscured. Intermediate geometry blade VL (e.g., McGrath Mac) or DL are alternatives in this situation.
# Response to an unsuccessful first (or subsequent) attempt at the intended airway technique
The following sections address difficulty and failure encountered with attempted tracheal intubation. The response to difficulty and failure with an SGA is discussed in section 8.
Table 5 Recommended options for responding to difficult supraglottic airway insertion
Options for responding to difficult supraglottic airway (SGA) insertion
• Ensure an adequate depth of general anesthesia for SGA insertion.
• Unless contraindicated, use a ''sniff'' position for SGA insertion, with lower neck flexion and head extension. 82,83 • Consider rotating the SGA 90°during advancement around the tongue. [84][85][86][87] • Use an alternate size 88,89 or design of SGA, including one with a different cuff material. 90 • In the context of failed tracheal intubation, release any applied cricoid pressure for SGA insertion. [91][92][93] • Consider neuromuscular blockade (evidence regarding benefit during SGA use is conflicting; however, no harm is reported). [94][95][96][97] • Consider SGA insertion facilitated by direct or video laryngoscopy. 89,90,[98][99][100][101][102] With a second-generation SGA, a tracheal tube introducer (''bougie'') placed through the SGA's esophageal drainage port can first be advanced into the esophagus to subsequently help guide the SGA into position. 103,104 • Progress to an alternate mode of ventilation, e.g., tracheal intubation or FMV.
FMV = face-mask ventilation; SGA = supraglottic airway Using similar technique and optimizing maneuvers as DL, Macintosh geometry VL (Mac-VL) enables laryngeal visualization to occur by direct eye-to-glottis sighting or indirect, on-screen videoscopic sighting. The videoscopic view may be better than that afforded by standard direct laryngoscopy [105][106][107] and may [108][109][110][111] or may not 112 be significantly better than that afforded by direct eye-to-glottis viewing with the same video laryngoscope. Higher firstpass 105,113 and overall 105,114 success rates have been reported with Mac-VL than with DL. As with DL, once a view of the glottis is obtained, tracheal tube delivery tends to be straightforward.
• C-MACÒ with Macintosh blade A • GlideScopeÒ DVM B
Hyper-angulated or hyper-curved blade video laryngoscopy (HA-VL)
Hyper-angulated blade VL (HA-VL) allows ''around the corner'' viewing of the glottis by indirect, videoscopic viewing only. The view with HA-VL is often superior to that obtained by DL [115][116][117] or Mac-VL. 117 First pass tracheal intubation success with HA-VL is frequently higher than with DL. 113 Tracheal intubation with HA-VL requires use of a stylet 118 or other adjunct and for the inexperienced airway manager, may be more challenging or take longer than with DL. 119,120 This can occur despite good glottic visualization. 121,122 It is important to maintain direct (i.e., non-videoscopic) intraoral visual contact with the advancing styleted tube until its tip is past the soft palate, to avoid inadvertent soft-tissue injuries. 123,124 In this regard, a malleable stylet is preferred and equally effective 118 to a rigid stylet. Some HA-VLs feature an integrated channel in the blade to help safely guide the tracheal tube to the glottis.
Non-channelled • Apply external laryngeal manipulation (not cricoid pressure).
• C-MACÒ D-blade • GlideScopeÒ LoPro •
• Ensure the Macintosh blade is inserted sufficiently deep into the vallecula to engage the hyoepiglottic ligament.
• Consider directly lifting the epiglottis (applies to both Macintosh and straight blades).
• Exaggerate head lift and ''sniff'' positions, [126][127][128][129] if not contraindicated.
• Release any applied cricoid pressure. 130 • If using Mac-VL, switch to indirect, videoscopic viewing [108][109][110] if direct eye-to-glottis viewing is suboptimal.
• For continued difficulty with glottic exposure, if the patient remains well-oxygenated, strongly consider progressing to HA-VL. 48 Options for response to difficulty with tracheal tube passage during DL or Mac-VL
• Use a tracheal tube introducer (''bougie''). The bougie is an effective adjunct when Mac-VL or DL results in a limited (e.g., Cormack-Lehane 2b or 3a) view. 40,131 The CAFG endorses the immediate availability of a bougie in all airway management locations. • If not using a bougie, use a stylet to optimally shape the tracheal tube.
• If difficulty with tube passage has occurred in the context of a suboptimal glottic view, consider progressing to HA-VL 48 if the patient remains well-oxygenated. DL = direct laryngoscopy; HA-VL = hyper-angulated blade video laryngoscopy; Mac-VL = Macintosh geometry blade video laryngoscopy 7.1 The hazards of multiple attempts at tracheal intubation Airway managers are susceptible to a variety of cognitive biases 160 that may negatively affect patient care 161 . One of the most concerning is perseveration, defined in the 2019 American Society of Anesthesiologists (ASA) closed claims publication as the ''consistent application of any airway management technique or tool more than twice without deviation or change of technique, or the return to a technique or tool that had previously been unsuccessful''. 1 Perseveration with multiple tracheal intubation attempts appears to be particularly prevalent in otherwise healthy adults 1 and in children where no difficulty was anticipated. 39 Most airway managers recognize that failure of an optimized attempt using one device should mean that another device, technique or operator should be employed during subsequent attempts. Yet even with the substitution of a different device, multiple attempts are correlated with adverse events. Thus, first-attempt success at the intended technique should always be a goal. Adverse outcomes associated with multiple attempts at tracheal intubation include hypoxemia, esophageal intubation, airway trauma, and cardiac arrest. This association exists in pre-hospital care (if tracheal intubation is used), 162,163 pediatric settings, [164][165][166] critical care, [167][168][169] emergency medicine, 43,44,[170][171][172] and in the operating room (OR) 38,39 (Table 9). Similar evidence exists regarding multiple attempts at SGA insertion. 38,166 As a result, virtually all national airway management guidelines in adults, 6,9,10,12,71,173-180 obstetrics, 181,182 and pediatrics [183][184][185] agree that a maximum of two to four optimized attempts (collectively, by all airway managers involved) at tracheal intubation occur before pausing to consider an alternate (''exit'') strategy, with the goal of returning the patient to a point of safety.
# Unsuccessful first or subsequent attempt at tracheal intubation with oxygen saturation in a safe range
The following narrative should be read in conjunction with the flow diagram depicted in the Figure . If a first attempt at tracheal intubation is unsuccessful, further attempts at tracheal intubation can be made according to the following guiding principles:
• Further intubation attempts should only be made if the peripheral oxygen saturation (SpO 2 ) remains in, or has been returned to, a safe range for the patient (e.g., C 90%). This may occur by FMV or SGA ventilation, the effectiveness of which can be seen by waveform capnography. It also includes the situation where the patient is not ventilated after an unsuccessful first intubation attempt, but the SpO 2 is maintained in a safe range because of pre-oxygenation and/or the use of apneic oxygenation. • For a further attempt at tracheal intubation, if not already applied, apneic oxygenation should be considered. This can be administered by via conventional nasal prongs at 5-15 LÁmin -1 or a high- • Partially withdraw the HA-VL blade during laryngoscopy, seeking to achieve no more than a limited view of the larynx (e.g., Grade 2). 132 This allows for both a wider field of view and also a straighter pathway for tube delivery. • Modify the curvature of the styleted tracheal tube to accommodate specific patient anatomy. When a semi-rigid or malleable stylet is used to facilitate HA-VL, it should generally be shaped to match the angulation or curvatureof the blade (i.e., not including the handle)-typically at angles between 60 and 90°. 118,133,134 • Centre the view of the glottis on the screen, then slide the styleted tube's tip along the undersurface of the blade to help direct it to the glottis. 135 • Withdraw the stylet by 4 cm once the tip of the tracheal tube has been passed through the glottis. By allowing the tracheal tube to reflect off the anterior tracheal wall, this facilitates its further advancement down the trachea. • For tube ''hang-up'' persisting after partial stylet withdrawal, rotation of the tube 45-90°to the right (clockwise) may help address tube impingement on the cricoid cartilage or a tracheal ring. 135 • Insertion of a styleted tube before 136 or concomitantly with 137 the videolaryngoscope blade may help with tube passage in the patient with a small mouth. Note that blind insertion of a styleted tracheal tube is contraindicated in some clinical circumstances (e.g., retropharyngeal abscess). • Changing to DL or Mac-VL may succeed if tube delivery continues to be problematic with HA-VL, 122,138,139 unless already proven unsuccessful.
# HA-VL (channelled blades)
• Slight withdrawal, caudad angulation of the blade and lifting of the scope may help better align the advancing tube with the glottic opening and trachea 140 . It is important to not use too small a tracheal tube, as it can exit the channel in an excessively caudad direction. A. Awaken the patient If feasible, when both ventilation and oxygenation are non-problematic, allowing the patient to emerge from general anesthesia after failed tracheal intubation may prevent deterioration to a CVCO scenario. Airway patency and gas exchange can be supported using FMV or an SGA until spontaneous ventilation resumes and the patient can maintain airway patency without assistance. The status of any neuromuscular blockade and sedative agents must be assessed and managed (e.g., with medications such as sugammadex, 190 naloxone, or flumazenil, as appropriate). Once a patient has emerged from general anesthesia, options include regional anesthesia, deferring elective surgery, or if the surgery is urgent, immediate awake oral/nasal tracheal intubation, or awake tracheotomy.
Awakening the patient after failed tracheal intubation in the context of a surgical emergency or critical illness (as with most emergency department or critical care intubations) might not be possible or appropriate, as the patient's clinical trajectory with deteriorating course over time may preclude a return to a functional respiratory or cognitive state. In this case, other exit strategy options should be considered.
B. Temporize with an SGA An SGA can be placed after failed tracheal intubation to temporize (e.g., pending the arrival of additional equipment or expertise) or to support the airway while the patient emerges from general anesthesia. In general, when tracheal intubation was the intended technique for an elective surgical case but has failed, proceeding with the case using only the SGA is inadvisable. 3 This follows from the trauma and swelling to the larynx that may have occurred with the preceding attempts at tracheal intubation. Also, if subsequent intraoperative SGA malfunction occurs, the fallback option of tracheal intubation has already proven to have failed. Nevertheless, in certain contexts (e.g., emergency Cesarean delivery [CD]), the potential benefit of proceeding with a surgical procedure with an SGA after failed tracheal intubation may exceed the risk, although the risk of aspiration must be considered.
A second-generation SGA should be used (ideally one that also supports FB-guided intubation) and a plan for intraoperative SGA failure should be considered.
The critically ill non-surgical patient successfully temporized by SGA or FMV after failed tracheal intubation will likely still require timely tracheal intubation (see next section) or FONA.
C. Proceed with a further attempt at tracheal intubation Pausing to consider exit strategy options after a maximum of three attempts at tracheal intubation helps to both avoid perseveration with failed techniques and maintain situational awareness. It does not absolutely preclude another attempt at tracheal intubation. Nevertheless, a further intubation attempt should only be considered as an exit strategy option with the following provisos: 1) ventilation and oxygenation by FMV or an SGA remain non-problematic; 2) the patient has already undergone prior attempts at tracheal intubation and the larynx may have been subjected to trauma, so an exit strategy intubation should be limited to a single attempt by an airway manager experienced with the planned technique; 3) the planned technique should have a high likelihood of addressing the anatomic constraints that contributed to the earlier failure(s); and 4) a second airway manager should be present. The intubation technique is chosen according to clinical judgement. Nevertheless, if not already attempted, an FB can often prove effective, used on its own or in conjunction with another device:
• Flexible bronchoscope use on its own: When used on its own, an intubating oropharyngeal airway 48 This is an effective combination, 48,[193][194][195] with each device working synergistically to address the limitations of the other. Once well advanced into the trachea, the FB acts as an extended flexible stylet to facilitate tracheal intubation, addressing the issue of difficult tracheal tube delivery with HA-VL used on its own. Similarly, the VL controls collapsing soft tissues in the anesthetized patient to create a patent pharyngeal conduit through which to advance the FB, and also enables visualization of tracheal tube passage through the larynx over the FB. Using both devices together may increase success more than using either device alone, but it does require practice in co-ordinating the tasks of two airway managers-i.e., one to maintain a stable VL view while another manages the FB. Apneic oxygenation should be used throughout.
A successful exit strategy tracheal intubation should prompt the airway manager to carefully consider a safe tracheal extubation strategy (see companion article). 8 Conversely, failure of an exit strategy tracheal intubation attempt should prompt re-consideration of other exit strategy options, including awakening the patient, temporizing with an SGA, or proceeding to FONA.
D. Front-of-neck (surgical) airway access Although very rarely indicated in the still-oxygenated elective surgical patient, this option may be appropriate after failed tracheal intubation of a critically ill patient, or for the patient requiring emergency surgery. Patient ventilation and oxygenation may be maintained by FMV or an SGA while FONA is performed by cricothyrotomy or tracheotomy.
# The ''cannot ventilate, cannot oxygenate'' situation
The CVCO situation is defined as the failure of tracheal intubation, face-mask-, and SGA ventilation (cannot ventilate), resulting in current or imminent hypoxemia (cannot oxygenate). Thus, in the context of tracheal intubation, this means that one or more intubation attempts has failed and, despite fallback attempts at ventilating and oxygenating the patient by optimized FMV and SGA ventilation, the patient is:
• Currently hypoxemic (e.g., SpO 2 is \ 90%) • Imminently hypoxemic (SpO 2 is currently C 90%-e.g., because of pre-oxygenation or the use of apneic oxygenation-but an absent or severely attenuated waveform capnograph for all of tracheal intubation, FMV, and SGA use has indicated a ''can't ventilate'' situation, so that hypoxemia will likely rapidly follow).
Depicted on the right-hand side of the Figure, the CVCO situation should be managed according to the following guiding principles: • Once recognized, the CVCO situation should be verbally declared (e.g., ''This is a can't ventilate, can't oxygenate situation and we need to perform a cricothyrotomy immediately'') and eFONA should proceed without delay. It is worth emphasizing that it is not desirable to allow hypoxemia to occur before transitioning to eFONA when hypoxemia is a predictable consequence of the ''cannot ventilate'' situation. Successfully performing eFONA before severe or prolonged hypoxemia has occurred in a CVCO situation will maximize the possibility of a good outcome.
• Help should be summoned.
• Equipment for eFONA should be obtained, the anterior neck quickly landmarked and the most qualified person already present should be delegated to perform eFONA.
Concurrent with the foregoing preparations for beginning eFONA, neuromuscular blockade should be confirmed or established, especially if tracheal intubation had proceeded with succinylcholine or without neuromuscular blockade. FMV generally gets easier with the onset of neuromuscular blockade or, at worst, remains unchanged. 77,[196][197][198][199] It may also facilitate SGA placement and performing eFONA. In addition to neuromuscular blockade, a single attempt at any or all of the following should be made, if not yet attempted:
• Placement of an SGA. A number of reports have indicated that an attempt at SGA placement was often overlooked prior to performing eFONA. 3,68 • Two-handed FMV with an oropharyngeal airway, facilitated by neuromuscular blockade. • Video laryngoscopic tracheal intubation, if not already attempted. The CAFG is of the opinion that an attempt at tracheal intubation facilitated by HA-VL should ideally have occurred prior to eFONA. Notwithstanding, in an already hypoxemic patient, this option implies that the video laryngoscope is already present, so that the attempt will not substantively delay the onset of eFONA, if unsuccessful.
If adequate oxygenation is restored with any of the foregoing, eFONA is not immediately required and the airway manager can now consider exit strategy options (FIGURE). Conversely, if the foregoing options have failed, then eFONA should proceed without delay (see next section).
The ASA Closed Claims 1 and NAP4 3 studies describe airway manager delay in the recognition of an evolving CVCO emergency as a major contributor to brain damage and death. While some CVCO situations may be immediately evident (e.g., cannot ventilate, currently hypoxemic), others may occur over time, making their recognition more challenging for those managing the patient (''change blindness''). 200,201 Thus, all team members should be explicitly empowered to say when they believe a trigger for declaring a CVCO situation has occurred. Multidisciplinary simulation exercises can help identify and break down barriers to having any team member speak up in such situations. 202,203 Although infrequent, CVCO emergencies are often unanticipated and can occur in otherwise healthy patients (e.g., those presenting for elective surgery). Therefore, all airway managers should regularly practice their skills in eFONA to maintain competence in the procedure. While surgeons familiar with the technique may prefer to perform rapid tracheotomy in the CVCO situation, 204 in the hands of non-surgeon clinicians, and because of anatomic advantages in adult patients, eFONA should generally proceed via the cricothyroid space. For its simplicity, ease of equipment stocking, generalizability to different airway manager types, and emerging evidence of first-pass success in various settings, 205,206 the CAFG recommends a scalpelbougie-tube approach for cricothyrotomy. If feasible, the neck should be fully extended. The location of the cricothyroid membrane (CTM) itself may be difficult to identify by external palpation in some patients, 207 so the CAFG recommends beginning cricothyrotomy with an initial 4-6 cm longitudinal incision over the estimated location of the midline of the larynx in all adult patients. Identifying the laryngeal cartilage and its midline may be aided by a ''laryngeal handshake'' (i.e., moving the laryngeal cartilage from side to side while attempting to palpate the cricothyroid space). 208 Following the longitudinal incision, re-palpation within the wound will allow more accurate identification of the CTM. A transverse incision is made through the CTM, then access to the opened trachea is maintained with the airway manager's finger or the scalpel blade turned into a cephalad-caudad orientation. The bougie is passed into the trachea behind the placeholder finger or alongside the blade, then with finger or blade removed, a 6.0-mm internal diameter cuffed tube (adult patient) is advanced over the bougie. The cuff is inflated and correct tube location confirmed. The CAFG recommends stocking the following equipment at every airway management location: disposable scalpel (#10, 20, or 21 blade), a bougie, and a 6.0 tracheal tube (for adult hospitals), all packaged together. Size-based pediatric equipment should be readily available in pediatric facilities. Pediatric eFONA options are discussed in section 11.6.
False passage of a bougie or tracheal tube can occur during cricothyrotomy or tracheotomy, so correct tube placement must be confirmed by waveform capnography. A flat trace should be considered to represent a malpositioned tracheal tube until proven otherwise and must not be attributed to hypoxemic cardiac arrest. 3,209 8 Supraglottic airway use as the intended technique Similar considerations to those appearing in section 7 on tracheal intubation apply to the use of an SGA as the intended airway management technique.
# Confirmation of tracheal intubation and continuous waveform capnography
The CAFG advocates continuous waveform capnography as the gold standard for confirming correct tracheal tube placement. Waveform capnography has excellent sensitivity and specificity (Table 10) and is widely available. Pattern recognition of capnographic waveforms can easily be learned. 211 For tracheal intubation by nasal, oral or front-of-neck routes, assessment of multiple sustained amplitude waveforms 212 are required to conclude the tracheal tube is correctly positioned and to avoid false positive results (e.g., CO 2 detection with esophageal intubation). Waveform capnography should also be routinely used to confirm effective ventilation by face-mask 15,71 or SGA. 213 Capnography will generally provide earlier feedback on their effectiveness than changes in SpO 2 .
Effectiveness of chest compressions as well as return of spontaneous circulation during cardiopulmonary resuscitation can also be assessed using waveform capnography. The 2015 American Heart Association guidelines for cardiopulmonary resuscitation in adults recommends waveform capnography as ''the most reliable method of confirming and monitoring correct placement of an ETT'' during cardiac arrest. 214 After cardiac arrest, CO 2 detectable by waveform capnography is likely to persist for at least 30 min, 215 although the waveform will be attenuated. In this context, a flat capnograph must not be ascribed to the absence of pulmonary perfusion-rather, esophageal intubation or false passage must be excluded (''no trace = wrong place''). 209 Colorimetric capnometry is less specific than waveform capnography, with additional causes of a false positive result (Table 10). It may have a role if waveform capnography is not available. Other modes of tracheal tube confirmation together with their potential pitfalls, sensitivities, and specificities are presented in Table 10.
The CAFG recommends the routine use of waveform capnography with at least one other method to confirm successful tracheal intubation. To help direct the airway manager's attention to the need for objective confirmation, we recommend routinely making a verbal declaration such as ''sustained CO 2 confirmed'' or ''good trace, right place'' once success has been determined. 209,216 Finally, the CAFG recommends ongoing waveform capnography monitoring in all intubated patients, in all hospital locations, including within-hospital transportation.
# The obstetric patient-special considerations
Many studies continue to indicate a higher risk of failed tracheal intubation in the parturient than in the general surgical population, 35,37,51,249,250 although this has been challenged by other studies. 36,251 Regardless, other patient and contextual factors amplify difficulty. The parturient can be physiologically unforgiving, the need for out-ofhours emergency work common, and the obstetrical suite can be isolated from access to difficult airway equipment or additional expertise.
Obstetrical suites should be well-equipped with difficult airway equipment including, but not limited to, secondgeneration SGAs, video laryngoscopes, a FB, and equipment for cricothyrotomy. 181 As rates of regional anesthesia for CD continue to be high, 36,252 trainees and attending staff with significant exposure to obstetrical practice must make the effort to attain and maintain competence in difficult airway techniques.
Antenatal airway screening of all obstetrical patients should ideally occur with multidisciplinary consultation when indicated. 253,254 Should a parturient possess a nonreassuring airway, early epidural catheter placement and testing should occur during labour. If CD under general anesthesia is required, the airway should be re-assessed, recognizing the dynamic nature of the airway during labour. 253,255 Landmarking neck anatomy including the cricothyroid space by external palpation is particularly challenging in this population; ultrasound has proven useful. 256,257 For CD under general anesthesia, the patient should be positioned optimally and pre-oxygenation undertaken with a tightly fitting face mask with a standard flow of 15 L min -1 . Evidence for the benefit of high-flow nasal oxygen (HFNO) therapy for the obstetric patient is mixed. It is less effective than a tightly applied face mask for preoxygenation [258][259][260] but may provide benefit during apnea 261 and laryngoscopy (provided airway patency is maintained). With potential benefit and minimal downside, apneic oxygenation with HFNO or standard nasal cannulae at flows of 5-15 L min -1 is recommended during apnea for the parturient undergoing general anesthesia. Cricoid pressure should be applied by a trained individual. After general anesthesia induction, gentle FMV (e.g., keeping positive inspiratory pressure \ 20 cm H 2 O) is recommended while awaiting the onset of neuromuscular blockade to help extend the safe apnea time during • Equipment malfunction or disconnect
• Severe bronchospasm
• Kinked or occluded tube
• Tracheal obstruction
• Tracheal tube cuff not inflated
• Obstruction of pulmonary circulation
• Failure to assess for sustained waveforms
• Tube lying in pharynx outside larynx (e.g., cuff above the cords)
• Recent extensive use of FMV or bilevel positive airway pressure non-invasive ventilation 222 • Ingestion of antacid or carbonated beverages Colorimetric capnometry 97-100% (non-arrest) 220,[223][224][225] 69-85% (arrest) 223,225,226 91-100% (non-arrest) 220,223,224 100% (arrest) 223,226 As above, plus:
• Low cardiac output/severe hypotension
• ETCO 2 \ 2-5%
• Neonates and infants 227 As above, plus:
• Contamination of detector with acidic gastric contents; 228 • Recent instillation of medications through the tracheal tube including epinephrine, atropine, surfactant, 229 naloxone.
# Visualization of tracheal tube between cords
No data No data • Adverse patient anatomy precludes a view of any aspect of the larynx during DL or Mac-VL
• ''Glottic impersonation'': entrance to hypopharynx is misinterpreted as the larynx during excess lifting pressure on laryngoscope 230 • Inadvertent intubation of a tracheoesophageal fisutla 231,232 Tube misting 100% 237,247,248 15-71% 237,247,248 No data • The esophagus is also a moist environment.
BMI = body mass index; DL = direct laryngoscopy; ETCO 2 = end-tidal carbon dioxide; FMV = face-mask ventilation; Mac-VL = Macintosh geometry blade video laryngoscopy; SGA = supraglottic airway subsequent laryngoscopy. 181 The CAFG recommends the primary use of VL to facilitate tracheal intubation of the parturient.
# Unsuccessful first attempt at tracheal intubation in the parturient
An unsuccessful optimized attempt at tracheal intubation in the parturient should be transitioned rapidly to FMV or SGA insertion. Help should be enlisted. Cricoid pressure should be released if thought to be contributing to difficulty. If face-mask-or SGA ventilation is successful and adequate patient oxygenation is maintained, a second attempt at tracheal intubation can be made with a different device or by a more experienced airway manager. The use of VL has been reported to be effective after failed DL in the parturient. 37,262 If the second attempt is unsuccessful, a failed tracheal intubation situation should be declared and exit strategy options considered. This is one fewer attempt than might be considered for the non-parturient, reflecting the parturient's adverse physiology.
10.2 Failed tracheal intubation in the parturient with SpO 2 in a safe range-exit strategy options
Having verbally declared the failed intubation situation, the airway manager should maintain oxygenation by facemask-or SGA ventilation while considering exit strategy options. Help should be sought, if available. Further actions are predicated on the status of the mother and the fetus.
• No fetal or maternal distress: If the situation is stable without maternal or fetal emergency, the mother can be allowed to emerge from general anesthesia. Once awake, use of regional anesthesia can be revisited if not contraindicated, or awake tracheal intubation can be performed. • Fetal or maternal distress exists: If the situation is unstable with either fetal or maternal emergency, an SGA should be placed (if not already done) to enable CD or maternal resuscitation to proceed. Cricoid pressure should be released. For CD while using an SGA, a generous surgical incision should be made, minimal fundal pressure applied, and vacuum extraction considered, as necessary. 263 Early use of an SGA in a rescue scenario is accepted practice in the parturient, with success rates reported to be between 86 and 100%. 37,51,250 In a review of 45 years of obstetric airway management in the United Kingdom, there was a steady, decade-over-decade increase in continuing with CD using SGAs after failed tracheal intubation, coinciding with their increasing use as rescue devices. 51 A second-generation SGA with an esophageal drainage port should be used, optimally incorporating a widediameter conduit to support FB-aided tracheal intubation, if chosen. When feasible, a suction catheter can be advanced down the drainage port to help drain the esophagus of any gastric contents. The catheter should be removed after suctioning is completed.
Once the fetus has been delivered or the maternal emergency stabilized, whether to complete the case using the SGA or to secure the airway by tracheal intubation before proceeding should be based on the context of the patient's body mass index, fasting status, and predicted surgical complexity and duration. Currently, there is no evidence to support or refute continuing with the case with a well-functioning SGA. Use of an SGA to complete CD after failed tracheal intubation is supported by studies of the elective use of SGAs for CD under general anesthesia rather than tracheal intubation. Most such studies originate from outside North America, in countries where general anesthesia is more commonly used for CD and the population may be of lower average body mass index. [58][59][60]264 With most using second-generation SGAs, the studies indicate a high success rate and minimal occurrence of gastric content aspiration. 265 Notwithstanding, the CAFG does not currently espouse SGA use for elective CD. This position might change as the role of ultrasound in assessing gastric contents and aspiration risk becomes more understood. 265 10.3 ''Cannot ventilate, cannot oxygenate'' in the parturient
The CVCO scenario in the parturient is also defined as failed tracheal intubation not rescued by attempts at both face-mask-or SGA ventilation, with current or imminent hypoxemia. Maternal oxygen desaturation is likely to occur rapidly, leading to fetal compromise and precluding maternal emergence from general anesthesia. Thus, cricothyrotomy must occur without delay. Once correct placement of a cuffed tracheal tube placed via cricothyrotomy is confirmed, CD can proceed.
# Tracheal extubation and the postpartum period
Maternal mortality data from both the USA and UK indicate that many of the reported obstetric-related airway catastrophes occurred during the postpartum period-i.e., at emergence after CD, in the postanesthesia care unit, or during postpartum surgical procedures (e.g., postpartum hemorrhage). 266,267 Vigilance during these phases is thus paramount.
11 The pediatric patient-special considerations
Respiratory events are the most common cause of adverse events during pediatric anesthesia. 268 These complications are age dependent, with neonates and infants being at highest risk. Elective management of patients \ 12 months of age with a known or suspected difficult airway should occur in a specialized centre, when feasible. 269 Young children are predisposed to adverse respiratory events during airway management because of their high metabolic demand and relatively small respiratory reserve. Resulting short apnea times can lead to hypoxemia, bradycardia, and cardiac arrest. 39 Supplementary oxygen before and during tracheal intubation is recommended to reduce the risk of hypoxemia. Options include HFNO 270 or oxygen applied buccally, via a laryngoscope, or through an advancing tracheal tube.
Airway assessment tools have not been validated in small children, but micrognathia, microstomia, macroglossia, and evidence of temporomandibular joint dysfunction are suggestive of airway management difficulty. Asthma, wheezing, upper respiratory tract infections, snoring, and smoking exposure are associated with critical respiratory events regardless of the airway device used.
# Pediatric airway obstruction
Help should be summoned and poor head/neck position, nasal/oral obstruction, secretions, foreign material, atelectasis, and gastric distension should be considered and treated promptly. Pharmacologic treatment should be employed for laryngospasm, bronchospasm, opioidmediated rigidity, and light anesthesia.
# Pediatric FMV
The incidence of difficult FMV (albeit with varying definitions) in children has been reported to be between 6.6 and 9.5%. 25,26 Impossible FMV is less common, with only six occurrences reported in 1,018 pediatric difficult intubation registry cases. 39
# Pediatric SGAs
Pediatric SGAs have significantly improved in recent years. 271 Fewer adverse respiratory events have been described with SGA use for infant airway management compared with tracheal intubation. Neonatal resuscitation with SGAs can result in fewer neonatal intensive care unit admissions and superior resuscitation rates compared with FMV and tracheal intubation.
# Pediatric flexible bronchoscopy through a conduit
Performing FB intubation through an SGA is particularly useful for difficult infant airways, compared with VL. 272 Supraglottic airways for this purpose should have a wide inlet, a short ventilation tube and should facilitate a good bronchoscopic view of the glottis. They should also allow for easy withdrawal of the SGA. The air-Q ILA TM , (CookgasÒ LLC, Mercury Medical, Clearwater, FL, USA) has shown comparatively higher airway leak pressures and superior flexible bronchoscopic views of the glottis than the LMA Unique (Teleflex, Inc., Wayne, PA, USA) in pediatric patients. 273
# Pediatric tracheal intubation
In a multicentre pediatric difficult intubation registry, easy tracheal intubation by an anesthesiologist occurred in up to 99.8% of pediatric cases. 39 Of the remaining cases that proved difficult, 20% had an airway-related complication. Risk factors for complications included C two intubation attempts, weight \ 2 kg, a short thyromental distance, and multiple DL attempts. 39 The CAFG recommends limiting DL attempts to two and rapidly transitioning to a FB or VL. When used after failed DL, a FB was successful in 54% of cases and VL succeeded in 55%. Cuffed tracheal tubes are recommended for all children[3 kg, with appropriate care to avoid cuff overinflation. 274 11.6 Pediatric eFONA Employing eFONA through the CTM in a neonate or infant is not feasible or recommended. At this age, the CTM is underdeveloped and difficult to landmark; the cartilages are also fragile and susceptible to injury. An open tracheotomy is preferred if an individual with the skills is present. Needle tracheotomy is an alternative, although one animal study suggests a low success rate and significant risk of tracheal compression by the advancing needle. 275 If needle cricothyrotomy is used, ventilation should ideally proceed using a Ventrain device (Ventinova Medical, Eindhoven, Netherlands). 276,277 For older children (i.e., [8-12 yr), the scalpel-bougie technique can be used via the CTM. There is no evidence that cricothyrotomy kits are superior to a scalpel cricothyrotomy technique.
12 Tracheal extubation of the at-risk airway Tracheal extubation is an elective procedure and is addressed further in the companion article 8 .
# Human factors in airway management
The term ''difficult airway'' typically relates to patient anatomy or physiology that adversely affects ease of airway management. Difficulty can also arise from how an airway manager and the assembled team performs during challenging airway management. This can sometimes be impacted by suboptimal organizational culture. Human factor issues have been reported to be contributory in 40-100% of airway management-related adverse outcomes. 1,278 Many human factor issues occurring during airway management relate to dysfunctional team dynamics. These are characterized by poor communication, inadequate leadership, and the lack of a shared mental model. 279 In situ multidisciplinary training improves team dynamics but is still not commonly done. 280 Checklists can improve communication, help ensure equipment availability, and aid in team briefing. [281][282][283] While the published evidence for tracheal intubation checklists has not shown decreased mortality, outcomes such as hypoxemia may be reduced. 284 Human factor issues that may impact airway management and their potential mitigation strategies are presented in Table 11. The published evidence base regarding these factors continues to evolve.
# Airway leads and quality assurance
The CAFG recommends designating an individual as departmental or hospital ''airway lead'' to help adopt or develop difficult airway protocols, recommend difficult airway equipment, and ensure equipment standardization across hospital locations. 3,288 The airway lead or a multidisciplinary airway committee can also help organize training events and assist in airway-related quality assurance by debriefing critical incidents or nearevents. Debriefing can provide opportunities to share concerns but also to help reinforce what went well. It is important that such quality assurance occurs using an objective ''just culture'' model, focusing more on organizational learning and less on the role of any one individual in the event.
# Documentation
All airway management events should be documented in the patient's paper or electronic medical record (EMR). Previously documented difficult or failed tracheal intubation is a robust predictor of subsequent difficulty. 289 In general, the airway technique used should be recorded, together with optimizing maneuvers or adjuncts used, view obtained, number of attempts, details of any challenges encountered as well as how they were resolved. Major (e.g., significant hypoxemia, hypotension, cardiac arrest) and minor (e.g., mucosal bleeding, dental injury) complications should be recorded. Suggestions for future airway management should also be recorded.
If performed, ease of FMV must always be recorded (e.g., with a mandatory field in an EMR). This is crucial information to help guide future planning for airway management.
The airway manager should personally inform the patient after a significantly difficult airway encounter and provide a written letter describing the difficulty and how it was resolved. Copies of the letter should be added to the patient's medical record and forwarded to the patient's primary care physician. The patient should be flagged as having a potentially difficult airway during subsequent hospital admissions, including use of in-hospital alert bracelets. Difficult airway information should also be submitted to local or national difficult airway databases, if available (e.g., www.medicalert.org/everybody/difficultairwayintubation-registry). In addition, using a robust incident reporting system will help address system-wide patient safety and quality of care issues. 290 In the future, it may be possible to routinely add photos or recordings of VL to the EMR, or for the patient to use secure, app-based technology to store or access their own airway-related information. 291 16 Airway management education Routine clinical practice may not be sufficient to maintain airway management skills. Performing a scalpel-bougie aided cricothyrotomy in a CVCO situation is a rare, yet high acuity event. Successfully performing such infrequently used skills requires deliberate practice, characterized by regular learning opportunities in a simulation environment that incorporates clear goals, focuses on technique, and provides timely expert feedback. [292][293][294][295] This option is safe for the learner, teacher, and patient. Mistakes can be corrected through coaching, and procedures can be simulated repetitively and interrupted for immediate feedback. As competence and comfort with a skill such as cricothyrotomy increases, the airway manager is more likely to consider its use as part of a plan rather than symbolic of a failure of the plan.
Valuable lessons in airway management can also occur through experiential learning in the OR. Nevertheless, the experience that develops over years is not necessarily equivalent to expertise. Expertise is gained by exposure to difficult airways, with learners pushing themselves to manage increasingly difficult experiences. 294 Learning is Table 11 Human factor-related issues in airway management, with potential mitigating strategies Potential human factor-related issues that may occur during management of the difficult airway in the unconscious patient, with mitigation strategies
# Issue
Possible mitigation strategies: by the airway manager by the assembled team by the organization Calling for help: The airway manager might overlook calling for help when difficulty occurs.
• Have personal triggers for calling for help, e.g., (1) whenever you first contemplate it; (2) failed intubation or failed SGA insertion after a maximum of 3 attempts or (3) a CVCO situation.
• Recognize that a helper can provide hands for tasks, so that the airway manager can concentrate on the ''big picture'' and reduce their stress level.
• Consider making a habit of asking a colleague to physically stand by when inducing a patient with anticipated airway risk.
• Strongly consider physically attending any request for backup, even if phrased as a ''heads-up''.
• A helper should announce their arrival by asking ''How can I help?''
• Any team member should be empowered to call for help, bring in equipment, or call a code blue independently.
• All departments should foster a culture of calling for help.
• During team training, e.g., during in situ simulation sessions, requesting help should always be debriefed as a critical action.
Loss of ''situation awareness.'' During an airway crisis, it can be difficult to correctly receive and process incoming information. This will impair diagnosis and decision-making and may promote inappropriate fixation on a single familiar but ineffective technique (perseveration). 285 • Maintaining situation awareness involves long-term memory content, which may be difficult to access during a critical event. Help from other staff provides the airway manager with additional processing capacity for integration of basic information. 285,286 • Call for help after 3 failed attempts at the intended technique: a fresh pair of eyes will help interrupt perseveration.
Be alert for the ''change blindness'' 200,201 that can occur when a critical airway event evolves over time.
A newly arrived helper may better be able to see the obvious.
• Use difficult airway techniques in dayto-day routine practice (e.g., the combination of VL and FB) so that their use is practiced, and so that you think of them when in difficulty.
• Perform a team briefing before embarking on all airway management. Include specific mention of triggers for moving from one plan to the next and empower all team members to speak up once they feel a trigger has occurred.
• Team members should be trained in the interpretation of waveform capnography and pulse oximetry and should be empowered to declare when waveform capnography is nonreassuring or the SpO 2 is decreasing.
• Ensure all team members have been empowered to suggest using an SGA for rescue or CVCO at any time and that they know the equipment's location.
• Mandate adherence to a standard operating procedure for the difficult airway by using an algorithm or cognitive aid based on the algorithm.
• Facilitate multidisciplinary in situ team simulation to practice using the algorithm or cognitive aid for difficult airway scenarios. A major objective during such sessions is to encourage and empower all team members to speak up.
• Airway workshops should include education on non-technical as well as technical skills. Common cognitive errors should be addressed.
Fear. Faced with a hypoxemic patient, the airway manager might experience a maladaptive sympathetic response. This might include fight (e.g., arguing with team members); flight (e.g., disbelief of patient vital signs) or freeze (e.g., not performing eFONA when indicated).
• Call for help early in any evolving airway event. Not being emotionally invested, a newly arrived colleague might possess better situation awareness.
• Have a strategy (a coordinated series of plans) for encountering difficulty in all patients, whether predicted or not. Moving smoothly and deliberately through the steps of a pre-planned strategy will help keep you in control of yourself as well as the situation.
Mentally rehearse the strategy on a regular basis.
• During an airway crisis, team members must recognize that the airway manager who induced the patient is deeply emotionally invested. They might be experiencing a profound sympathetic response, compromising thinking or motor skills. Any team member should call for help if they feel it is in the best interest of the patient.
• Once qualified help arrives, the initial airway manager should consider moving to a supportive role on the team, providing information and suggestions.
• High acuity but rare events such as CVCO should be ''overlearned'' during simulation sessions. 286 This will help demystify them and make their management more routine in clinicians' minds.
Barriers to use of eFONA can include not knowing which procedure to employ (''device confusion''), lack of confidence in one's ability to perform the procedure, or a ''freeze'' response to fear. The reluctance to act may manifest by insisting a surgeon or better qualified person be called to perform eFONA.
• By training in eFONA, all airway managers must be prepared to proceed with eFONA themselves.
• Deliberately practice eFONA on a parttask trainer at least twice a year.
• When encountering difficulty, follow the department's recommended algorithm or cognitive aid.
• Team performance in rare emergencies such as CVCO benefits from in situ simulation.
• Swapping team roles during simulation sessions may reveal latent errors in communication and equipment.
• The organization should ensure that all airway managers are trained in and prepared to perform eFONA.
• Minimize choices to a single technique for high-stress procedures such as eFONA (e.g., scalpel-bougie-tube for the adult patient).
• Make task trainers easily accessible for individual clinician eFONA practice. This can include 3D-printed models of the larynx.
optimally achieved by assessing the trainee's background knowledge and skill before starting in the OR, establishing educational goals, and supervising performance with immediate feedback. 296 Thus, a knowledgeable teacher can optimize learning for trainees in the OR. 297,298 Making educational programs multidisciplinary can further augment benefit by creating positive relationships between disciplines.
# Summary and key recommendations
As the literature on airway management evolves, guidelines and recommendations must be updated regularly. 299 Published national airway management guidelines espouse largely consistent management principles. This invites an opportunity to develop a universal lexicon of terms to describe common airway management situations 300 and accepted principles on how to manage them. 301 When such universal guidance is published, it must still be applied to the national or local context in which the airway manager practices. In this third iteration of airway management recommendations from the CAFG, there are few guiding principles and recommendations:
• Resources allowing, VL, with appropriately selected blade type, should be used for the first attempt at tracheal intubation. • Multiple attempts at tracheal intubation and even SGA insertion are associated with adverse events; firstattempt success should be a goal. • If unsuccessful on the first attempt, further attempts can be made at the intended technique provided patient ventilation and oxygenation are maintained. A stepwise progression through different optimizing maneuvers, devices, or airway managers should occur. • Total attempts at the intended technique should be limited to three or fewer before pausing to consider exit strategy options. Patient ventilation and oxygenation should be maintained while considering and then executing the exit strategy. • Exit strategy options to consider after declaring failed tracheal intubation include awakening the patient, temporizing with an SGA, proceeding with one further controlled attempt at tracheal intubation with a different technique, or FONA. • Avoid use of vague language, such as ''we should…'', ''somebody…''
• Delegate specific tasks by name.
• Use 3-step ''closed loop'' communication: 287 (a) Transmit message to receiver, by name.
(b) Receiver to verbally acknowledge message.
(c) Transmitter verifies with the receiver that the message has been received and correctly understood.
• Listen to suggestions or observations from anyone present, regardless of (perceived) hierarchy.
• Help avoid detrimental task fixation (e.g., on tracheal intubation) by delegating an individual to monitor the overall clinical situation or to look after other aspects of a resuscitation.
• All team members should practice graded assertiveness, when indicated, e.g., by use of the ''PACE'' mnemonic:
Probe to see if others are aware of an issue the team member has identified.
Alert others of the problem.
Challenge the current action if necessary, or to seek clarification.
Emergency; give explicit instruction, e.g., ''you must do a surgical airway now''.
• Passage of time during an airway crisis can appear distorted. A team member should be tasked with keeping the rest of the team appraised.
• A flat hierarchy between colleagues or a (perceived) hierarchy between members of different professions can both be problematic. Roles should be respectfully clarified by either party.
• Avoid assumptions: the loudest voice is not necessarily the most knowledgeable.
• Train airway managers in the relevant principles of CRM.
• Train all team members to use ''PACE'' (or similar) graded assertiveness prompts during multidisciplinary simulation sessions.
• Wear name tags in locations where team members are likely to not know each other (e.g., a trauma code).
CRM = crisis resource management; CVCO = ''cannot ventilate, cannot oxygenate''; eFONA = emergency front of neck airway access; FB = flexible bronchoscope; SGA = supraglottic airway; SpO 2 = peripheral oxygen saturation by pulse oximetry; VL = video laryngoscopy
• A CVCO situation is defined by the failure of tracheal intubation, FMV, and SGA use, with imminent or current hypoxemia. Neuromuscular blockade should be ensured, and eFONA undertaken in a timely fashion. • The CAFG recommends that a scalpel-bougie-tube technique be used for adult eFONA, and that the necessary equipment for eFONA, packaged together, be stocked at every hospital airway management location. • Similar principles are broadly applicable to the parturient and to the pediatric patient. • Human factors often contribute to airway-related adverse events; efforts should be made to educate airway managers about common pitfalls. • An airway lead is recommended for all hospitals to help many aspects of airway management at an organizational level.
Without doubt, no matter how well addressed, it will always be preferable to avoid having to manage a difficult airway presenting in the unconscious patient. To this end, thorough patient airway evaluation should be made, followed by appropriate decision-making and safe implementation of the plan. These aspects of safe management of a patient with a difficult airway are addressed further in the companion article 8 , as is advice on tracheal extubation of the difficult airway patient.
Author contributions See Appendix.
#
Acknowledgements The members of the CAFG thank Brooke | None | None |
937d64bc8a465b420ab0ee16672c3a9952b62a3a | cma | None | This guideline provides recommendations to primary and emergency care providers on how to assess the need for diagnostic imaging in five common situations: low-back pain (adults), minor head injuries (all ages), uncomplicated headache (adults), hip and knee pain (adults), and suspected pulmonary embolism (non-pregnant adults). Management of these conditions is beyond the scope of this guideline. However, in some cases, notes and alternatives to imaging are provided for additional clinical context.- Imaging is not recommended for uncomplicated headache unless red flags are present (page 2). - CT head scans are not recommended in adults and children who have suffered minor head injuries unless positive for a head injury clinical decision rule (page 3). - Chest CT for suspected pulmonary embolism is not recommended in low-risk patients with a normal D-dimer result (page 5). - Imaging is not recommended for low back pain unless red flags are present (page 7). - MRIs of hip or knee joints are not recommended in patients with co-existent pain and moderate to severe osteoarthritis unless red flags are present (page 8). - Practitioners are encouraged to consult a radiologist if they have any concerns or questions regarding which imaging test is appropriate for a given problem.# Background
The purpose of this guideline is to communicate best practice for imaging in common situations in primary and emergency care, in order to promote appropriate use of imaging resources in BC. Access to diagnostic imaging services, and the ability to respond to emergency/urgent imaging requests, will depend on local availability. When in doubt, direct consultation with a radiologist is encouraged.
# Appropriate Use of CT for Uncomplicated Headache in Adults
Objective: to guide decision-making regarding the use of head CT in adults with uncomplicated headache.
Rationale: CT of the head exposes the patient to radiation. The need for imaging with CT must be balanced against the risk of radiation. When in doubt, consult with the relevant specialist locally or through the RACE Line.
Recommendation: Imaging is not recommended for uncomplicated headache unless red flags are present.
Consider imaging in the following "red flag" situations : 1 - sudden onset of severe headache (thunderclap)
- recurrent headache with unexplained focal neurological signs 2 - Most headaches are benign and self-limiting and do not require a CT head scan or MRI for diagnosis.
# Patient and Caregiver Resources
- Imaging Tests for Headaches: When you need them and when you don't -Choosing Wisely Canada
# Appropriate Use of CT for Minor Head Injury in Adults and Children
Objective: to guide decision making regarding the use of head CT in adults and children with minor head injury.
Rationale: CT of the head exposes the patient to radiation. Practitioners should consider the risk of CT radiation exposure.
Radiation risks are highest in infants and decrease with age. The following clinical decision rules balance the benefit of identifying a treatable brain injury with the risks associated with radiation exposure. When in doubt, consult with the relevant specialist locally or through the RACE Line.
Recommendation: Do not request CT head scans in patients who have suffered minor head injuries unless positive for a validated head injury clinical decision rule such as:
- Adults age 16+: Canadian CT Head Rule (below)
- Children: PECARN Rule (page 4)
In situations where CT is not readily available, consultation with a specialist is encouraged to help guide medevac decisions.
# Canadian CT Head Rule (for adults and adolescents age 16+) 3
The Canadian CT Head Rule can be applied to patients with a "minor" head injury.
In this context, "minor" means a head injury with Glasgow Coma Scale (GCS) 13-15 AND with one of:
- a witnessed loss of consciousness (LOC), or - amnesia to the head injury event, or - witnessed disorientation.
A CT head is recommended for patients who fulfil the inclusion criteria above AND any ONE of the following findings:
- Severe mechanism of injury: motor vehicle crash with patient ejection, death of another passenger, or rollover; pedestrian or bicyclist without helmet struck by a motorised vehicle; falls of more than 3 feet for children <age 2 or 5 feet for children age 2+, or head struck by a high-impact object ∫ Patients with certain isolated findings (i.e., with no other findings suggestive of traumatic brain injury), such as isolated LOC, isolated headache, isolated vomiting, and certain types of isolated scalp haematomas in infants older than 3 months, have a risk of clinically-important traumatic brain injury substantially lower than 1%. § Risk of clinically-important traumatic brain injury is exceedingly low, generally lower than risk of CT-induced malignancies. Therefore, CT scans are not indicated for most patients in this group.
# Appropriate Use of CT for Suspected Pulmonary Embolism in the Non-Pregnant Adult
Objective: To guide decision making regarding the use of CT in a stable, non-pregnant adult patient presenting with a suspected pulmonary embolism (PE), based on history and physical exam.
Rationale: CT of the chest exposes the patient to radiation. The need for imaging with CT must be balanced against the risk of radiation. When in doubt, consult with the relevant specialist locally or through the RACE Line.
# Key points:
- Patients at high risk of PE should be referred to the emergency department and not managed initially in the community.
- Practitioners are reminded to consider risk factors that might alter the pre-test probability. This strategy applies to the majority of people and does not account for unique risk factors (e.g., anabolic steroids, athletes, elderly, paraplegics, etc.).
If patients have persistent symptoms beyond 24-48 hours, they should go to the emergency department for further assessment.
- Use a clinical decision rule such as the Wells Score (Table 1) to determine whether the patient is low-risk or high-risk.
- For low risk adult patients:
- If PERC score (Table 2) is 0, then PE is ruled out. There is no need for further investigation.
- If PERC score (Table 2) is >0, a D-dimer should be ordered. If D-dimer is positive, further imaging should be ordered.
- Do not request imaging (CT pulmonary angiogram or ventilation-perfusion lung scan) for pulmonary embolism in those with a normal D-dimer result (see below).
- For high risk adult patients: Start empiric treatment with anticoagulant therapy if confirmatory imaging (CTPA, VQ lung scan) is not immediately available.
Recommendation: When a stable, non-pregnant adult patient presents with signs and symptoms suspicious for PE, the following sequential steps should be done to determine whether a CTPA is required: 5 1. Assess pre-test probability using a clinical decision rule (e.g., Wells Score). 14,15 - If the total Wells score is ≥4.5 (PE likely), proceed to imaging.
- If <4.5 (PE unlikely), proceed to the pulmonary embolism rule-out criteria (PERC Rule).
# PERC Rule
- If the patient is low-risk (PE unlikely) and the PERC score is 0 (all of the items are true), the likelihood of PE is <2% and CTPA is not recommended.
- If the patient is low-risk and the PERC score is >0 (one or more items is not true), proceed to D-dimer. No unilateral leg swelling 0 1
No hemoptysis 0 1
No surgery or trauma ≤ 4 weeks 0 1
No history of VTE 0 1
No estrogen use 0 1
# D-dimer: CTPA is not recommended if D-dimer is below the normal range for your institution.
Clinicians may use a negative age-adjusted D-dimer result using a high-sensitivity assay to exclude the diagnosis of PE in patients older than 50 years who have a low risk for acute PE according to a validated risk score (e.g., Wells score or simplified, revised Geneva score).
For more detailed guidance on diagnosis of PE, refer to the BC Emergency Medicine Network Point-of-Care Emergency Clinical Summary, available from: bcemergencynetwork.ca/clinical_resource/pulmonary-embolism-diagnosis/
# Diagnostic imaging for suspected PE in pregnant patients
- Specialist consultation is recommended (radiology, obstetrics)
- It is unclear whether CTPA or ventilation-perfusion (V/Q) scanning is preferable in pregnant patients 5,6 - Radiation dose from CTPA and V/Q scanning may be dependent on the scanners available at a given site
# Appropriate Imaging for Acute Low Back Pain in Adults
Objective: to guide decision making regarding whether imaging is needed in an adult patient presenting to primary care or the emergency department with acute low back pain (defined as low back pain of less than 6 weeks duration).
Rationale: X-ray and CT expose the patient to radiation. The need for imaging must be balanced against the risk of radiation. When in doubt, consult with the relevant specialist locally or through the RACE Line. Imaging of low back pain without red flags is unlikely to change management or improve treatment. 6 -10 Acute (new onset) low back pain usually resolves by 6 weeks. 9,11 Recommendation: Diagnostic imaging (x-ray, CT or MRI) for low back pain of less than 6 weeks duration is not recommended unless one of the following red flags is present: 1,12 - severe or progressive neurologic deficit, e.g., cauda equina - significant acute traumatic event immediately preceding onset of symptoms
# How this guideline was developed
The five recommendations in this guideline were agreed to by a provincial expert advisory group on medical imaging in British Columbia. 13 The recommendations were developed by consensus to decrease the rate of inappropriate medical imaging. 13 They are informed by the Canadian Association of Radiologists (CAR) Choosing Wisely Canada Top 5 recommendations. 1 Where available, key references are provided. In situations where there is a lack of rigorous evidence, we provide best clinical opinion to support decision making and high-quality patient care. For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook.
# Appropriate Use of MRI for Hip and Knee Pain in Adults Age ≥ 40
Objective: to guide decision-making regarding whether MRI is needed in a patient ≥ age 40 presenting to primary care or the emergency department with hip or knee pain and osteoarthritis in the subject joint.
# Rationale:
The purpose of an MRI for knee or hip is primarily for surgical planning. In most cases, using MRI does not add useful information for patients with moderate-to-severe OA especially for those with chronic degenerative conditions. A weight-bearing x-ray is recommended to identify OA.
# Recommendation:
In the absence of red flags, acute or chronic hip or knee pain with plain film x-ray evidence of moderate-tosevere osteoarthritis OA does not require MRI. MRI should be reserved for evaluation of possible red flag diagnoses or common conditions treatable with arthroscopy, e.g., meniscus and ligamentous tears.
# MRI Knee and Hip Appropriateness Criteria
For patients 40 years of age and older, one of the following red flags must apply in order to be eligible for MRI knee or hip:
- MRI was recommended on a previous imaging report (please attach report) - Previous knee or hip surgery- - Suspected infection- - Suspected tumour - Osteonecrosis - Fixed locked knee- - Patient had a weight-bearing x-ray within the past 6 months and referring clinician has confirmed mild or no evidence of osteoarthritis in the knee or hip *Knee or hip pain in the settings of previous surgery, suspected infection, or fixed locked knee may be urgent or emergent. Consider discussion with an orthopedic surgeon prior to requesting an MRI. All orthopedic emergencies require immediate consultation.
# Key messages for counselling patients:
- Having an x-ray can inform the appropriate investigation pathway.
- In absence of red flag symptoms, there is no evidence for the utility of MRI in patients with significant OA.
- Most orthopaedic surgeons do not require obligatory MRI prior to consultation. If an MRI is required, the surgeon can request it. - Discuss options for treatment and pain management including a trial of acetaminophen and NSAIDS.
# Patient and caregiver resources MRI for Knee and Hip -when is it appropriate? Information for patients (Vancouver Coastal Health)
The principles of the Guidelines and Protocols Advisory Committee are to:
- encourage appropriate responses to common medical situations - recommend actions that are sufficient and efficient, neither excessive nor deficient - permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: [email protected] Website: www.BCGuidelines.ca | This guideline provides recommendations to primary and emergency care providers on how to assess the need for diagnostic imaging in five common situations: low-back pain (adults), minor head injuries (all ages), uncomplicated headache (adults), hip and knee pain (adults), and suspected pulmonary embolism (non-pregnant adults). Management of these conditions is beyond the scope of this guideline. However, in some cases, notes and alternatives to imaging are provided for additional clinical context.• Imaging is not recommended for uncomplicated headache unless red flags are present (page 2). • CT head scans are not recommended in adults and children who have suffered minor head injuries unless positive for a head injury clinical decision rule (page 3). • Chest CT for suspected pulmonary embolism is not recommended in low-risk patients with a normal D-dimer result (page 5). • Imaging is not recommended for low back pain unless red flags are present (page 7). • MRIs of hip or knee joints are not recommended in patients with co-existent pain and moderate to severe osteoarthritis unless red flags are present (page 8). • Practitioners are encouraged to consult a radiologist if they have any concerns or questions regarding which imaging test is appropriate for a given problem.# Background
The purpose of this guideline is to communicate best practice for imaging in common situations in primary and emergency care, in order to promote appropriate use of imaging resources in BC. Access to diagnostic imaging services, and the ability to respond to emergency/urgent imaging requests, will depend on local availability. When in doubt, direct consultation with a radiologist is encouraged.
# Appropriate Use of CT for Uncomplicated Headache in Adults
Objective: to guide decision-making regarding the use of head CT in adults with uncomplicated headache.
Rationale: CT of the head exposes the patient to radiation. The need for imaging with CT must be balanced against the risk of radiation. When in doubt, consult with the relevant specialist locally or through the RACE Line.
Recommendation: Imaging is not recommended for uncomplicated headache unless red flags are present.
Consider imaging in the following "red flag" situations : 1 • sudden onset of severe headache (thunderclap)
• recurrent headache with unexplained focal neurological signs 2 • Most headaches are benign and self-limiting and do not require a CT head scan or MRI for diagnosis.
# Patient and Caregiver Resources
• Imaging Tests for Headaches: When you need them and when you don't -Choosing Wisely Canada
# Appropriate Use of CT for Minor Head Injury in Adults and Children
Objective: to guide decision making regarding the use of head CT in adults and children with minor head injury.
Rationale: CT of the head exposes the patient to radiation. Practitioners should consider the risk of CT radiation exposure.
Radiation risks are highest in infants and decrease with age. The following clinical decision rules balance the benefit of identifying a treatable brain injury with the risks associated with radiation exposure. When in doubt, consult with the relevant specialist locally or through the RACE Line.
Recommendation: Do not request CT head scans in patients who have suffered minor head injuries unless positive for a validated head injury clinical decision rule such as:
• Adults age 16+: Canadian CT Head Rule (below)
• Children: PECARN Rule (page 4)
In situations where CT is not readily available, consultation with a specialist is encouraged to help guide medevac decisions.
# Canadian CT Head Rule (for adults and adolescents age 16+) 3
The Canadian CT Head Rule can be applied to patients with a "minor" head injury.
In this context, "minor" means a head injury with Glasgow Coma Scale (GCS) 13-15 AND with one of:
• a witnessed loss of consciousness (LOC), or • amnesia to the head injury event, or • witnessed disorientation.
A CT head is recommended for patients who fulfil the inclusion criteria above AND any ONE of the following findings:
• Severe mechanism of injury: motor vehicle crash with patient ejection, death of another passenger, or rollover; pedestrian or bicyclist without helmet struck by a motorised vehicle; falls of more than 3 feet for children <age 2 or 5 feet for children age 2+, or head struck by a high-impact object ∫ Patients with certain isolated findings (i.e., with no other findings suggestive of traumatic brain injury), such as isolated LOC, isolated headache, isolated vomiting, and certain types of isolated scalp haematomas in infants older than 3 months, have a risk of clinically-important traumatic brain injury substantially lower than 1%. § Risk of clinically-important traumatic brain injury is exceedingly low, generally lower than risk of CT-induced malignancies. Therefore, CT scans are not indicated for most patients in this group.
# Appropriate Use of CT for Suspected Pulmonary Embolism in the Non-Pregnant Adult
Objective: To guide decision making regarding the use of CT in a stable, non-pregnant adult patient presenting with a suspected pulmonary embolism (PE), based on history and physical exam.
Rationale: CT of the chest exposes the patient to radiation. The need for imaging with CT must be balanced against the risk of radiation. When in doubt, consult with the relevant specialist locally or through the RACE Line.
# Key points:
• Patients at high risk of PE should be referred to the emergency department and not managed initially in the community.
• Practitioners are reminded to consider risk factors that might alter the pre-test probability. This strategy applies to the majority of people and does not account for unique risk factors (e.g., anabolic steroids, athletes, elderly, paraplegics, etc.).
If patients have persistent symptoms beyond 24-48 hours, they should go to the emergency department for further assessment.
• Use a clinical decision rule such as the Wells Score (Table 1) to determine whether the patient is low-risk or high-risk.
• For low risk adult patients:
o If PERC score (Table 2) is 0, then PE is ruled out. There is no need for further investigation.
o If PERC score (Table 2) is >0, a D-dimer should be ordered. If D-dimer is positive, further imaging should be ordered.
o Do not request imaging (CT pulmonary angiogram [CTPA] or ventilation-perfusion [VQ] lung scan) for pulmonary embolism in those with a normal D-dimer result (see below).
• For high risk adult patients: Start empiric treatment with anticoagulant therapy if confirmatory imaging (CTPA, VQ lung scan) is not immediately available.
Recommendation: When a stable, non-pregnant adult patient presents with signs and symptoms suspicious for PE, the following sequential steps should be done to determine whether a CTPA is required: 5 1. Assess pre-test probability using a clinical decision rule (e.g., Wells Score). 14,15 • If the total Wells score is ≥4.5 (PE likely), proceed to imaging.
• If <4.5 (PE unlikely), proceed to the pulmonary embolism rule-out criteria (PERC Rule).
# PERC Rule
• If the patient is low-risk (PE unlikely) and the PERC score is 0 (all of the items are true), the likelihood of PE is <2% and CTPA is not recommended.
• If the patient is low-risk and the PERC score is >0 (one or more items is not true), proceed to D-dimer. No unilateral leg swelling 0 1
No hemoptysis 0 1
No surgery or trauma ≤ 4 weeks 0 1
No history of VTE 0 1
No estrogen use 0 1
# D-dimer: CTPA is not recommended if D-dimer is below the normal range for your institution.
Clinicians may use a negative age-adjusted D-dimer result using a high-sensitivity assay to exclude the diagnosis of PE in patients older than 50 years who have a low risk for acute PE according to a validated risk score (e.g., Wells score or simplified, revised Geneva score).
For more detailed guidance on diagnosis of PE, refer to the BC Emergency Medicine Network Point-of-Care Emergency Clinical Summary, available from: bcemergencynetwork.ca/clinical_resource/pulmonary-embolism-diagnosis/
# Diagnostic imaging for suspected PE in pregnant patients
• Specialist consultation is recommended (radiology, obstetrics)
• It is unclear whether CTPA or ventilation-perfusion (V/Q) scanning is preferable in pregnant patients 5,6 • Radiation dose from CTPA and V/Q scanning may be dependent on the scanners available at a given site
# Appropriate Imaging for Acute Low Back Pain in Adults
Objective: to guide decision making regarding whether imaging is needed in an adult patient presenting to primary care or the emergency department with acute low back pain (defined as low back pain of less than 6 weeks duration).
Rationale: X-ray and CT expose the patient to radiation. The need for imaging must be balanced against the risk of radiation. When in doubt, consult with the relevant specialist locally or through the RACE Line. Imaging of low back pain without red flags is unlikely to change management or improve treatment. 6 -10 Acute (new onset) low back pain usually resolves by 6 weeks. 9,11 Recommendation: Diagnostic imaging (x-ray, CT or MRI) for low back pain of less than 6 weeks duration is not recommended unless one of the following red flags is present: 1,12 • severe or progressive neurologic deficit, e.g., cauda equina • significant acute traumatic event immediately preceding onset of symptoms
•
# How this guideline was developed
The five recommendations in this guideline were agreed to by a provincial expert advisory group on medical imaging in British Columbia. 13 The recommendations were developed by consensus to decrease the rate of inappropriate medical imaging. 13 They are informed by the Canadian Association of Radiologists (CAR) Choosing Wisely Canada Top 5 recommendations. 1 Where available, key references are provided. In situations where there is a lack of rigorous evidence, we provide best clinical opinion to support decision making and high-quality patient care. For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook.
# Appropriate Use of MRI for Hip and Knee Pain in Adults Age ≥ 40
Objective: to guide decision-making regarding whether MRI is needed in a patient ≥ age 40 presenting to primary care or the emergency department with hip or knee pain and osteoarthritis in the subject joint.
# Rationale:
The purpose of an MRI for knee or hip is primarily for surgical planning. In most cases, using MRI does not add useful information for patients with moderate-to-severe OA especially for those with chronic degenerative conditions. A weight-bearing x-ray is recommended to identify OA.
# Recommendation:
In the absence of red flags, acute or chronic hip or knee pain with plain film x-ray evidence of moderate-tosevere osteoarthritis OA does not require MRI. MRI should be reserved for evaluation of possible red flag diagnoses or common conditions treatable with arthroscopy, e.g., meniscus and ligamentous tears.
# MRI Knee and Hip Appropriateness Criteria
For patients 40 years of age and older, one of the following red flags must apply in order to be eligible for MRI knee or hip:
• MRI was recommended on a previous imaging report (please attach report) • Previous knee or hip surgery* • Suspected infection* • Suspected tumour • Osteonecrosis • Fixed locked knee* • Patient had a weight-bearing x-ray within the past 6 months and referring clinician has confirmed mild or no evidence of osteoarthritis in the knee or hip *Knee or hip pain in the settings of previous surgery, suspected infection, or fixed locked knee may be urgent or emergent. Consider discussion with an orthopedic surgeon prior to requesting an MRI. All orthopedic emergencies require immediate consultation.
# Key messages for counselling patients:
• Having an x-ray can inform the appropriate investigation pathway.
• In absence of red flag symptoms, there is no evidence for the utility of MRI in patients with significant OA.
• Most orthopaedic surgeons do not require obligatory MRI prior to consultation. If an MRI is required, the surgeon can request it. • Discuss options for treatment and pain management including a trial of acetaminophen and NSAIDS.
# Patient and caregiver resources MRI for Knee and Hip -when is it appropriate? Information for patients (Vancouver Coastal Health)
The principles of the Guidelines and Protocols Advisory Committee are to:
• encourage appropriate responses to common medical situations • recommend actions that are sufficient and efficient, neither excessive nor deficient • permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: [email protected] Website: www.BCGuidelines.ca
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This guideline is based on scientific evidence current as of the effective date.
The guideline was developed by the Guidelines and Protocols Advisory Committee and adopted by the Medical Services Commission. | None | None |
f0f4806fbcc5a26cf2f49e6d2c8d1a94af419cf7 | cma | None | People living with HIV (PLWH) aged 18 years or older may be vaccinated for COVID-19 if they meet current Public Health criteria for priority groups and if they have no contraindications (see below). These are not live-virus vaccines and are not expected to be associated with more serious adverse events among immunocompromised individuals. However, PLWH who have CD4 counts <200 cells/uL should be counselled regarding the unknown efficacy and safety of the vaccines given that immunocompromised subjects were not included in these vaccine studies.SARS-CoV-2 emerged in late 2019. The virus was named SARS-CoV-2 because of its similarity to the coronavirus responsible for the illness known as severe acute respiratory syndrome (SARS-CoV). This virus (SARS-CoV-2) is responsible for the clinical disease COVID-19. SARS-CoV-2 spike glycoprotein (S), which is a main target for neutralizing antibody, binds to cellular receptors to initiate infection. Disease symptoms may vary; however, respiratory infection is most common, with outcomes including pneumonia and acute respiratory distress syndrome (ARDS), leading to multiorgan failure and death1. Morbidity and mortality is most strongly correlated with age, being highest in those with increasing age above 50 yr, and particularly high above 80 yr. Increased risk is also associated with additional medical comorbidities such as diabetes, hypertension, obesity and cardiovascular disease2, 3.# Health Canada approved COVID-19 vaccines
At this time only the Pfizer-BioNTech (BNT162b2 mRNA) vaccine has been approved for use in Canada. This vaccine consists of a modified messenger RNA (mRNA) molecule enclosed in a lipid nanoparticle. The mRNA encodes the SARS-CoV-2 spike protein. Receipt of two doses of the vaccine has been demonstrated to induce robust antibody and T cell -mediated immune response. In a phase 2/3 clinical trial in 37,706 adults (age 16 years or older) randomized to receive either the active vaccine or a placebo, receipt of the BNT162b2 mRNA vaccine, dosed as two doses 21 days apart, was found to have an efficacy of 95% (95% Credible Interval 90.3, 97.6%) at preventing laboratory-confirmed COVID-19 infection4. Outcomes were similar across age groups. Individuals with underlying immune suppressive conditions or using immune suppressive therapy were excluded from study participation, however PLWH were included in the study (See below).
Other COVID-19 mRNA vaccines under evaluation A phase 3 trial involving 27, 817 individuals randomized to receive vaccine or placebo dosed as two doses one month apart, with a median follow-up of >2 months post second dose, an efficacy of 94.1% (95% CI 89.3%, 96.8%) was demonstrated5. When stratified by age group the efficacy was 95.6% (95% CI: 90.6%, 97.9%) for participants 18 to <65 years, and 86.4% (95% CI: 61.4%, 95.5%) for participants ≥65 years of age.
# mRNA-based COVID-19 vaccines and HIV
Data for use of the mRNA vaccines in PLWH are currently limited. In the BNT162b2 mRNA study, only one individual living with HIV was included in data submitted to the FDA, although supplementary data from the clinical trial indicates 121 individuals were enrolled4, 8. In the mRNA-1273 study, 176 PLWH were included, with data for vaccine efficacy available for 156 of these individuals in the FDA submission5. Only one case of COVID-19 infection was observed in this trial, in a placebo recipient.
PLWH are expected to have similar vaccine responses to those without HIV, although immune response may be sub-optimal in those with immune compromise. Further outcome studies are anticipated to address this concern.
# III PRIORITY POPULATIONS FOR VACCINE COVERAGE IN BRITISH COLUMBIA
At present, priority populations identified for vaccination by the National Advisory Committee on Immunization (NACI) and adapted by BC Public Health include9:
- Long-term care residents and staff It is expected these criteria will be updated based on vaccine availability and as further trial data from the mRNA vaccines, as well as other types of COVID-19 vaccines become available.
# IV CONTRAINDICATIONS TO THE PFIZER-BIONTECH (BNT162B2 MRNA) VACCINE
The Pfizer-BioNTech (BNT162b2 mRNA) vaccine should not be administered if there is:
A history of severe allergic reaction (e.g. anaphylaxis) to a previous dose of the same mRNA vaccine, or A history of severe allergic reaction (e.g. anaphylaxis) to any component of the mRNA vaccine.
V PRECAUTIONS a) Allergic reactions. Those who have a past history of other life-threatening allergic reactions (e.g. anaphylaxis to other vaccines, injectable medicines, foods, venoms, etc) should consult with their physician before receiving the vaccine). Epinephrine should be immediately available for potential anaphylactic reactions for all vaccinees, not just those with an allergic reaction history. b) Pregnancy and breast feeding. Pregnant or breast-feeding individuals should not receive the vaccine due to the absence of evidence for its use in these settings. However, there is no know evidence to indicate toxicity in pregnancy. Pregnancy should be avoided for at least 2 months after the second dose of the vaccine. Pregnant or breast-feeding individuals who are in a priority group for COVID-19 vaccination (e.g. health care workers) may choose to be vaccinated after informed consent and a risk assessment of the possible benefit and risk for the individual and the fetus or infant.
c) Acute febrile illness. Vaccination should be postponed until there is complete resolution of the acute illness. Postponing the vaccination will avoid the confusion associated with the inability to differentiate vaccine-related adverse effects from those caused by the acute febrile illness. It will also reduce the risk of infection transmission (COVID-19 or others) to vaccine health care providers. therapeutic range) may be vaccinated, but a fine needle (23 or 25 gauge) should be used followed by firm pressure applied to the site without rubbing for at least 2 minutes. e) Immune suppression and HIV. Individuals who have impaired immunity due to HIV, immunosuppressive therapies, or other disorders were excluded from the vaccine clinical trials mentioned above. As a result, those with impaired immunity should be counselled regarding the unknown efficacy and safety of the vaccine among those who are immunocompromised. However, since the Pfizer and Moderna vaccines are not live virus vaccines, they are not expected to be associated with an increased risk of adverse events in immunocompromised patients. People living with HIV on HAART with undetectable pVL and CD4 counts above 200/mm3 are likely to be at no additional risk if vaccinated with the Pfizer or Moderna vaccines. On the other hand, the risk is less clear among those with detectable pVL or low CD4 counts below 200/mm3. All such persons may be offered the vaccine after risk/benefit counselling. | People living with HIV (PLWH) aged 18 years or older may be vaccinated for COVID-19 if they meet current Public Health criteria for priority groups and if they have no contraindications (see below). These are not live-virus vaccines and are not expected to be associated with more serious adverse events among immunocompromised individuals. However, PLWH who have CD4 counts <200 cells/uL should be counselled regarding the unknown efficacy and safety of the vaccines given that immunocompromised subjects were not included in these vaccine studies.SARS-CoV-2 emerged in late 2019. The virus was named SARS-CoV-2 because of its similarity to the coronavirus responsible for the illness known as severe acute respiratory syndrome (SARS-CoV). This virus (SARS-CoV-2) is responsible for the clinical disease COVID-19. SARS-CoV-2 spike glycoprotein (S), which is a main target for neutralizing antibody, binds to cellular receptors to initiate infection. Disease symptoms may vary; however, respiratory infection is most common, with outcomes including pneumonia and acute respiratory distress syndrome (ARDS), leading to multiorgan failure and death1. Morbidity and mortality is most strongly correlated with age, being highest in those with increasing age above 50 yr, and particularly high above 80 yr. Increased risk is also associated with additional medical comorbidities such as diabetes, hypertension, obesity and cardiovascular disease2, 3.# Health Canada approved COVID-19 vaccines
At this time only the Pfizer-BioNTech (BNT162b2 mRNA) vaccine has been approved for use in Canada. This vaccine consists of a modified messenger RNA (mRNA) molecule enclosed in a lipid nanoparticle. The mRNA encodes the SARS-CoV-2 spike protein. Receipt of two doses of the vaccine has been demonstrated to induce robust antibody and T cell -mediated immune response. In a phase 2/3 clinical trial in 37,706 adults (age 16 years or older) randomized to receive either the active vaccine or a placebo, receipt of the BNT162b2 mRNA vaccine, dosed as two doses 21 days apart, was found to have an efficacy of 95% (95% Credible Interval [CI] 90.3, 97.6%) at preventing laboratory-confirmed COVID-19 infection4. Outcomes were similar across age groups. Individuals with underlying immune suppressive conditions or using immune suppressive therapy were excluded from study participation, however PLWH were included in the study (See below).
Other COVID-19 mRNA vaccines under evaluation A phase 3 trial involving 27, 817 individuals randomized to receive vaccine or placebo dosed as two doses one month apart, with a median follow-up of >2 months post second dose, an efficacy of 94.1% (95% CI 89.3%, 96.8%) was demonstrated5. When stratified by age group the efficacy was 95.6% (95% CI: 90.6%, 97.9%) for participants 18 to <65 years, and 86.4% (95% CI: 61.4%, 95.5%) for participants ≥65 years of age.
# mRNA-based COVID-19 vaccines and HIV
Data for use of the mRNA vaccines in PLWH are currently limited. In the BNT162b2 mRNA study, only one individual living with HIV was included in data submitted to the FDA, although supplementary data from the clinical trial indicates 121 individuals were enrolled4, 8. In the mRNA-1273 study, 176 PLWH were included, with data for vaccine efficacy available for 156 of these individuals in the FDA submission5. Only one case of COVID-19 infection was observed in this trial, in a placebo recipient.
PLWH are expected to have similar vaccine responses to those without HIV, although immune response may be sub-optimal in those with immune compromise. Further outcome studies are anticipated to address this concern.
# III PRIORITY POPULATIONS FOR VACCINE COVERAGE IN BRITISH COLUMBIA
At present, priority populations identified for vaccination by the National Advisory Committee on Immunization (NACI) and adapted by BC Public Health include9:
• Long-term care residents and staff It is expected these criteria will be updated based on vaccine availability and as further trial data from the mRNA vaccines, as well as other types of COVID-19 vaccines become available.
# IV CONTRAINDICATIONS TO THE PFIZER-BIONTECH (BNT162B2 MRNA) VACCINE
The Pfizer-BioNTech (BNT162b2 mRNA) vaccine should not be administered if there is:
A history of severe allergic reaction (e.g. anaphylaxis) to a previous dose of the same mRNA vaccine, or A history of severe allergic reaction (e.g. anaphylaxis) to any component of the mRNA vaccine.
V PRECAUTIONS a) Allergic reactions. Those who have a past history of other life-threatening allergic reactions (e.g. anaphylaxis to other vaccines, injectable medicines, foods, venoms, etc) should consult with their physician before receiving the vaccine). Epinephrine should be immediately available for potential anaphylactic reactions for all vaccinees, not just those with an allergic reaction history. b) Pregnancy and breast feeding. Pregnant or breast-feeding individuals should not receive the vaccine due to the absence of evidence for its use in these settings. However, there is no know evidence to indicate toxicity in pregnancy. Pregnancy should be avoided for at least 2 months after the second dose of the vaccine. Pregnant or breast-feeding individuals who are in a priority group for COVID-19 vaccination (e.g. health care workers) may choose to be vaccinated after informed consent and a risk assessment of the possible benefit and risk for the individual and the fetus or infant.
c) Acute febrile illness. Vaccination should be postponed until there is complete resolution of the acute illness. Postponing the vaccination will avoid the confusion associated with the inability to differentiate vaccine-related adverse effects from those caused by the acute febrile illness. It will also reduce the risk of infection transmission (COVID-19 or others) to vaccine health care providers. therapeutic range) may be vaccinated, but a fine needle (23 or 25 gauge) should be used followed by firm pressure applied to the site without rubbing for at least 2 minutes. e) Immune suppression and HIV. Individuals who have impaired immunity due to HIV, immunosuppressive therapies, or other disorders were excluded from the vaccine clinical trials mentioned above. As a result, those with impaired immunity should be counselled regarding the unknown efficacy and safety of the vaccine among those who are immunocompromised. However, since the Pfizer and Moderna vaccines are not live virus vaccines, they are not expected to be associated with an increased risk of adverse events in immunocompromised patients. People living with HIV on HAART with undetectable pVL and CD4 counts above 200/mm3 are likely to be at no additional risk if vaccinated with the Pfizer or Moderna vaccines. On the other hand, the risk is less clear among those with detectable pVL or low CD4 counts below 200/mm3. All such persons may be offered the vaccine after risk/benefit counselling. | None | None |
6005051120a83edc643e1a917a53e2b33e98568f | cma | None | # Guideline Resource Unit
Background Currently, patients and families living with advanced cancer experience significant distress when the transition from cancer-directed therapies to ongoing palliative-focused care occurs abruptly. 1 Late or no palliative care use is associated with more aggressive and costly end-of life care. 2 In Alberta, 60% of patients with metastatic gastrointestinal cancers had a late (within 2 months of death) or no palliative care referral. 3,4 This was associated with aggressive care in 50% of those patients, as compared to 25% in those who received early palliative care. Choosing Wisely Canada, 5 the American Society of Clinical Oncology (ASCO), 6,7 and other guidelines all recommend that palliative care should not be delayed or avoided in patients with metastatic cancer who are also pursuing disease-directed treatment. Additionally, the Accreditation Canada standards include a recommendation for "a process for initiating palliative and end of life care" (/). There is extensive evidence that integrating an early palliative approach with cancer care improves outcomes for patients with advanced cancer. This approach has been described by Temel's five elements of an early palliative approach to care, 13 Hannon's elements of early palliative care, 20 and Boucher's best supportive care checklist. 21 Improved methods of tracking and addressing symptoms are associated with less emergency room usage and improved quality of life and survival. 22 Refer to the accompanying Evidence Table for a comprehensive review of the literature.
# Definitions
To create clarity around the concepts in this guideline, the following definitions are provided:
# How is advanced cancer defined?
Advanced cancer is defined as those with distant metastases, late-stage disease, cancer that is life limiting, and/or with prognosis of 6 to 24 months. 6 Advanced colorectal cancer is generally not amenable to surgical resection of all sites of disease, and usually represents an incurable situation. As a small number of advanced colorectal cancer patients may achieve prolonged remission or cure, the potential for cure is not an exclusion for use of this guideline.
# What is the palliative approach to care?
Palliative care is defined by the World Health Organization as "an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual. Palliative care:
- provides relief from pain and other distressing symptoms.
Guideline Resource Unit
- affirms life and regards dying as a normal process.
- intends neither to hasten or postpone death.
- integrates the psychological and spiritual aspects of patient care.
- offers a support system to help patients live as actively as possible until death.
- offers a support system to help the family cope during the patient's illness and in their own bereavement. - uses a team approach to address the needs of patients and their families, including bereavement counselling, if indicated. - will enhance quality of life, and may also positively influence the course of illness.
- is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications." 23 In brief, the palliative approach to care includes whole person care, quality-of-life focus, and mortality acknowledgement. 24 3. When is palliative care defined as "early"?
Early palliative care starts close to the initial diagnosis of advanced cancer, specifically the "Integration of palliative care into standard oncology care: ASCO clinical practice guideline update" suggests within 8 weeks of diagnosis. 6 Palliative care continues as an added layer of support throughout a disease trajectory, including concurrently with cancer modifying therapy (e.g., chemotherapy), or when patients choose to not have cancer modifying therapy, or when there are no cancer modifying options available. Palliative therapy options may include best supportive care, radiation, surgical or systemic therapy.
Figure 1 shows how the early palliative care pathway is intended to be used in conjunction with the CancerControl Alberta Metastatic Colorectal Cancer Guideline and forms a continuum of care with other guidelines and pathways. Guideline Resource Unit 1) CancerControl Alberta guidelines for diagnosis and treatment of early stage colon cancer and early stage rectal cancer. 2) Metastatic colorectal cancer guideline. 3) Integrating an early palliative approach into advanced colorectal cancer care. 4) Acknowledging the prognostic uncertainty and the possibility that either disease progression to death or prolonged remission are potential outcomes when entering each of the pathways. While there are no CancerControl Alberta guidelines for this final box, there are Alberta Health Services (AHS) resources for both end of life care and prolonged remission/survival.
# Who provides the palliative approach to care?
The Canadian Society of Palliative Care Physicians identifies that a palliative approach "specifically acknowledges the capability of health care professionals who do not specialize in palliative care to attend to the needs of people who have advancing serious illnesses, regardless of the sector of care (e.g., home care, residential, hospital) and the stage the patient is at in the disease trajectory." 25 In Alberta, the Palliative and End of Life Care (PEOLC) Alberta Provincial Framework 26 outlines three levels of palliative and end of life care provincially accessible to patients and families/caregivers a :
- Primary Level: All health care providers should have primary palliative care basic core competencies, and this approach to care should be available in all care settings. 26,27 Care is delivered by interdisciplinary primary care providers (e.g., oncology, family practice teams, urban integrated home care), which provide "clinical management and care co-ordination, including assessments, interventions, referrals and triage". Providers manage psychosocial, physical and spiritual aspects of care along with communication (e.g., discussion of prognosis, Advance Care Planning, initial management of symptoms). Clinicians may utilize secondary and tertiary palliative care services through consultative processes to further support patients and their families. - Secondary Level: Secondary palliative care provides specialized palliative care consultation, advice, and services to primary providers, their patients and families. 26 This includes care in various and specialized settings, such as the patient's home, long term care, and hospice. Secondary palliative care providers (e.g., palliative care consultants) give advice and support in an interdisciplinary team setting. Not all patients with palliative care needs will require secondary level of care. - Tertiary Level: Tertiary palliative care is delivered by specialized interdisciplinary palliative care teams for complex cases, symptom management, or psychosocial concerns not responding to interventions. 26,28,29 This level of care is supported by tertiary resources, for example, interventional procedures, diagnostics, in-patient palliative care units and frequent skilled assessments.
a Family/caregiver is defined in this guideline as inclusive of those the patient self-identifies as family (biological and family of choice) and any caregivers (outside of the health system including legally appointed and patient selected).
Guideline Resource Unit
# What is meant by integrated?
There are many definitions of integrated care. 30 In this guideline, integrated care is understood as care that combines a palliative approach to care with disease-specific management, in a collaborative, coordinated and flexible manner dependent on a person's and family/caregiver's range of needs. 27 Guideline Goal
To improve the quality of life for people affected by advanced colorectal cancer by integrating an early palliative care approach into advanced cancer care.
Guideline Questions 1. What triggers should be used to indicate the need to apply an early, integrated palliative approach to care? 2. What are the essential components of an early palliative approach to care? 3. How can these components be integrated into advanced colorectal cancer care?
# Search Strategy
This guideline was developed to outline the integrated early palliative approach to care recommendations for patients with advanced colorectal cancer. It was informed by the results of randomized controlled trials and systematic reviews up to 2018 (see Evidence Table ). It takes into consideration related information presented at local, national, and international meetings, as well as the Alberta Provincial Gastrointestinal and Palliative Care Tumour Teams' interpretation of the data. This guideline was informed from the following clinical practice guidelines:
- Cancer Care Ontario, based on the Gold Standards Framework 31 - Accreditation Canada (/) - British Columbia clinical practice guidelines and protocols (BCGuidelines.ca)
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with advanced colorectal cancer. Different principles may apply to pediatric patients.
# Discussion
This guideline has been summarized in the "Integrating an Early Palliative Approach into Advanced Colorectal Cancer Care Pathway" (www.ahs.ca/GURU under "Gastrointestinal" heading then "Metastatic Colorectal Cancer: Early Palliative Approach" and select "Interactive Care Pathway").
# Guideline Resource Unit
# What are the Essential Components of an Early Palliative Approach to Care?
Several recent analyses of trials integrating oncology and palliative care point towards specific key elements of an early palliative care approach that support whole person care, quality-of-life focus, and mortality acknowledgement. 6,13,21,32 In Alberta, these have been synthesized into four components, as shown in Figure 2. Figure 2. Four essential components of an early palliative approach to care.
# What is Illness Comprehension & Coping?
Illness comprehension is the extent to which the person understands and internalizes the scope of their illness including prognosis, treatment and care options. It is a complex psychological construct that is dynamic and is interrelated with illness adjustment and coping. 33
# What is Advance Care Planning?
Advance care planning (ACP) is a process that supports adults at any age or stage of health in understanding and sharing their personal values, life goals, and preferences regarding future medical care. The goal of ACP is to help ensure that people receive medical care that is consistent with their values, goals and preferences during serious and chronic illness. 34 ACP is not the same as Goals of Care Designation (GCD) determination. In Alberta, the ACP process is aimed at all adults and includes five elements that a person undertakes: Guideline Resource Unit
- Think about: Thinking about their own values related to their health and well-being.
- Learn: Learning about their health or illness conditions, including prognosis and the kind of decisions they might be faced with in the future. - Choose: Choosing an alternate decision maker (ADM) in the event they lose capacity for decision making. - Communicate: Communicating with their ADM, other family or people close to them and with their health care provider about who their chosen ADM is and the kind of wishes and values they would like to guide their care in the event they lose capacity. - Document: Documenting in a Personal Directive to legally appoint their agent (ADM) for personal decision making in the event they lose capacity. The Personal Directive also allows a person to document those wishes, beliefs and values that they want the agent to understand when making decisions about their personal matters.
# What is Coordination of Care?
The definition is malleable based on perspective. The Agency for Healthcare Research and Quality uses the following working definition: "care coordination is the deliberate organization of patient care activities between two or more participants (including the patient) involved in a patient's care to facilitate the appropriate delivery of health care services. Organizing care involves the marshalling of personnel and other resources needed to carry out all required patient care activities and is often managed by the exchange of information among participants responsible for different aspects of care." 35 The five key elements comprising care coordination are: a) numerous health care providers are involved; b) providers are dependent upon each other to carry out separate activities in a patient's care; c) each provider needs adequate knowledge about their own and others' roles, and available resources; d) providers rely on exchange of information; and e) integration of care activities has the goal of facilitating appropriate delivery of health care services. As complexity increases, the patient's ability to coordinate care themselves decreases and the need for participatory provider coordination increases.
# Recommendations and Implementation Strategy
Step 1: SCREENING Clinicians caring for patients with advanced cancer should use the following opportunities to screen for those who may benefit from an early, integrated palliative approach to care:
- During assessment for symptom burden (physical and psychosocial) 2. With transition points in care or indication of advanced disease trajectory 3. When patient or family/caregiver asks for palliative or supportive care 4. Clinician judgement
# Guideline Resource Unit
All advanced colorectal cancer patients should be screened to identify those who may benefit from an early palliative approach to care on a systematic basis. 36 Opportunities for screening include:
# Symptom burden and patient concerns:
- Review symptom burden in combination with the Edmonton Symptom Assessment System Revised (ESAS-r) scores. 37,38 A score ≥ 7/10 on the ESAS-r is considered severe. 36,39,40 ESAS-r data are available for Alberta patients from the "Putting Patients First" (PPF) form (Appendix 1). - Utilize the CancerControl Alberta Patient Reported Outcome (PRO) dashboards proactively.
The PRO Clinic List dashboard shows the symptom burden of all patients booked into a clinic. It highlights which patients had high symptom burden on their last visit, for review in the current visit. The Clinic List has a direct link to each patient's individual PRO trended dashboard where the clinician can view each patient's symptom trajectory (PPF data from ESAS-r and Canadian Problem Checklist (CPC) responses) over the last 6 visits in more detail (Appendix 2). This is an Alberta specific method in cancer centres entering PPF data into the electronic medical record.
# Monitoring for transition points in care or indicators of advanced disease trajectory:
- Progression on current therapy.
- When disease is recognized as incurable.
- When on second-line systemic therapy. 41,42 - There are no further disease-modifying treatments available.
- When unable to receive first-line systemic therapy, or patient declines further diseasemodifying treatment. - There is a decrease in performance status or functional decline (e.g., the patient is confined to bed or chair more than 50% of waking hours). (ECOG ≥ 3, Appendix 3) - When the clinician estimates the patient's prognosis as 12 months or less. One way this can be achieved is by clinicians asking themselves the Surprise Question: "Would I be surprised if the patient were to die in the next 12 months?" An answer of no indicates a higher likelihood of death within the next year. 31,43,44 - When a patient with incurable cancer is discharged from the cancer centre for ongoing care in the community.
# When patient or family/caregiver requests palliative care services or information.
1.4 When clinician judgement determines the patient or family/caregiver would benefit from an early palliative approach to care:
- Patient and/or family/caregiver are having (or anticipating) difficulties with illness understanding, including naming the diagnosis, illness history, symptoms, causality and prognosis, ACP, mortality distress. 45 Patients who screen positive for one or more of these screening methods meet criteria for use of an early integrated palliative approach to care. Patients who screen negative should be rescreened regularly.
Once screened and meeting criteria, routinely and systematically identify the patient's unmet needs and functional status. This is a critical step to determine the most appropriate supportive care interventions and service type needed. Evidence points to the need to use an assessment tool systematically, in order to not miss suffering. 22,46 Assessment tools allow identification of the specific issues of concern to the patient and family/caregiver. Randomized controlled trials (RCTs) demonstrate that intentional monitoring and addressing of symptoms and problems as identified by patients is helpful in maintaining quality of life and possibly associated with increased survival. 13,22,46,47 There is limited high grade evidence to guide which exact assessment tools to use. 48 We recommend the use of CancerControl Alberta's standardized tools to assess patient needs (Table 1). 49 The frequency of reassessment of need varies between the RCTs, but all agree that "routine" monitoring is needed. Thus, we recommend assessment of patient needs at most clinical encounters. Note that clinical encounters can be initiated by patients (e.g., patient portal entered symptom scores or phone calls to clinics regarding worsening symptoms). Step 2: IDENTIFY PATIENT NEEDS Once patients have been screened and meet criteria, clinicians should identify unmet patient needs. This can be guided by the four essential components of an early palliative approach to care (Figure 2) and corresponding assessment tools (Table 1). Patient needs should be reassessed at regular intervals.
Guideline Resource Unit
# Putting Patients First (PPF)
The PPF tool includes the CPC and the ESAS-r and has been adopted as a provincial standard in Alberta. 49 The CPC was developed by the Screening for Distress Working Group of the Canadian Partnership Against Cancer; 50 it is a comprehensive standardized tool for assessment that has been validated for screening for distress and encapsulates domains relevant to many of the early palliative care intervention studies. 13 Assessment domains include: emotional, social/ family/ spiritual, practical, physical, mobility, nutritional, informational and the option to include open ended "other" concerns.
The ESAS-r is an internationally validated tool to assess patient symptoms. 37,38
# Serious Illness Care Program (SICP)
Beyond the CPC, there are more in-depth methods to assess illness understanding and coping. One of these is the SICP (Appendix 4), which also elicits patient values as a part of ACP. 51 Refer to section 3.3 for more detail.
# Eastern Cooperative Oncology Group (ECOG) and Palliative Performance Scale (PPS)
There are many ways to assess functional status and needs. 52 The ECOG (Appendix 3) functional scale can indicate declining function that might be associated with increasing patient needs. The ECOG score might suggest both the level (e.g. ambulatory, home care, supportive living) and type of supports (e.g., mobility aids, hospital bed, toileting assistance) needed by the patient. 53 The PPS is the standard tool used in palliative care to measure performance status using five observable parameters: ambulation, ability to do activities, self-care, food/fluid intake, and consciousness level (Appendix 4). 54 Similar to ECOG, the PPS can indicate the need for additional support including hospice care.
# Advance Care Planning/Goals of Care Designation (ACP/GCD) Tracking Record
Existing literature has several methods for assessing the degree to which a patient has engaged in prior ACP or their preferences related to decision-making. 34 The PPF tool includes the items "Would you like information on Goals of Care or advance care planning (green sleeve)?", "Understanding my illness and/or treatment", "Talking with my health care team" and "Making treatment decisions", which allow patients to indicate their self-perceived need for more information related to ACP. In Alberta, the ACP/GCD Tracking Record also provides prompts for clinicians, with five suggested questions to assess prior ACP activities, and is the document in use provincially to record patient needs related to ACP (Appendix 5). The SICP also guides clinicians to elicit a patient's informational needs related to their prognosis, "How much information about what is likely to come with your illness would you like from me?" 51
# Coordination of Care
Patients with cancer are at high risk of receiving poorly coordinated care in multiple settings from many providers, and lack of coordination is associated with poor symptom control, medical errors, and higher costs, 2,55 Improvement in cancer care coordination leads to better patient experience and higher quality of end of life care. 55,56 Many factors impact patient complexity, including personal factors (e.g., social determinants of health), interactions with providers (e.g., no family physician), Guideline Resource Unit system complexities (e.g., rural location), societal influences, and changes over time. 57 Care coordination needs tend to increase with complexity. It is important to assess care coordination needs (e.g., patient and family/caregiver factors, number of providers, complexity of treatment plan), however there is limited evidence to recommend one assessment tool over another. 58 Practical concerns identified on the PPF may indicate higher needs around care coordination for issues such as financial concerns, difficulty getting to and from appointments, and language barriers.
Primary providers should initiate management of unmet needs. 26 Defining which care provider is primarily responsible and whether they refer to additional care providers for support and interventions can be dependent on both the referring clinicians' own competencies in managing the issue and on the locally available consultation services.
# Illness Comprehension and Coping
Evidence has shown that addressing a patient's understanding of their illness, how they are coping and how those close to them are coping, is associated with improved patient outcomes. 12,32,45,51,59,60 In addition to consulting secondary palliative care providers, Table 2 shows some other methods that can be used to support patients and family/caregivers. Step 3: PRIMARY PROVIDER MANAGEMENT OF UNMET NEEDS Primary palliative care management of unmet patient needs is strongly recommended using the four essential components of an early palliative approach to care as a guide:
- Illness comprehension and coping 2. Management of symptoms by providers and patients' self-management 3. Advance care planning and patient's preferred method of decision making 4. Coordination of care Patient preference, available time and clinician skills may be factors in the extent to which exploring patient illness understanding and coping occurs during clinical encounters, and clinician judgment is required about whether and when to refer for additional formal coping supports. This guideline encourages primary providers to explore and identify techniques to use in their practice.
# Management of Symptoms by Providers and Patients
Providers: Management of symptoms is a cornerstone of palliative care. 23 Symptoms may be managed pharmacologically (e.g. steroids, opioids), non-pharmacologically (e.g., behaviour modification, meditation), and/or by physical interventions (e.g., stents, palliative surgery, radiation). Conversations Cancer Consult Recording App with the aim of improving their recall of key conversations and enhancing their self-management and ease of decision-making. More information is at www.ahs.ca and search "My Care Conversations Cancer Consult Recording App" or visit: .
# ACP and Patient's Preferred Method of Decision Making
By preparing patients and those who may have to make in-the-moment decisions on their behalf, ACP is associated with a number of benefits. 64 Choosing Wisely Canada recommends "don't delay advance care planning conversations". The AHS procedure on ACP and GCD states, "all adults who have capacity should be given the opportunity to participate in ACP as a part of routine care, started early in a longitudinal relationship with a health care provider and revisited when the health or wishes of an adult changes". 65,66 Encourage patients to have conversations about ACP throughout cancer treatment. Clinicians, within their scope of practice, can be instrumental in:
- Encouraging reflection on and expression of personal values, beliefs and preferences related to personal goals, health care and their preferred method of decision making (e.g., shared decision making, supported decision making with family/caregiver, self-determined, physiciandirected).
- Sharing prognostic information, tailored to the patient's readiness and preferences around illness understanding. - Supporting the patient in selecting an appropriate ADM.
- Encouraging the patient to communicate with their ADM, family/caregivers, other health care team members about their values, beliefs and preferences and who they have selected as ADM.
- Encouraging the patient to create a Personal Directive.
- Documenting ACP conversations on the ACP/GCD Tracking Record.
Resources: Patient and health care provider resources are available at www.conversationsmatter.ca.
The SICP was developed in a cancer outpatient clinical context to provide a systematic approach to increasing meaningful conversations between seriously ill people and their clinicians about their values and priorities. 51 It has been adapted for use in family physician clinics and other settings 67 and is in an early phase of adoption within AHS. This is a helpful bridging process between ACP and GCD determination, as shown in Figure 3. 65,66 In Alberta, Goals of Care Designations (GCD) are medical orders that describe the general and sometimes specific focus of a patient's desired care approach, harmonized with what is medically appropriate to provide. They also create awareness of a person's care choices in relation to the care sector they are living in or being cared for. They ideally arise from fully informed conversations between patients (or their alternate decision-maker) and health care providers. The use of GCD is described in an AHS level 1 provincial policy and procedure. GCD should be determined when clinically indicated and should be reviewed at the request of the patient or ADM, after transfers, or if there is a significant change in the patient's condition or circumstances.
# Goals of Care Designations:
GCD are a useful component of an early palliative approach to care because they are a mechanism that "helps make our system more patient-centred, improves continuity of care, supports care quality and safety for patients, reduces unwanted transfers and procedures, reduces decisional burden and moral distress for families and caregivers, and helps prevent inappropriate consumption of resources." Per AHS, "once a Goals of Care Designation conversation has been held, and if clinically indicated, a Goals of Care Designation order shall be created and documented in the Advance Care Planning/Goals of Care Designation Tracking Record." By documenting in a common place, follow up can be shared between the care team. The Green Sleeve is a plastic pocket used in Alberta as the specific resource to contain and transfer ACP documentation (e.g., GCD order, Advance Care Planning/Goals of Care Designation Tracking Record, Personal Directive copies, Guardianship Orders).
# Guideline Resource Unit
# Coordination of Care
Coordination of care is usually the responsibility of all health care providers. The important coordination activities are: 35 - Establish accountability or negotiate responsibility - Communicate - Facilitate transitions - Create a proactive plan of care - Support self-management goals - Link to community resources - Align resources with patient and population needs - Monitor, follow up, and respond to change In certain zones this coordination might be achieved through a patient navigator and/or home care case manager. These coordinators are particularly valued by rural zone patients. 63 Advanced Cancer Resources: To assist health care providers in coordination activities, compilations of advanced cancer resources are available. These Zone-specific tips are being made in collaboration with local palliative programs as "Local Tips for Providers":
- Calgary (www.ahs.ca/GURU > Guidelines > Gastrointestinal > Metastatic Colorectal Cancer:
Early Palliative Approach > "Local Tips For Providers"). Includes information on caregiver support and community based resources, and these provincially funded programs Referral Based Services for Advanced Cancer Care: Lack of provider role clarity and variation in service availability, along with variation in patient need (i.e. functional and ambulatory status), can make it challenging to identify when and which specialist palliative care or other supportive care services are needed. Relevant supportive services that may assist in fulfilling an early palliative approach to care include: integrated home care, EMS Assess Treat and Refer program, community paramedic program, psychosocial oncology, and rehabilitation oncology. See "Referral Based Services for Advanced Cancer Care" document for provider types available, their description and referral criteria. Note that the Alberta Referral Directory (ARD) is the centralized location for referral information. More resources for improving referrals and access to services can be found at "Access Improvement" ().
Specialist Palliative Care Services: Specialist palliative care services provide secondary or tertiary advice or care when needs of the patient are complex and beyond the scope of the primary care team. 25 The palliative consultant can also support the primary care team in providing a primary palliative approach to care. Quality indicators suggest that palliative-focused home care nursing support is an important element in improving quality of care and reducing inappropriate use of resources. 3,68,69 When providers are making referrals to palliative care services, clarification should be provided to the patient explaining that palliative care is an added layer of support that can be used alongside cancer treatments. 70 Patient friendly palliative care descriptions are available in the CancerControl Alberta patient education guides (see Section 3.2). Some examples of when referral to specialist palliative care would be appropriate are:
- severe symptoms (≥ 7 ESAS-r). Note clinician judgement is required as patients with severe psychosocial-related symptoms (e.g., depression and anxiety) might instead need a referral to psychosocial oncology providers. - palliative care unit or hospice referral.
- assisting with conflict resolution or health care decision making.
- clarification of goals of treatment or management plan.
# Communication and Documentation:
Standardized communication increases consistency, minimizes duplication and improves teamwork while promoting patient safety. All providers involved in the patient's care should send updates to other providers when there are changes in the patient's condition, needs, or status. Important elements include patient's cancer illness understanding, prognosis, and details of ACP and GCD (Green Sleeve). Effective communication reduces the need for patients and families to repeat information. Patients and families need information to prepare for and improve care transitions; this may include written information or instructions, action plans, goals, signs or symptoms of declining health status, and contact information for the team. Family physicians also want to be kept informed and involved. 71
# Guideline Resource Unit
The following communication tools should be used to enable standardized communication:
- Shared care letters: At transition points in care, communication between the cancer centre and family physician should be emphasized by use of a "Shared Care" letter. The physician version of the letter outlines collaborative care where primary palliative care and symptom management can be shared between providers. It indicates cancer modifying care to be managed by medical oncology and non-cancer related care to be managed by family physician. This letter is initiated when second-line therapy is ordered or patient is determined to have advanced disease. The patient version of the letter should be given to the patient during the clinic visit. - Green Sleeve: The Green Sleeve is a plastic pocket used in Alberta as the specific resource to contain and transfer ACP documentation (e.g., GCD order, ACP/GCD Tracking Record, Personal Directive copies, Guardianship Orders).
At any point after a cancer diagnosis and often as cancer progresses, patients and their families/ caregivers may have questions, worries or preferences about dying, death or preparation for after death. Clinicians are a valued source of information or guidance about end of life topics and can help ensure that key activities, like preparing a will or addressing guardianship issues for dependents, have been addressed. Topics that people may want to inquire about include:
- How to recognize when death is near and what dying may look like, including modes of death e.g. "natural death", palliative sedation for intractable symptom issues in final hours or days, death during resuscitation or medical management in hospital, or MAID. - How to proactively anticipate and manage changing needs (e.g., if a patient is likely to lose the ability to take oral medication or become bed bound). - Possible care locations before death (home, care facility, hospice, hospital).
Managing existential distress, death anxiety and changes in personal role or close relationships may involve the supports outlined in section 3.1; other topics in end of life care are listed below.
# End of Life Planning
- Review ACP discussions and patient preferences for care at end of life. - Determine the most appropriate GCD that reflects the person's values and clinical context.
- Revisit caregiver supports.
- Ensure patient is on Alberta Health Palliative Coverage Program (also known as "Palliative Blue Cross" or "Palliative Drug Coverage"). - Discuss possible and preferred location(s) of care towards end of life (e.g., home, hospice, hospital, or other facility). o Develop a plan for expected death in the community if patient would like to remain at home: AHS expected death in the home toolkit can be found on Insite or at Resources that help prepare for death can be found on Insite by searching "Care before death" or "What to expect when a loved one is dying" o For information on "Care after death" in acute care visit
# Estate and Funeral Planning
Remind patients and their family/caregivers to begin this planning early on. For example, a will and financial enduring power of attorney are part of estate planning. Assist them to connect to the appropriate resources to fulfill this planning, such as social work or their lawyer.
# Hospice Access
Hospice care is a specialized service available in certain locations that provides 24/7 facility-based palliative care to those who are approaching end of life and whose needs cannot be met at home/other location. There are highly specific criteria for referral to hospice and access is determined by secondary palliative care clinicians. See the "Referral Based Services for Advanced Cancer Care" document and/or talk to your local palliative care clinician about whether hospice may be appropriate for a specific patient and family/caregiver.
# Medical Assistance in Dying (MAID)
AHS has developed the MAID policy to guide medical assistance in dying services. This policy is posted on the AHS Medical Assistance in Dying website and available from the Care Coordination Service upon request. A physician FAQ sheet is available.
# Grief and Bereavement
Ask patients about their emotional supports and let patients and caregivers know that grief and bereavement resources are available both before and after death. Most services are accessed by self-referral and clinicians can help by providing the access information. See "Referral Based Services for Advanced Cancer Care" document for grief and bereavement resources.
Guideline Resource Unit
# Clinic List Report:
This report can be generated for any clinic in CancerControl Alberta (CCA) based on location, date and provider, and is intended to support clinic preparation or team huddle prior to the start of clinic.
It pulls all information from ARIA (CancerControl Alberta's EMR) about the clinic including notes entered by clinicians regarding a patient's next visit, as well as the symptom burden the patient reported on their last PRO symptom screen (Putting Patients First form), along with when that screen was filled out, and other relevant information re: goals of care and % weight change in the last 3 months.
Clinicians can easily click on the patient name or ACB# to link to each individual's Trended PRO Dashboard.
This report can be generated for any patient in CancerControl Alberta (CCA) who has completed a Putting Patients First (PPF) form and the staff have entered it as part of the clinical documentation. It is intended to support both the patient and the provider team to visualize the patient's symptom burden over time and to highlight areas of high symptom burden. It also links clinical response and referrals made to each clinical visit/PRO report.
It pulls all info from ARIA (CancerControl Alberta's EMR) entered by clinicians regarding all previous visits. Patients get a "patient friendly" simplified version when they check in for their visit as a reference for when they fill in today's "Symptom Tracking Report" (which we refer to as the Putting Patient's First form).
For access to this report, contact [email protected].
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Gastrointestinal and Palliative Care Tumour Teams. Members of the Alberta Provincial Gastrointestinal and Palliative Care Tumour Teams include: medical oncologists, radiation oncologists, palliative care consultants, surgical oncologists, family physicians, allied health professionals, nurse practitioners, registered nurses, and patient and family advisors. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Gastrointestinal and Palliative Care Tumour Teams and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in October, 2018 and underwent revisions in July 2019.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations | # Guideline Resource Unit
Background Currently, patients and families living with advanced cancer experience significant distress when the transition from cancer-directed therapies to ongoing palliative-focused care occurs abruptly. 1 Late or no palliative care use is associated with more aggressive and costly end-of life care. 2 In Alberta, 60% of patients with metastatic gastrointestinal cancers had a late (within 2 months of death) or no palliative care referral. 3,4 This was associated with aggressive care in 50% of those patients, as compared to 25% in those who received early palliative care. Choosing Wisely Canada, 5 the American Society of Clinical Oncology (ASCO), 6,7 and other guidelines [8][9][10][11] all recommend that palliative care should not be delayed or avoided in patients with metastatic cancer who are also pursuing disease-directed treatment. Additionally, the Accreditation Canada standards include a recommendation for "a process for initiating palliative and end of life care" (https://accreditation.ca/standards/). There is extensive evidence that integrating an early palliative approach with cancer care improves outcomes for patients with advanced cancer. [12][13][14][15][16][17][18][19] This approach has been described by Temel's five elements of an early palliative approach to care, 13 Hannon's elements of early palliative care, 20 and Boucher's best supportive care checklist. 21 Improved methods of tracking and addressing symptoms are associated with less emergency room usage and improved quality of life and survival. 22 Refer to the accompanying Evidence Table for a comprehensive review of the literature.
# Definitions
To create clarity around the concepts in this guideline, the following definitions are provided:
# How is advanced cancer defined?
Advanced cancer is defined as those with distant metastases, late-stage disease, cancer that is life limiting, and/or with prognosis of 6 to 24 months. 6 Advanced colorectal cancer is generally not amenable to surgical resection of all sites of disease, and usually represents an incurable situation. As a small number of advanced colorectal cancer patients may achieve prolonged remission or cure, the potential for cure is not an exclusion for use of this guideline.
# What is the palliative approach to care?
Palliative care is defined by the World Health Organization as "an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual. Palliative care:
• provides relief from pain and other distressing symptoms.
Guideline Resource Unit
• affirms life and regards dying as a normal process.
• intends neither to hasten or postpone death.
• integrates the psychological and spiritual aspects of patient care.
• offers a support system to help patients live as actively as possible until death.
• offers a support system to help the family cope during the patient's illness and in their own bereavement. • uses a team approach to address the needs of patients and their families, including bereavement counselling, if indicated. • will enhance quality of life, and may also positively influence the course of illness.
• is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications." 23 In brief, the palliative approach to care includes whole person care, quality-of-life focus, and mortality acknowledgement. 24 3. When is palliative care defined as "early"?
Early palliative care starts close to the initial diagnosis of advanced cancer, specifically the "Integration of palliative care into standard oncology care: ASCO clinical practice guideline update" suggests within 8 weeks of diagnosis. 6 Palliative care continues as an added layer of support throughout a disease trajectory, including concurrently with cancer modifying therapy (e.g., chemotherapy), or when patients choose to not have cancer modifying therapy, or when there are no cancer modifying options available. Palliative therapy options may include best supportive care, radiation, surgical or systemic therapy.
Figure 1 shows how the early palliative care pathway is intended to be used in conjunction with the CancerControl Alberta Metastatic Colorectal Cancer Guideline and forms a continuum of care with other guidelines and pathways. Guideline Resource Unit 1) CancerControl Alberta guidelines for diagnosis and treatment of early stage colon cancer and early stage rectal cancer. 2) Metastatic colorectal cancer guideline. 3) Integrating an early palliative approach into advanced colorectal cancer care. 4) Acknowledging the prognostic uncertainty and the possibility that either disease progression to death or prolonged remission are potential outcomes when entering each of the pathways. While there are no CancerControl Alberta guidelines for this final box, there are Alberta Health Services (AHS) resources for both end of life care and prolonged remission/survival.
# Who provides the palliative approach to care?
The Canadian Society of Palliative Care Physicians identifies that a palliative approach "specifically acknowledges the capability of health care professionals who do not specialize in palliative care to attend to the needs of people who have advancing serious illnesses, regardless of the sector of care (e.g., home care, residential, hospital) and the stage the patient is at in the disease trajectory." 25 In Alberta, the Palliative and End of Life Care (PEOLC) Alberta Provincial Framework 26 outlines three levels of palliative and end of life care provincially accessible to patients and families/caregivers a :
• Primary Level: All health care providers should have primary palliative care basic core competencies, and this approach to care should be available in all care settings. 26,27 Care is delivered by interdisciplinary primary care providers (e.g., oncology, family practice teams, urban integrated home care), which provide "clinical management and care co-ordination, including assessments, interventions, referrals and triage". Providers manage psychosocial, physical and spiritual aspects of care along with communication (e.g., discussion of prognosis, Advance Care Planning, initial management of symptoms). Clinicians may utilize secondary and tertiary palliative care services through consultative processes to further support patients and their families. • Secondary Level: Secondary palliative care provides specialized palliative care consultation, advice, and services to primary providers, their patients and families. 26 This includes care in various and specialized settings, such as the patient's home, long term care, and hospice. Secondary palliative care providers (e.g., palliative care consultants) give advice and support in an interdisciplinary team setting. Not all patients with palliative care needs will require secondary level of care. • Tertiary Level: Tertiary palliative care is delivered by specialized interdisciplinary palliative care teams for complex cases, symptom management, or psychosocial concerns not responding to interventions. 26,28,29 This level of care is supported by tertiary resources, for example, interventional procedures, diagnostics, in-patient palliative care units and frequent skilled assessments.
a Family/caregiver is defined in this guideline as inclusive of those the patient self-identifies as family (biological and family of choice) and any caregivers (outside of the health system including legally appointed and patient selected).
Guideline Resource Unit
# What is meant by integrated?
There are many definitions of integrated care. 30 In this guideline, integrated care is understood as care that combines a palliative approach to care with disease-specific management, in a collaborative, coordinated and flexible manner dependent on a person's and family/caregiver's range of needs. 27 Guideline Goal
To improve the quality of life for people affected by advanced colorectal cancer by integrating an early palliative care approach into advanced cancer care.
Guideline Questions 1. What triggers should be used to indicate the need to apply an early, integrated palliative approach to care? 2. What are the essential components of an early palliative approach to care? 3. How can these components be integrated into advanced colorectal cancer care?
# Search Strategy
This guideline was developed to outline the integrated early palliative approach to care recommendations for patients with advanced colorectal cancer. It was informed by the results of randomized controlled trials and systematic reviews up to 2018 (see Evidence Table ). It takes into consideration related information presented at local, national, and international meetings, as well as the Alberta Provincial Gastrointestinal and Palliative Care Tumour Teams' interpretation of the data. This guideline was informed from the following clinical practice guidelines:
• Cancer Care Ontario, based on the Gold Standards Framework 31 • Accreditation Canada (https://accreditation.ca/standards/) • British Columbia clinical practice guidelines and protocols (BCGuidelines.ca)
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with advanced colorectal cancer. Different principles may apply to pediatric patients.
# Discussion
This guideline has been summarized in the "Integrating an Early Palliative Approach into Advanced Colorectal Cancer Care Pathway" (www.ahs.ca/GURU under "Gastrointestinal" heading then "Metastatic Colorectal Cancer: Early Palliative Approach" and select "Interactive Care Pathway").
# Guideline Resource Unit
# What are the Essential Components of an Early Palliative Approach to Care?
Several recent analyses of trials integrating oncology and palliative care point towards specific key elements of an early palliative care approach that support whole person care, quality-of-life focus, and mortality acknowledgement. 6,13,21,32 In Alberta, these have been synthesized into four components, as shown in Figure 2. Figure 2. Four essential components of an early palliative approach to care.
# What is Illness Comprehension & Coping?
Illness comprehension is the extent to which the person understands and internalizes the scope of their illness including prognosis, treatment and care options. It is a complex psychological construct that is dynamic and is interrelated with illness adjustment and coping. 33
# What is Advance Care Planning?
Advance care planning (ACP) is a process that supports adults at any age or stage of health in understanding and sharing their personal values, life goals, and preferences regarding future medical care. The goal of ACP is to help ensure that people receive medical care that is consistent with their values, goals and preferences during serious and chronic illness. 34 ACP is not the same as Goals of Care Designation (GCD) determination. In Alberta, the ACP process is aimed at all adults and includes five elements that a person undertakes: Guideline Resource Unit
• Think about: Thinking about their own values related to their health and well-being.
• Learn: Learning about their health or illness conditions, including prognosis and the kind of decisions they might be faced with in the future. • Choose: Choosing an alternate decision maker (ADM) in the event they lose capacity for decision making. • Communicate: Communicating with their ADM, other family or people close to them and with their health care provider about who their chosen ADM is and the kind of wishes and values they would like to guide their care in the event they lose capacity. • Document: Documenting in a Personal Directive to legally appoint their agent (ADM) for personal decision making in the event they lose capacity. The Personal Directive also allows a person to document those wishes, beliefs and values that they want the agent to understand when making decisions about their personal matters.
# What is Coordination of Care?
The definition is malleable based on perspective. The Agency for Healthcare Research and Quality uses the following working definition: "care coordination is the deliberate organization of patient care activities between two or more participants (including the patient) involved in a patient's care to facilitate the appropriate delivery of health care services. Organizing care involves the marshalling of personnel and other resources needed to carry out all required patient care activities and is often managed by the exchange of information among participants responsible for different aspects of care." 35 The five key elements comprising care coordination are: a) numerous health care providers are involved; b) providers are dependent upon each other to carry out separate activities in a patient's care; c) each provider needs adequate knowledge about their own and others' roles, and available resources; d) providers rely on exchange of information; and e) integration of care activities has the goal of facilitating appropriate delivery of health care services. As complexity increases, the patient's ability to coordinate care themselves decreases and the need for participatory provider coordination increases.
# Recommendations and Implementation Strategy
Step 1: SCREENING Clinicians caring for patients with advanced cancer should use the following opportunities to screen for those who may benefit from an early, integrated palliative approach to care:
1. During assessment for symptom burden (physical and psychosocial) 2. With transition points in care or indication of advanced disease trajectory 3. When patient or family/caregiver asks for palliative or supportive care 4. Clinician judgement
# Guideline Resource Unit
All advanced colorectal cancer patients should be screened to identify those who may benefit from an early palliative approach to care on a systematic basis. 36 Opportunities for screening include:
# Symptom burden and patient concerns:
• Review symptom burden in combination with the Edmonton Symptom Assessment System Revised (ESAS-r) scores. 37,38 A score ≥ 7/10 on the ESAS-r is considered severe. 36,39,40 ESAS-r data are available for Alberta patients from the "Putting Patients First" (PPF) form (Appendix 1). • Utilize the CancerControl Alberta Patient Reported Outcome (PRO) dashboards proactively.
The PRO Clinic List dashboard shows the symptom burden of all patients booked into a clinic. It highlights which patients had high symptom burden on their last visit, for review in the current visit. The Clinic List has a direct link to each patient's individual PRO trended dashboard where the clinician can view each patient's symptom trajectory (PPF data from ESAS-r and Canadian Problem Checklist (CPC) responses) over the last 6 visits in more detail (Appendix 2). This is an Alberta specific method in cancer centres entering PPF data into the electronic medical record.
# Monitoring for transition points in care or indicators of advanced disease trajectory:
• Progression on current therapy.
• When disease is recognized as incurable.
• When on second-line systemic therapy. 41,42 • There are no further disease-modifying treatments available.
• When unable to receive first-line systemic therapy, or patient declines further diseasemodifying treatment. • There is a decrease in performance status or functional decline (e.g., the patient is confined to bed or chair more than 50% of waking hours). (ECOG ≥ 3, Appendix 3) • When the clinician estimates the patient's prognosis as 12 months or less. One way this can be achieved is by clinicians asking themselves the Surprise Question: "Would I be surprised if the patient were to die in the next 12 months?" An answer of no indicates a higher likelihood of death within the next year. 31,43,44 • When a patient with incurable cancer is discharged from the cancer centre for ongoing care in the community.
# When patient or family/caregiver requests palliative care services or information.
1.4 When clinician judgement determines the patient or family/caregiver would benefit from an early palliative approach to care:
• Patient and/or family/caregiver are having (or anticipating) difficulties with illness understanding, including naming the diagnosis, illness history, symptoms, causality and prognosis, ACP, mortality distress. 45 Patients who screen positive for one or more of these screening methods meet criteria for use of an early integrated palliative approach to care. Patients who screen negative should be rescreened regularly.
Once screened and meeting criteria, routinely and systematically identify the patient's unmet needs and functional status. This is a critical step to determine the most appropriate supportive care interventions and service type needed. Evidence points to the need to use an assessment tool systematically, in order to not miss suffering. 22,46 Assessment tools allow identification of the specific issues of concern to the patient and family/caregiver. Randomized controlled trials (RCTs) demonstrate that intentional monitoring and addressing of symptoms and problems as identified by patients is helpful in maintaining quality of life and possibly associated with increased survival. 13,22,46,47 There is limited high grade evidence to guide which exact assessment tools to use. 48 We recommend the use of CancerControl Alberta's standardized tools to assess patient needs (Table 1). 49 The frequency of reassessment of need varies between the RCTs, but all agree that "routine" monitoring is needed. Thus, we recommend assessment of patient needs at most clinical encounters. Note that clinical encounters can be initiated by patients (e.g., patient portal entered symptom scores or phone calls to clinics regarding worsening symptoms). Step 2: IDENTIFY PATIENT NEEDS Once patients have been screened and meet criteria, clinicians should identify unmet patient needs. This can be guided by the four essential components of an early palliative approach to care (Figure 2) and corresponding assessment tools (Table 1). Patient needs should be reassessed at regular intervals.
Guideline Resource Unit
# Putting Patients First (PPF)
The PPF tool includes the CPC and the ESAS-r and has been adopted as a provincial standard in Alberta. 49 The CPC was developed by the Screening for Distress Working Group of the Canadian Partnership Against Cancer; 50 it is a comprehensive standardized tool for assessment that has been validated for screening for distress and encapsulates domains relevant to many of the early palliative care intervention studies. 13 Assessment domains include: emotional, social/ family/ spiritual, practical, physical, mobility, nutritional, informational and the option to include open ended "other" concerns.
The ESAS-r is an internationally validated tool to assess patient symptoms. 37,38
# Serious Illness Care Program (SICP)
Beyond the CPC, there are more in-depth methods to assess illness understanding and coping. One of these is the SICP (Appendix 4), which also elicits patient values as a part of ACP. 51 Refer to section 3.3 for more detail.
# Eastern Cooperative Oncology Group (ECOG) and Palliative Performance Scale (PPS)
There are many ways to assess functional status and needs. 52 The ECOG (Appendix 3) functional scale can indicate declining function that might be associated with increasing patient needs. The ECOG score might suggest both the level (e.g. ambulatory, home care, supportive living) and type of supports (e.g., mobility aids, hospital bed, toileting assistance) needed by the patient. 53 The PPS is the standard tool used in palliative care to measure performance status using five observable parameters: ambulation, ability to do activities, self-care, food/fluid intake, and consciousness level (Appendix 4). 54 Similar to ECOG, the PPS can indicate the need for additional support including hospice care.
# Advance Care Planning/Goals of Care Designation (ACP/GCD) Tracking Record
Existing literature has several methods for assessing the degree to which a patient has engaged in prior ACP or their preferences related to decision-making. 34 The PPF tool includes the items "Would you like information on Goals of Care or advance care planning (green sleeve)?", "Understanding my illness and/or treatment", "Talking with my health care team" and "Making treatment decisions", which allow patients to indicate their self-perceived need for more information related to ACP. In Alberta, the ACP/GCD Tracking Record also provides prompts for clinicians, with five suggested questions to assess prior ACP activities, and is the document in use provincially to record patient needs related to ACP (Appendix 5). The SICP also guides clinicians to elicit a patient's informational needs related to their prognosis, "How much information about what is likely to come with your illness would you like from me?" 51
# Coordination of Care
Patients with cancer are at high risk of receiving poorly coordinated care in multiple settings from many providers, and lack of coordination is associated with poor symptom control, medical errors, and higher costs, 2,55 Improvement in cancer care coordination leads to better patient experience and higher quality of end of life care. 55,56 Many factors impact patient complexity, including personal factors (e.g., social determinants of health), interactions with providers (e.g., no family physician), Guideline Resource Unit system complexities (e.g., rural location), societal influences, and changes over time. 57 Care coordination needs tend to increase with complexity. It is important to assess care coordination needs (e.g., patient and family/caregiver factors, number of providers, complexity of treatment plan), however there is limited evidence to recommend one assessment tool over another. 58 Practical concerns identified on the PPF may indicate higher needs around care coordination for issues such as financial concerns, difficulty getting to and from appointments, and language barriers.
Primary providers should initiate management of unmet needs. 26 Defining which care provider is primarily responsible and whether they refer to additional care providers for support and interventions can be dependent on both the referring clinicians' own competencies in managing the issue and on the locally available consultation services.
# Illness Comprehension and Coping
Evidence has shown that addressing a patient's understanding of their illness, how they are coping and how those close to them are coping, is associated with improved patient outcomes. 12,32,45,51,59,60 In addition to consulting secondary palliative care providers, Table 2 shows some other methods that can be used to support patients and family/caregivers. Step 3: PRIMARY PROVIDER MANAGEMENT OF UNMET NEEDS Primary palliative care management of unmet patient needs is strongly recommended using the four essential components of an early palliative approach to care as a guide:
1. Illness comprehension and coping 2. Management of symptoms by providers and patients' self-management 3. Advance care planning and patient's preferred method of decision making 4. Coordination of care Patient preference, available time and clinician skills may be factors in the extent to which exploring patient illness understanding and coping occurs during clinical encounters, and clinician judgment is required about whether and when to refer for additional formal coping supports. This guideline encourages primary providers to explore and identify techniques to use in their practice.
# Management of Symptoms by Providers and Patients
Providers: Management of symptoms is a cornerstone of palliative care. 23 Symptoms may be managed pharmacologically (e.g. steroids, opioids), non-pharmacologically (e.g., behaviour modification, meditation), and/or by physical interventions (e.g., stents, palliative surgery, radiation). Conversations Cancer Consult Recording App with the aim of improving their recall of key conversations and enhancing their self-management and ease of decision-making. More information is at www.ahs.ca and search "My Care Conversations Cancer Consult Recording App" or visit: https://www.ahs.ca/cancer/Page16144.aspx.
# ACP and Patient's Preferred Method of Decision Making
By preparing patients and those who may have to make in-the-moment decisions on their behalf, ACP is associated with a number of benefits. 64 Choosing Wisely Canada recommends "don't delay advance care planning conversations". The AHS procedure on ACP and GCD states, "all adults who have capacity should be given the opportunity to participate in ACP as a part of routine care, started early in a longitudinal relationship with a health care provider and revisited when the health or wishes of an adult changes". 65,66 Encourage patients to have conversations about ACP throughout cancer treatment. Clinicians, within their scope of practice, can be instrumental in:
• Encouraging reflection on and expression of personal values, beliefs and preferences related to personal goals, health care and their preferred method of decision making (e.g., shared decision making, supported decision making with family/caregiver, self-determined, physiciandirected).
• Sharing prognostic information, tailored to the patient's readiness and preferences around illness understanding. • Supporting the patient in selecting an appropriate ADM.
• Encouraging the patient to communicate with their ADM, family/caregivers, other health care team members about their values, beliefs and preferences and who they have selected as ADM.
• Encouraging the patient to create a Personal Directive.
• Documenting ACP conversations on the ACP/GCD Tracking Record.
Resources: Patient and health care provider resources are available at www.conversationsmatter.ca.
The SICP was developed in a cancer outpatient clinical context to provide a systematic approach to increasing meaningful conversations between seriously ill people and their clinicians about their values and priorities. 51 It has been adapted for use in family physician clinics and other settings 67 and is in an early phase of adoption within AHS. This is a helpful bridging process between ACP and GCD determination, as shown in Figure 3. 65,66 In Alberta, Goals of Care Designations (GCD) are medical orders that describe the general and sometimes specific focus of a patient's desired care approach, harmonized with what is medically appropriate to provide. They also create awareness of a person's care choices in relation to the care sector they are living in or being cared for. They ideally arise from fully informed conversations between patients (or their alternate decision-maker) and health care providers. The use of GCD is described in an AHS level 1 provincial policy and procedure. GCD should be determined when clinically indicated and should be reviewed at the request of the patient or ADM, after transfers, or if there is a significant change in the patient's condition or circumstances.
# Goals of Care Designations:
GCD are a useful component of an early palliative approach to care because they are a mechanism that "helps make our system more patient-centred, improves continuity of care, supports care quality and safety for patients, reduces unwanted transfers and procedures, reduces decisional burden and moral distress for families and caregivers, and helps prevent inappropriate consumption of resources." Per AHS, "once a Goals of Care Designation conversation has been held, and if clinically indicated, a Goals of Care Designation order shall be created and documented in the Advance Care Planning/Goals of Care Designation Tracking Record." By documenting in a common place, follow up can be shared between the care team. The Green Sleeve is a plastic pocket used in Alberta as the specific resource to contain and transfer ACP documentation (e.g., GCD order, Advance Care Planning/Goals of Care Designation Tracking Record, Personal Directive copies, Guardianship Orders).
# Guideline Resource Unit
# Coordination of Care
Coordination of care is usually the responsibility of all health care providers. The important coordination activities are: 35 • Establish accountability or negotiate responsibility • Communicate • Facilitate transitions • Create a proactive plan of care • Support self-management goals • Link to community resources • Align resources with patient and population needs • Monitor, follow up, and respond to change In certain zones this coordination might be achieved through a patient navigator and/or home care case manager. These coordinators are particularly valued by rural zone patients. 63 Advanced Cancer Resources: To assist health care providers in coordination activities, compilations of advanced cancer resources are available. These Zone-specific tips are being made in collaboration with local palliative programs as "Local Tips for Providers":
• Calgary (www.ahs.ca/GURU > Guidelines > Gastrointestinal > Metastatic Colorectal Cancer:
Early Palliative Approach > "Local Tips For Providers"). Includes information on caregiver support and community based resources, and these provincially funded programs Referral Based Services for Advanced Cancer Care: Lack of provider role clarity and variation in service availability, along with variation in patient need (i.e. functional and ambulatory status), can make it challenging to identify when and which specialist palliative care or other supportive care services are needed. Relevant supportive services that may assist in fulfilling an early palliative approach to care include: integrated home care, EMS Assess Treat and Refer program, community paramedic program, psychosocial oncology, and rehabilitation oncology. See "Referral Based Services for Advanced Cancer Care" document for provider types available, their description and referral criteria. Note that the Alberta Referral Directory (ARD) is the centralized location for referral information. More resources for improving referrals and access to services can be found at "Access Improvement" (https://www.ahs.ca/info/Page13719.aspx).
Specialist Palliative Care Services: Specialist palliative care services provide secondary or tertiary advice or care when needs of the patient are complex and beyond the scope of the primary care team. 25 The palliative consultant can also support the primary care team in providing a primary palliative approach to care. Quality indicators suggest that palliative-focused home care nursing support is an important element in improving quality of care and reducing inappropriate use of resources. 3,68,69 When providers are making referrals to palliative care services, clarification should be provided to the patient explaining that palliative care is an added layer of support that can be used alongside cancer treatments. 70 Patient friendly palliative care descriptions are available in the CancerControl Alberta patient education guides (see Section 3.2). Some examples of when referral to specialist palliative care would be appropriate are:
• severe symptoms (≥ 7 ESAS-r). Note clinician judgement is required as patients with severe psychosocial-related symptoms (e.g., depression and anxiety) might instead need a referral to psychosocial oncology providers. • palliative care unit or hospice referral.
• assisting with conflict resolution or health care decision making.
• clarification of goals of treatment or management plan.
# Communication and Documentation:
Standardized communication increases consistency, minimizes duplication and improves teamwork while promoting patient safety. All providers involved in the patient's care should send updates to other providers when there are changes in the patient's condition, needs, or status. Important elements include patient's cancer illness understanding, prognosis, and details of ACP and GCD (Green Sleeve). Effective communication reduces the need for patients and families to repeat information. Patients and families need information to prepare for and improve care transitions; this may include written information or instructions, action plans, goals, signs or symptoms of declining health status, and contact information for the team. Family physicians also want to be kept informed and involved. 71
# Guideline Resource Unit
The following communication tools should be used to enable standardized communication:
• Shared care letters: At transition points in care, communication between the cancer centre and family physician should be emphasized by use of a "Shared Care" letter. The physician version of the letter outlines collaborative care where primary palliative care and symptom management can be shared between providers. It indicates cancer modifying care to be managed by medical oncology and non-cancer related care to be managed by family physician. This letter is initiated when second-line therapy is ordered or patient is determined to have advanced disease. The patient version of the letter should be given to the patient during the clinic visit. • Green Sleeve: The Green Sleeve is a plastic pocket used in Alberta as the specific resource to contain and transfer ACP documentation (e.g., GCD order, ACP/GCD Tracking Record, Personal Directive copies, Guardianship Orders).
At any point after a cancer diagnosis and often as cancer progresses, patients and their families/ caregivers may have questions, worries or preferences about dying, death or preparation for after death. Clinicians are a valued source of information or guidance about end of life topics and can help ensure that key activities, like preparing a will or addressing guardianship issues for dependents, have been addressed. Topics that people may want to inquire about include:
• How to recognize when death is near and what dying may look like, including modes of death e.g. "natural death", palliative sedation for intractable symptom issues in final hours or days, death during resuscitation or medical management in hospital, or MAID. • How to proactively anticipate and manage changing needs (e.g., if a patient is likely to lose the ability to take oral medication or become bed bound). • Possible care locations before death (home, care facility, hospice, hospital).
Managing existential distress, death anxiety and changes in personal role or close relationships may involve the supports outlined in section 3.1; other topics in end of life care are listed below.
# End of Life Planning
• Review ACP discussions and patient preferences for care at end of life. • Determine the most appropriate GCD that reflects the person's values and clinical context.
• Revisit caregiver supports.
• Ensure patient is on Alberta Health Palliative Coverage Program (also known as "Palliative Blue Cross" or "Palliative Drug Coverage"). • Discuss possible and preferred location(s) of care towards end of life (e.g., home, hospice, hospital, or other facility). o Develop a plan for expected death in the community if patient would like to remain at home: AHS expected death in the home toolkit can be found on Insite or at https://www.albertahealthservices.ca/info/Page15828.aspx Resources that help prepare for death can be found on Insite by searching "Care before death" or "What to expect when a loved one is dying" o For information on "Care after death" in acute care visit https://insite.albertahealthservices.ca/cad/Page12024.aspx
# Estate and Funeral Planning
Remind patients and their family/caregivers to begin this planning early on. For example, a will and financial enduring power of attorney are part of estate planning. Assist them to connect to the appropriate resources to fulfill this planning, such as social work or their lawyer.
# Hospice Access
Hospice care is a specialized service available in certain locations that provides 24/7 facility-based palliative care to those who are approaching end of life and whose needs cannot be met at home/other location. There are highly specific criteria for referral to hospice and access is determined by secondary palliative care clinicians. See the "Referral Based Services for Advanced Cancer Care" document and/or talk to your local palliative care clinician about whether hospice may be appropriate for a specific patient and family/caregiver.
# Medical Assistance in Dying (MAID)
AHS has developed the MAID policy to guide medical assistance in dying services. This policy is posted on the AHS Medical Assistance in Dying website and available from the Care Coordination Service upon request. A physician FAQ sheet is available.
# Grief and Bereavement
Ask patients about their emotional supports and let patients and caregivers know that grief and bereavement resources are available both before and after death. Most services are accessed by self-referral and clinicians can help by providing the access information. See "Referral Based Services for Advanced Cancer Care" document for grief and bereavement resources.
Guideline Resource Unit
# Clinic List Report:
This report can be generated for any clinic in CancerControl Alberta (CCA) based on location, date and provider, and is intended to support clinic preparation or team huddle prior to the start of clinic.
It pulls all information from ARIA (CancerControl Alberta's EMR) about the clinic including notes entered by clinicians regarding a patient's next visit, as well as the symptom burden the patient reported on their last PRO symptom screen (Putting Patients First form), along with when that screen was filled out, and other relevant information re: goals of care and % weight change in the last 3 months.
Clinicians can easily click on the patient name or ACB# to link to each individual's Trended PRO Dashboard.
#
This report can be generated for any patient in CancerControl Alberta (CCA) who has completed a Putting Patients First (PPF) form and the staff have entered it as part of the clinical documentation. It is intended to support both the patient and the provider team to visualize the patient's symptom burden over time and to highlight areas of high symptom burden. It also links clinical response and referrals made to each clinical visit/PRO report.
It pulls all info from ARIA (CancerControl Alberta's EMR) entered by clinicians regarding all previous visits. Patients get a "patient friendly" simplified version when they check in for their visit as a reference for when they fill in today's "Symptom Tracking Report" (which we refer to as the Putting Patient's First form).
For access to this report, contact [email protected].
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Gastrointestinal and Palliative Care Tumour Teams. Members of the Alberta Provincial Gastrointestinal and Palliative Care Tumour Teams include: medical oncologists, radiation oncologists, palliative care consultants, surgical oncologists, family physicians, allied health professionals, nurse practitioners, registered nurses, and patient and family advisors. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Gastrointestinal and Palliative Care Tumour Teams and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in October, 2018 and underwent revisions in July 2019.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial Gastrointestinal and Palliative Care Tumour Teams and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2020) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of CancerControl Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerControl Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of
| None | None |
b3de0d168b1f0c980b07e6832e790b03fb02f457 | cma | None | This guideline applies to adult patients 19 and older with suspected obstructive sleep apnea (OSA). While sleep apnea may occur in 1-4% of children 1 , pediatric diagnosis and management is beyond the scope of this guideline. For a brief pediatric overview, see Appendix A: Sleep Apnea in Children. Other conditions that may contribute to daytime sleepiness are also out of the scope of this guideline. Please see Appendix B: Other Conditions Associated with Daytime Sleepiness.- If OSA is suspected, conduct a detailed history and a physical examination, focused on the upper airway. 2 - The STOP-Bang questionnaire can be used to help determine if a patient is at increased risk of moderate to severe OSA. 2 - While the most common symptom of OSA is excessive daytime sleepiness, the clinical presentation can vary. Completion of the Epworth Sleepiness Scale is recommended. 2 - Patients with untreated OSA may have increased perioperative morbidity. 3 Consider appropriate screening when referring patients for potential surgery (e.g., STOP-Bang Questionnaire). See also the BC Surgical Rehabilitation Toolkit for further information.# Testing and Referral
- Home Sleep Apnea Test (HSAT) should not be used to screen asymptomatic patients. HSAT is only recommended for the diagnosis of OSA in symptomatic patients who are determined to be at an increased risk of moderate-to-severe OSA, and who have no exclusion criteria (see Requisition). 2 - A negative or equivocal HSAT does not exclude OSA. If an HSAT is negative, inconclusive or technically inadequate, and OSA is suspected, polysomnography is recommended. 2 - BC now has a Standard Requisition for HSAT that referring practitioners are required to use.
- Symptomatic patients for which the HSAT is not the appropriate diagnostic test should be referred for a sleep disorder consultation for polysmnography. 2
Management and Follow-up - When assessing whether a patient should be treated, it is important to consider the severity of the symptoms, presence and severity of any comorbid disease, presence of any safety-critical occupation and the results of all sleep studies. - OSA is a serious chronic disease that warrants regular follow-up, short-term to ensure initial compliance and response to treatment and long-term to confirm continued effectiveness. 3 - Patients with OSA may be prone to drowsiness while driving. Physicians caring for these patients should be familiar with BC's Driver Medical Fitness Information for Medical Professionals. - Surgery for OSA, including minimally invasive techniques to reduce tissue volume, incurs typical surgical risks. Since there may be effective medical alternatives to surgery, prior referral to a sleep disorder physician is recommended.
# Types of Sleep Apnea
There are four types of sleep apnea:
- Obstructive sleep apnea (OSA) is the most common type of sleep apnea encountered in primary care. It is characterized by complete cessation or transient reduction in breathing with maintained or increasing respiratory effort. Home Sleep Apnea Testing (HSAT) should only be performed on patients who present with an increased risk of moderate-to-severe OSA. - Other less common types of sleep apnea include:
Central sleep apnea is characterized by complete cessation or transient reduction in breathing with absent respiratory effort. This occurs in patients with neurological disease or in association with drug/substance abuse or high altitude. Cheyne-Stokes breathing is characterized by a crescendo-decrescendo pattern of respiration between central apnea.
This frequently occurs in patients with heart failure or cerebrovascular disease. Complex sleep apnea is characterized by the persistence or emergence of central apneas or hypopneas when treated with Continuous Positive Airway Pressure (CPAP or BiPAP) and obstructive apnea has been resolved. This may occur in up to 10% of patients with OSA treated with CPAP.
Sleep hypoventilation is a sleep disorder characterized by significant hypercapnia and hypoxemia during sleep. This usually occurs in patients with OSA and morbid obesity or obstructive or restrictive lung disease. These patients usually require urgent evaluation. 4
# Epidemiology
OSA is associated with poor quality of life 6,8,9 and has been linked to severe chronic health conditions such as obesity, diabetes, metabolic syndrome 3,10 and neuro-psychiatric problems. 10 Moderate-severe OSA is associated with an increased risk of cardiovascular disease, resulting in hypertension, coronary disease, stroke, heart failure, and atrial fibrillation. 5 OSA is widely underdiagnosed; 86% to 95% of individuals found in population surveys with clinically significant OSA report no prior OSA diagnosis. 6 The 13 - traumatic brain injury 14 - nasal and nasopharyngeal obstruction 15 - neuromuscular disease 16 - Marfan syndrome 17 - polycystic ovarian disease 18 Risks of Untreated or Undertreated OSA 2,19-21
Untreated or undertreated OSA pose serious risks and have been associated with: daytime sleepiness, impaired quality of life, motor vehicle crashes, occupational injury, systemic hypertension, type 2 diabetes, cardiac arrhythmia, aortic dilatation/ dissection, coronary artery disease, heart failure, stroke, depression, cognitive impairment, cancer, ocular disease, pneumonia, renal dysfunction, dementia, seizures, hypogonadism, maternal/fetal health, post-operative complications, and premature death.
Patients with untreated OSA may have increased perioperative morbidity (postoperative cardiac events, acute respiratory failure, desaturation and reintubation); 21 consider appropriate screening when referring patients for potential surgery (e.g., using the STOP-Bang Questionnaire, Appendix C: STOP-Bang Questionnaire). See also the BC Surgical Rehabilitation Toolkit for further information.
# History and Physical Examination
- History and physical examination are crucial first steps towards the recognition and diagnosis of OSA. 2 Patient history should focus on nocturnal breathing abnormalities, daytime sleepiness, and family and personal medical history. - Consider using the STOP-Bang questionnaire to help determine if a patient is at increased risk of moderate to severe OSA (Appendix C: STOP-Bang Questionnaire). 2 - Determine the patient's risk factors for OSA (see list on pages 2-3 above).
- While the clinical presentation of OSA can vary, the most common symptom is excessive daytime sleepiness. Inquire about the impact of daytime sleepiness (e.g., "Have you had any accidents or near misses related to sleepiness while driving?" or "Have you ever had to stop an activity due to sleepiness?"). Request completion of the Epworth Sleepiness Scale. A score of greater than 10 suggests significant daytime sleepiness, although a score of 10 or less does not exclude daytime sleepiness or OSA. - All patients should be questioned about driving or safety critical occupation (e.g., truck, taxi, bus drivers, railway engineers, commercial pilots 22 ) where sleepiness could be a hazard, whether they operate heavy equipment, the class of their driver's license and whether they have fallen asleep at the wheel or have come close to doing so in the past 5 years.
Physical examination:
- Head and neck examination are important. Measure the neck circumference if feasible Examine the upper airway and it may be useful to evaluate the Mallampati score -Mallampati Classification (Appendix D: Mallampati Classification). A higher Mallampati classification has been associated with OSA diagnosis and increased AHI.
For every 1-point increase in the Mallampati score, the odds of having OSA increased by more than 2-fold. 23 .
# Testing and Referral
- To determine if a patient requires a diagnostic test for OSA, it is important to first identify if they are at increased risk of moderate-to-severe OSA. This is indicated by the presence of excessive daytime sleepiness or fatigue and at least two of the following three criteria: witnessed apneas or gasping or choking habitual loud snoring diagnosed hypertension
- If the patient is at an increased risk of moderate-to-severe OSA, then the Home Sleep Apnea Test (HSAT) is an appropriate diagnostic test, rather than a polysomnography. - However, HSAT is not the appropriate test if one or more of the following exclusion criteria apply (any one item precludes HSAT): concern for non-respiratory sleep disorder (e.g., chronic insomnia, sleep walking/talking) risk of hypoventilation (e.g., neuromuscular disease, BMI ≥ 40 kg/m 2 ) chronic/regular opiate medication use significant cardiopulmonary disease (e.g., history of stroke, heart failure, moderate-to-severe lung disease) previous negative or equivocal HSAT age < 16 years inability to complete necessary steps for self-administered HSAT (e.g., cognitive, physical, or other barriers)
- Recognizing that some patients may not have a bed partner, the referring physician may, while conducting a physical examination, assess whether there is a reasonable suspicion of nocturnal breathing events such as apneas, gasping, choking or habitual loud snoring. - HSAT is not recommended for pediatric patients, however, physician evaluation, rather than age, may be the best way to determine whether an adolescent presents as an adult. - Patients at increased risk of moderate-to-severe OSA but with one of more of the exclusion criteria above should be referred to a sleep disorder physician for potential polysomnography (PSG). - Referral for HSAT is limited to: Registrants of the College of Physicians and Surgeons of British Columbia Nurse practitioners or other designated health professional as authorized by the College of Physicians and Surgeons of British Columbia. - If an HSAT is negative, equivocal, or the patient has been mis-referred:
- The diagnostic facility is to notify the referring physician that the patient did not/does not meet the requirements for an HSAT and recommend a sleep disorder consultation and/or Level 1 polysomnogram study (preferred), or 2. The diagnostic facility's Medical Director or interpreting physician may refer the patient for a sleep disorder consultation and/or Level 1 study and notify the originating/referring physician, ensuring the originating/referring physician receives a copy of the HSAT result. In this case the Medical Director or interpreting physician is responsible for patient follow up as the ordering physician and cannot assume the original referring physician will provide patient follow up on the test.
Facilities must have a policy and procedure for notifying the referring physician of critical results immediately.
- To order HSAT or to request a referral for a sleep disorder consultation, see Associated Documents.
- For patients with suspected OSA, Figure 1. outlines the patient pathway.
# Interpretation of Results
- The diagnostic sleep report should provide an assessment as to whether the patient has OSA and whether it is mild, moderate, or severe. - Apnea Hypopnea Index (AHI): Is defined by the number of apnea and hypopnea per hour of measured sleep. - In addition to symptoms and presence of comorbid disease, AHI is one of the criteria used to determine the severity of sleep apnea.
AHI values should be considered in conjunction with clinical presentation, including a patient's symptoms, co-morbidities and occupation, and all sleep monitoring abnormalities such as degree of hypoxemia (see Table 1: AHI Interpretation below).
# OSA Management
When assessing whether a patient should be treated it is important to consider the severity of the symptoms, presence and severity of any comorbid disease, presence of any safety-critical occupation and all the sleep monitoring abnormalities.
Patients with OSA and daytime sleepiness and/or sleep related arterial oxygen desaturation appear more likely to develop vascular complication if left untreated. It is important to treat most patients with OSA if they have comorbid disease or work in a safety critical occupation such as a commercial driver. Treatment should be considered in patients with fatigue and/or sleepiness even if the AHI is in the milder range.
Patients with OSA may be prone to drowsiness while driving. Physicians caring for these patients should be familiar with BC's Driver Medical Fitness Information for Medical Professionals. Surgical options are primarily for patients with tonsillar hypertrophy or craniofacial abnormalities and require referral to a sleep disorder physician and to the appropriate surgeon for more comprehensive evaluations.
# Healthy Behaviours and Diet:
The importance of healthy behaviours and diet, including exercise and weight loss, should be recommended for patients with elevated BMI, although it is not adequate as a stand-alone therapy if the patient is sleepy or has moderate to severe OSA. Weight loss is more successful if the patient uses definitive therapy to control their OSA and then retest after their weight goal is achieved to see if definitive therapy is still required.
# Continuous Positive Airway Pressure (CPAP):
CPAP is generally the most effective treatment for OSA. If a patient is diagnosed with OSA and is unwilling or intolerant of CPAP, consider alternate therapies or refer to sleep disorder physician.
Positional Therapy: Avoiding sleeping in the supine position is an option if testing shows that OSA is primarily in the supine position. There are electronic devices that can monitor and record sleeping positions.
Other devices (oral, etc.): Oral appliances may be useful for mild to moderate OSA or those intolerant/unwilling to use CPAP and can be effective for some patients.
For additional OSA management information, see Appendix F: OSA Management Options. For additional information on oral and other devices, see Appendix G: Oral and Other Devices.
# Follow-Up
- OSA is a serious chronic disease that warrants regular follow-up; short-term to ensure initial compliance and response to treatment and long-term to confirm continued effectiveness. 3 - There is no need to re-test if the patient is doing well on long-term CPAP therapy and there is no change in clinical status.
Annual follow-up is recommended with CPAP download Indications for retesting: Persistent daytime symptoms, abnormal overnight oximetry or residual sleep disordered breathing based on CPAP download - Whatever treatment is used, the patient should be followed until the AHI is normal (less than 5 events per hour), the Epworth Sleepiness Scale score is 10 or less, the patient feels rested, and a bed partner reports no residual snoring. Ideally, the patient is using the treatment every night, all night. - CPAP machines also provide a patient accessible read out of 'events per hour' . This is an index of residual sleep apnea and not a true AHI as it is not derived from sleep monitoring but is a useful daily indication of therapy effectiveness.
# Problem Solving CPAP therapy
After treatment, non-adherence to CPAP therapy, CPAP intolerance and persistent sleepiness after therapy may occur. Considerations include:
- CPAP non-adherence: Lack of interest/understanding of OSA -importance of treatment can be reinforced; depends on indications for treatment and severity of disease. 24 CPAP intolerance -is common and should be addressed by the CPAP provider. 24 See table below for common causes of intolerance. See Table 2: CPAP Intolerance and Treatment Recommendations below.
# Methodology
These guideline recommendations are tailored to support practice in British Columbia and are based on the ADAPTE Collaboration guideline adaption methodology. 25 Clinical recommendations were developed based on the sourced guidelines, 2,3,19, a Primary Care Pathway: Uncomplicated Obstructive Sleep Apnea, 24 as well as expert clinical consensus where evidence was insufficient or unavailable.
The source guidelines were chosen following an environmental scan of internationally available guidelines. Guidelines were chosen for adaptation following an evaluation using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. 30 In situations where there is a lack of rigorous evidence, best clinical opinion has been provided to support decision making and high-quality patient care.
The guideline development process includes significant engagement and consultation with primary care providers, sleep disorder physicians, and key stakeholders. For more information about Guidelines and Protocols Advisory Committee (GPAC) guideline development processes, refer to the GPAC handbook available at BCGuidelines.ca.
The level and quality of evidence for the key recommendations are based on those used by the AASM: Clinical Practice Guideline for Diagnostic Testing for Adult Obstructive Sleep Apnea (2017). 2 Please refer to those guidelines for a summary of the levels of evidence (table 5). Where evidence was insufficient or unavailable expert clinical consensus was used and is indicated in the key recommendations as "expert opinion".
# Resources
# Abbreviations
The principles of the Guidelines and Protocols Advisory Committee are to:
- encourage appropriate responses to common medical situations - recommend actions that are sufficient and efficient, neither excessive nor deficient - permit exceptions when justified by clinical circumstances | This guideline applies to adult patients 19 and older with suspected obstructive sleep apnea (OSA). While sleep apnea may occur in 1-4% of children 1 , pediatric diagnosis and management is beyond the scope of this guideline. For a brief pediatric overview, see Appendix A: Sleep Apnea in Children. Other conditions that may contribute to daytime sleepiness are also out of the scope of this guideline. Please see Appendix B: Other Conditions Associated with Daytime Sleepiness.• If OSA is suspected, conduct a detailed history and a physical examination, focused on the upper airway. 2 • The STOP-Bang questionnaire can be used to help determine if a patient is at increased risk of moderate to severe OSA. 2 • While the most common symptom of OSA is excessive daytime sleepiness, the clinical presentation can vary. Completion of the Epworth Sleepiness Scale is recommended. 2 • Patients with untreated OSA may have increased perioperative morbidity. 3 Consider appropriate screening when referring patients for potential surgery (e.g., STOP-Bang Questionnaire). See also the BC Surgical Rehabilitation Toolkit for further information.# Testing and Referral
• Home Sleep Apnea Test (HSAT) should not be used to screen asymptomatic patients. HSAT is only recommended for the diagnosis of OSA in symptomatic patients who are determined to be at an increased risk of moderate-to-severe OSA, and who have no exclusion criteria (see Requisition). 2 • A negative or equivocal HSAT does not exclude OSA. If an HSAT is negative, inconclusive or technically inadequate, and OSA is suspected, polysomnography is recommended. 2 • BC now has a Standard Requisition for HSAT that referring practitioners are required to use.
• Symptomatic patients for which the HSAT is not the appropriate diagnostic test should be referred for a sleep disorder consultation for polysmnography. 2
# [Expert Opinion]
Management and Follow-up • When assessing whether a patient should be treated, it is important to consider the severity of the symptoms, presence and severity of any comorbid disease, presence of any safety-critical occupation and the results of all sleep studies. • OSA is a serious chronic disease that warrants regular follow-up, short-term to ensure initial compliance and response to treatment and long-term to confirm continued effectiveness. 3 • Patients with OSA may be prone to drowsiness while driving. Physicians caring for these patients should be familiar with BC's Driver Medical Fitness Information for Medical Professionals. [Expert Opinion] • Surgery for OSA, including minimally invasive techniques to reduce tissue volume, incurs typical surgical risks. Since there may be effective medical alternatives to surgery, prior referral to a sleep disorder physician is recommended.
# Types of Sleep Apnea
There are four types of sleep apnea:
• Obstructive sleep apnea (OSA) is the most common type of sleep apnea encountered in primary care. It is characterized by complete cessation or transient reduction in breathing with maintained or increasing respiratory effort. Home Sleep Apnea Testing (HSAT) should only be performed on patients who present with an increased risk of moderate-to-severe OSA. • Other less common types of sleep apnea include:
Central sleep apnea is characterized by complete cessation or transient reduction in breathing with absent respiratory effort. This occurs in patients with neurological disease or in association with drug/substance abuse or high altitude. Cheyne-Stokes breathing is characterized by a crescendo-decrescendo pattern of respiration between central apnea.
This frequently occurs in patients with heart failure or cerebrovascular disease. Complex sleep apnea is characterized by the persistence or emergence of central apneas or hypopneas when treated with Continuous Positive Airway Pressure (CPAP or BiPAP) and obstructive apnea has been resolved. This may occur in up to 10% of patients with OSA treated with CPAP.
Sleep hypoventilation is a sleep disorder characterized by significant hypercapnia and hypoxemia during sleep. This usually occurs in patients with OSA and morbid obesity or obstructive or restrictive lung disease. These patients usually require urgent evaluation. 4
# Epidemiology
OSA is associated with poor quality of life 6,8,9 and has been linked to severe chronic health conditions such as obesity, diabetes, metabolic syndrome 3,10 and neuro-psychiatric problems. 10 Moderate-severe OSA is associated with an increased risk of cardiovascular disease, resulting in hypertension, coronary disease, stroke, heart failure, and atrial fibrillation. 5 OSA is widely underdiagnosed; 86% to 95% of individuals found in population surveys with clinically significant OSA report no prior OSA diagnosis. 6 The 13 • traumatic brain injury 14 • nasal and nasopharyngeal obstruction 15 • neuromuscular disease 16 • Marfan syndrome 17 • polycystic ovarian disease 18 Risks of Untreated or Undertreated OSA 2,19-21
Untreated or undertreated OSA pose serious risks and have been associated with: daytime sleepiness, impaired quality of life, motor vehicle crashes, occupational injury, systemic hypertension, type 2 diabetes, cardiac arrhythmia, aortic dilatation/ dissection, coronary artery disease, heart failure, stroke, depression, cognitive impairment, cancer, ocular disease, pneumonia, renal dysfunction, dementia, seizures, hypogonadism, maternal/fetal health, post-operative complications, and premature death.
Patients with untreated OSA may have increased perioperative morbidity (postoperative cardiac events, acute respiratory failure, desaturation and reintubation); 21 consider appropriate screening when referring patients for potential surgery (e.g., using the STOP-Bang Questionnaire, Appendix C: STOP-Bang Questionnaire). See also the BC Surgical Rehabilitation Toolkit for further information.
# History and Physical Examination
• History and physical examination are crucial first steps towards the recognition and diagnosis of OSA. 2 Patient history should focus on nocturnal breathing abnormalities, daytime sleepiness, and family and personal medical history. • Consider using the STOP-Bang questionnaire to help determine if a patient is at increased risk of moderate to severe OSA (Appendix C: STOP-Bang Questionnaire). 2 • Determine the patient's risk factors for OSA (see list on pages 2-3 above).
• While the clinical presentation of OSA can vary, the most common symptom is excessive daytime sleepiness. Inquire about the impact of daytime sleepiness (e.g., "Have you had any accidents or near misses related to sleepiness while driving?" or "Have you ever had to stop an activity due to sleepiness?"). Request completion of the Epworth Sleepiness Scale. A score of greater than 10 suggests significant daytime sleepiness, although a score of 10 or less does not exclude daytime sleepiness or OSA. • All patients should be questioned about driving or safety critical occupation (e.g., truck, taxi, bus drivers, railway engineers, commercial pilots 22 ) where sleepiness could be a hazard, whether they operate heavy equipment, the class of their driver's license and whether they have fallen asleep at the wheel or have come close to doing so in the past 5 years.
Physical examination:
• Head and neck examination are important. Measure the neck circumference if feasible Examine the upper airway and it may be useful to evaluate the Mallampati score -Mallampati Classification (Appendix D: Mallampati Classification). A higher Mallampati classification has been associated with OSA diagnosis and increased AHI.
For every 1-point increase in the Mallampati score, the odds of having OSA increased by more than 2-fold. 23 .
# Testing and Referral
• To determine if a patient requires a diagnostic test for OSA, it is important to first identify if they are at increased risk of moderate-to-severe OSA. This is indicated by the presence of excessive daytime sleepiness or fatigue and at least two of the following three criteria: witnessed apneas or gasping or choking habitual loud snoring diagnosed hypertension
• If the patient is at an increased risk of moderate-to-severe OSA, then the Home Sleep Apnea Test (HSAT) is an appropriate diagnostic test, rather than a polysomnography. • However, HSAT is not the appropriate test if one or more of the following exclusion criteria apply (any one item precludes HSAT): concern for non-respiratory sleep disorder (e.g., chronic insomnia, sleep walking/talking) risk of hypoventilation (e.g., neuromuscular disease, BMI ≥ 40 kg/m 2 ) chronic/regular opiate medication use significant cardiopulmonary disease (e.g., history of stroke, heart failure, moderate-to-severe lung disease) previous negative or equivocal HSAT age < 16 years inability to complete necessary steps for self-administered HSAT (e.g., cognitive, physical, or other barriers)
• Recognizing that some patients may not have a bed partner, the referring physician may, while conducting a physical examination, assess whether there is a reasonable suspicion of nocturnal breathing events such as apneas, gasping, choking or habitual loud snoring. • HSAT is not recommended for pediatric patients, however, physician evaluation, rather than age, may be the best way to determine whether an adolescent presents as an adult. • Patients at increased risk of moderate-to-severe OSA but with one of more of the exclusion criteria above should be referred to a sleep disorder physician for potential polysomnography (PSG). • Referral for HSAT is limited to: Registrants of the College of Physicians and Surgeons of British Columbia Nurse practitioners or other designated health professional as authorized by the College of Physicians and Surgeons of British Columbia. • If an HSAT is negative, equivocal, or the patient has been mis-referred:
1. The diagnostic facility is to notify the referring physician that the patient did not/does not meet the requirements for an HSAT and recommend a sleep disorder consultation and/or Level 1 polysomnogram study (preferred), or 2. The diagnostic facility's Medical Director or interpreting physician may refer the patient for a sleep disorder consultation and/or Level 1 study and notify the originating/referring physician, ensuring the originating/referring physician receives a copy of the HSAT result. In this case the Medical Director or interpreting physician is responsible for patient follow up as the ordering physician and cannot assume the original referring physician will provide patient follow up on the test.
Facilities must have a policy and procedure for notifying the referring physician of critical results immediately.
• To order HSAT or to request a referral for a sleep disorder consultation, see Associated Documents.
• For patients with suspected OSA, Figure 1. outlines the patient pathway.
# Interpretation of Results
• The diagnostic sleep report should provide an assessment as to whether the patient has OSA and whether it is mild, moderate, or severe. • Apnea Hypopnea Index (AHI): Is defined by the number of apnea and hypopnea per hour of measured sleep. • In addition to symptoms and presence of comorbid disease, AHI is one of the criteria used to determine the severity of sleep apnea.
AHI values should be considered in conjunction with clinical presentation, including a patient's symptoms, co-morbidities and occupation, and all sleep monitoring abnormalities such as degree of hypoxemia (see Table 1: AHI Interpretation below).
# OSA Management
When assessing whether a patient should be treated it is important to consider the severity of the symptoms, presence and severity of any comorbid disease, presence of any safety-critical occupation and all the sleep monitoring abnormalities.
Patients with OSA and daytime sleepiness and/or sleep related arterial oxygen desaturation appear more likely to develop vascular complication if left untreated. It is important to treat most patients with OSA if they have comorbid disease or work in a safety critical occupation such as a commercial driver. Treatment should be considered in patients with fatigue and/or sleepiness even if the AHI is in the milder range.
Patients with OSA may be prone to drowsiness while driving. Physicians caring for these patients should be familiar with BC's Driver Medical Fitness Information for Medical Professionals.[Expert opinion] Surgical options are primarily for patients with tonsillar hypertrophy or craniofacial abnormalities and require referral to a sleep disorder physician and to the appropriate surgeon for more comprehensive evaluations.
# Healthy Behaviours and Diet:
The importance of healthy behaviours and diet, including exercise and weight loss, should be recommended for patients with elevated BMI, although it is not adequate as a stand-alone therapy if the patient is sleepy or has moderate to severe OSA. Weight loss is more successful if the patient uses definitive therapy to control their OSA and then retest after their weight goal is achieved to see if definitive therapy is still required.
# Continuous Positive Airway Pressure (CPAP):
CPAP is generally the most effective treatment for OSA. If a patient is diagnosed with OSA and is unwilling or intolerant of CPAP, consider alternate therapies or refer to sleep disorder physician.
Positional Therapy: Avoiding sleeping in the supine position is an option if testing shows that OSA is primarily in the supine position. There are electronic devices that can monitor and record sleeping positions.
Other devices (oral, etc.): Oral appliances may be useful for mild to moderate OSA or those intolerant/unwilling to use CPAP and can be effective for some patients.
For additional OSA management information, see Appendix F: OSA Management Options. For additional information on oral and other devices, see Appendix G: Oral and Other Devices.
# Follow-Up
• OSA is a serious chronic disease that warrants regular follow-up; short-term to ensure initial compliance and response to treatment and long-term to confirm continued effectiveness. 3 • There is no need to re-test if the patient is doing well on long-term CPAP therapy and there is no change in clinical status.
Annual follow-up is recommended with CPAP download Indications for retesting: Persistent daytime symptoms, abnormal overnight oximetry or residual sleep disordered breathing based on CPAP download • Whatever treatment is used, the patient should be followed until the AHI is normal (less than 5 events per hour), the Epworth Sleepiness Scale score is 10 or less, the patient feels rested, and a bed partner reports no residual snoring. Ideally, the patient is using the treatment every night, all night. • CPAP machines also provide a patient accessible read out of 'events per hour' . This is an index of residual sleep apnea and not a true AHI as it is not derived from sleep monitoring but is a useful daily indication of therapy effectiveness.
# Problem Solving CPAP therapy
After treatment, non-adherence to CPAP therapy, CPAP intolerance and persistent sleepiness after therapy may occur. Considerations include:
• CPAP non-adherence: Lack of interest/understanding of OSA -importance of treatment can be reinforced; depends on indications for treatment and severity of disease. 24 CPAP intolerance -is common and should be addressed by the CPAP provider. 24 See table below for common causes of intolerance. See Table 2: CPAP Intolerance and Treatment Recommendations below.
# Methodology
These guideline recommendations are tailored to support practice in British Columbia and are based on the ADAPTE Collaboration guideline adaption methodology. 25 Clinical recommendations were developed based on the sourced guidelines, 2,3,19,[26][27][28][29] a Primary Care Pathway: Uncomplicated Obstructive Sleep Apnea, 24 as well as expert clinical consensus where evidence was insufficient or unavailable.
The source guidelines were chosen following an environmental scan of internationally available guidelines. Guidelines were chosen for adaptation following an evaluation using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. 30 In situations where there is a lack of rigorous evidence, best clinical opinion has been provided to support decision making and high-quality patient care.
The guideline development process includes significant engagement and consultation with primary care providers, sleep disorder physicians, and key stakeholders. For more information about Guidelines and Protocols Advisory Committee (GPAC) guideline development processes, refer to the GPAC handbook available at BCGuidelines.ca.
The level and quality of evidence for the key recommendations are based on those used by the AASM: Clinical Practice Guideline for Diagnostic Testing for Adult Obstructive Sleep Apnea (2017). 2 Please refer to those guidelines for a summary of the levels of evidence (table 5). Where evidence was insufficient or unavailable expert clinical consensus was used and is indicated in the key recommendations as "expert opinion".
# Resources
# Abbreviations
The principles of the Guidelines and Protocols Advisory Committee are to:
• encourage appropriate responses to common medical situations • recommend actions that are sufficient and efficient, neither excessive nor deficient • permit exceptions when justified by clinical circumstances
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This draft guideline is based on scientific evidence current as of effective date.
The guideline was developed by the Guidelines and Protocols Advisory Committee and adopted by the Medical Services Commission.
For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook. • The prevalence of OSA in children is 1 -4% with one of the more common causes being tonsillar hypertrophy.
• Nasal congestion or enlarged adenoids can aggravate oral-pharyngeal obstruction by causing increased negative pressure when trying to inhale through a restricted nasal airway. A trial of a nasal steroid may be helpful followed by a referral to ENT for persistent nasal restriction. • Other common conditions associated with OSA are micro or retrognathia, Down's Syndrome, craniofacial syndromes (including cleft palate pre and post repair), obesity, neuromuscular disorders and metabolic disorders. • Severe craniofacial disorders require an ENT evaluation or referral to a craniofacial clinic at BC Children's Hospital.
• OSA symptoms in children are similar to adults with snoring, pauses in breathing, snorting, choking, gasping, daytime fatigue and sleepiness. In addition, impaired daytime concentration may be misdiagnosed as ADHD, behavioural and emotional problems or learning disabilities. Children can also present with slow growth, failure to thrive, and secondary enuresis. • Polysomnography remains the gold standard for OSA diagnosis in children. HSAT is not recommended as it is not sensitive enough to be accurate. Children with suspected OSA should be referred to a physician with pediatric sleep experience or the Sleep Clinic at BC Children's Hospital.
# Appendix B: Other Conditions Associated with Daytime Sleepiness
Other conditions associated with excessive daytime sleepiness include: 24 • Examiner should be seated opposite the patient at eye-level. A higher Mallampati score has been associated with OSA diagnosis and increased AHI. For every 1-point increase in the Mallampati score, the odds of having OSA increased by more than 2-fold. 23
# Class I Class II Class III Class IV
# Appendix G: Oral and Other Devices
Mandibular Advancement Device (MAD) is an appliance that fits over the upper and lower teeth with an adjustment to push the lower jaw forward. The device brings the tongue forward creating a more patent airway. Although expensive, for those that it works for, a custom device can be as effective as CPAP and often better tolerated. Patients may experience jaw or dental pain from MAD's which may inhibit use. Some movement and misalignment of the teeth may occur, but usually resolves itself if treatment is discontinued within the first year of treatment. Note there are many brands of MAD's. The ones using rigid bars or screws are likely to be more effective than those using elastic straps to pull the lower jaw forward.
Tongue Retaining Device is a flexible, silicone device that fits behind the lips in front of the teeth. It is a relatively inexpensive way of controlling snoring or very mild OSA with few side effects, compliance is generally low.
"Boil and bite" devices are much less expensive but are bulky and made of a soft material that does not last as long. They are usually patient-fitted, more prone to complications and much less effective. Boil and bite devices are not recommended for treatment of OSA.
Other devices used by patients: Devices such as adhesive nasal strips and nasal dilators may help nasal air flow but do not directly address the obstruction in the oral-pharyngeal airway that causes OSA. Similarly, chin straps may keep the mouth closed but do not correct the oral-pharyngeal airway obstruction. There is also a very real danger of an improperly applied strap pushing the jaw back and causing more obstruction. | None | None |
6a781ed71a171eab9aac1cda531b9fccdfc705b3 | cma | None | Background & aims: Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders, affecting about 10% of the general population globally. The aim of this consensus was to develop guidelines for the management of IBS. Methods: A systematic literature search identified studies on the management of IBS. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a multidisciplinary group of clinicians and a patient. Results: Consensus was reached on 28 of 31 statements. Irritable bowel syndrome is diagnosed based on symptoms; serological testing is suggested to exclude celiac disease, but routine testing for C-reactive protein (CRP), fecal calprotectin or food allergies is not recommended. A trial of a low fermentable oligosaccharides, disaccharides, monosaccharides, polyols (FODMAP) diet is suggested, while a gluten-free diet is not. Psyllium, but not wheat bran, supplementation may help reduce symptoms. Alternative therapies such as peppermint oil and probiotics are suggested, while herbal therapies and acupuncture are not. Cognitive behavioural therapy and hypnotherapy are suggested psychological therapies. Among the suggested or recommended pharmacological therapies are antispasmodics, certain antidepressants, eluxadoline, lubiprostone, and linaclotide. Loperamide, cholestyramine and osmotic laxatives are not recommended for overall IBS symptoms. The nature of the IBS symptoms (diarrhea-predominant or constipation-predominant) should be considered in the choice of pharmacological treatments. Conclusions: Patients with IBS may benefit from a multipronged, individualized approach to treatment, including dietary modifications, psychological and pharmacological therapies.#
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders. It is characterized by recurrent abdominal pain and altered bowel habits (i.e., constipation, diarrhea or both), often with associated bloating (1).
Globally, IBS is estimated to affect about 10% of the general population, but prevalence rates are highly variable (2,3). From country to country, the prevalence ranges from 1.1% to 45.0% but has been estimated at 12% (95% CI, 7%-17%) generally in North America (2), with a similar prevalence in Canada specifically (4). Rates also vary according to diagnostic criteria (2)(3)(4)(5). A large survey, across the United States, United Kingdom and Canada found that the Rome IV (~6%) prevalence rates were significantly lower than Rome III rates (~11%) in all countries (5). Women appear to be affected about 1.5 to two times more often than men, and the prevalence appears to decrease with increasing age (2)(3)(4)(5).
The current recommended diagnostic criteria for IBS are the Rome IV criteria: abdominal pain (≥1 day per week for ≥3 months) associated with defecation or a change in bowel habits (1,6). Irritable bowel syndrome is then subtyped according to the abnormality of stool consistency, including constipation-predominant (IBS-C, >25% hard stools and 25% loose stools and 25% loose stools and >25% hard stools); and unclassified (IBS-U <25% loose stools and <25% hard stools) (1). However, the available randomized clinical trials (RCTs) have used a variety of criteria, including Manning, Rome I, II, III, IV or questionnaire-defined. Therefore, for this consensus, IBS was pragmatically defined as abdominal pain associated with change in bowel habit for at least three months, and studies were included if they met this definition, regardless of criteria used. When diagnosing IBS, a full history and relevant examination are recommended, with limited use of diagnostic tests as discussed in the recommendations section of this consensus.
There have been guidelines on the management of IBS (7,8), but there has been an emergence of new therapies and new RCTs on current therapies because these guidelines have been published. The purpose of this guideline is to critically review the literature relating to diagnostic testing and the psychological and pharmacological treatment of IBS and to develop a consensus on specific recommendations for patients with any IBS, IBS-C or IBS-D.
# METHODS
# Scope and Purpose
These consensus statements focused on specific questions, identified and discussed by the participants, regarding the management of IBS. The development of this clinical practice guideline began in January 2017, with the full consensus group participating in a face-to-face meeting in May 2017; supplementary statements on breath testing were added after the meeting.
# Sources and Searches
The editorial office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University performed a systematic literature search of MEDLINE (1946to March 2017, EMBASE (1980to March 2017, and CENTRAL (Cochrane Central Register of Controlled Trials). Evidence was first gathered from the most recently published, high-quality systematic reviews (primarily from the American College of Gastroenterology monograph published in 2014 (7), on which PM was a co-author). These meta-analyses were then updated with any further data identified in the literature searches up to March 2017. The updated search strategies are described in Appendix 1 online. Study inclusion criteria were parallel group RCTs (crossover studies were included if the data were available from the first period such that parallel group data could be obtained), using any definition of IBS, including a dichotomous outcome measure relating to global IBS symptom improvement, human studies, and English publications. Further details regarding the search strategies used for preparing the initial consensus statements can be found in Appendix 1 online. Two additional systematic searches (up to May 2017) were performed after the consensus meeting to address statements eight and nine, with key search terms including irritable bowel syndrome, breath tests, and lactose intolerance.
# Review and Grading of Evidence
A methodologist (PM) used the GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach (9) to assess the risk of bias (of individual studies and overall across studies), indirectness, inconsistency, imprecision and other considerations (including publication bias) to determine the overall quality of evidence for each statement. The quality of evidence (QoE) for the individual statements was classified as high, moderate, low or very low as described in GRADE methodology (9,10) and used in prior Canadian Association of Gastroenterology (CAG) consensus documents (11)(12)(13)(14)(15)(16). GRADE assessments were validated by a second, nonparticipating methodologist, then reviewed and agreed upon by voting members of the consensus group at the meeting.
Approved product labeling from government regulatory agencies varies from country to country, and though not ignored, recommendations are based on evidence from the literature and consensus discussion and may not fully reflect the product labeling for a given country.
# Consensus Process
This Canadian consensus group consisted of 12 voting participants with experience in the area of IBS, including the chair (PM), gastroenterologists, general practitioners, a psychiatrist, a psychologist, a patient representative, and the moderator (also a gastroenterologist, WP).
The CAG web-based consensus platform (ECD solutions, Atlanta, Georgia, USA) was used to initiate the consensus process before the face-to-face consensus meeting held in Chicago, Illinois, USA in May 2017. The meeting chair (PM) and the steering committee (CA, GM, CK and the patient-representative ) developed the initial questions. The voting members then used the web-based platform to vote on their level of agreement and provide comments on the questions which were to be used to develop the recommendation statements during the meeting. A summary report of the literature search results was provided to the participants before the meeting.
At the meeting, the methodologist/chair (PM) presented the data and provided the group with a review of the GRADE evaluations which informed the quality of evidence determination for each of the questions. Recommendation statements were developed that were subsequently voted on anonymously via touchpads. A statement achieved consensus and was accepted if ≥75% of participants voted four (agree) or five (strongly agree) on a scale of one to five (with one, two, and three indicating disagree strongly, disagree, and neutral, respectively). Following acceptance of a statement, participants voted on the strength of the recommendation. A level of agreement of ≥75% of participants was needed to classify a statement as 'strong' (we recommend); if this threshold was not met, the statement defaulted to 'conditional' (we suggest). The strength of the recommendation considered risk-benefit balance, patients' values and preferences, cost and resource allocation, and the quality of the evidence. Therefore, it was possible for a recommendation to be classified as strong despite having low-quality evidence or conditional despite the existence of high-quality evidence (17). A strong recommendation is indicative of a more broadly applicable statement ('most patients should receive the recommended course of action'), whereas a conditional recommendation suggests that clinicians should 'recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences' (17).
At the meeting, the group did not reach consensus on three of the initial 31 statements (no recommendation A-C); thus, these statements were rejected. The evidence has been discussed in the text, but the consensus group did not make a recommendation (neither for nor against) offering these treatments to IBS patients.
The initial manuscript was drafted by the meeting chair/ methodologist (PM) and was then reviewed and revised by the remaining members of the consensus group. The manuscript was made available to all CAG members for comments for a two-week period before submission for publication, as per CAG policy for all clinical practice guidelines.
In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months before the consensus meeting were provided by all participants and made available to all group members.
# Role of the Funding Sources | Background & aims: Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders, affecting about 10% of the general population globally. The aim of this consensus was to develop guidelines for the management of IBS. Methods: A systematic literature search identified studies on the management of IBS. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a multidisciplinary group of clinicians and a patient. Results: Consensus was reached on 28 of 31 statements. Irritable bowel syndrome is diagnosed based on symptoms; serological testing is suggested to exclude celiac disease, but routine testing for C-reactive protein (CRP), fecal calprotectin or food allergies is not recommended. A trial of a low fermentable oligosaccharides, disaccharides, monosaccharides, polyols (FODMAP) diet is suggested, while a gluten-free diet is not. Psyllium, but not wheat bran, supplementation may help reduce symptoms. Alternative therapies such as peppermint oil and probiotics are suggested, while herbal therapies and acupuncture are not. Cognitive behavioural therapy and hypnotherapy are suggested psychological therapies. Among the suggested or recommended pharmacological therapies are antispasmodics, certain antidepressants, eluxadoline, lubiprostone, and linaclotide. Loperamide, cholestyramine and osmotic laxatives are not recommended for overall IBS symptoms. The nature of the IBS symptoms (diarrhea-predominant or constipation-predominant) should be considered in the choice of pharmacological treatments. Conclusions: Patients with IBS may benefit from a multipronged, individualized approach to treatment, including dietary modifications, psychological and pharmacological therapies.#
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders. It is characterized by recurrent abdominal pain and altered bowel habits (i.e., constipation, diarrhea or both), often with associated bloating (1).
Globally, IBS is estimated to affect about 10% of the general population, but prevalence rates are highly variable (2,3). From country to country, the prevalence ranges from 1.1% to 45.0% but has been estimated at 12% (95% CI, 7%-17%) generally in North America (2), with a similar prevalence in Canada specifically (4). Rates also vary according to diagnostic criteria (2)(3)(4)(5). A large survey, across the United States, United Kingdom and Canada found that the Rome IV (~6%) prevalence rates were significantly lower than Rome III rates (~11%) in all countries (5). Women appear to be affected about 1.5 to two times more often than men, and the prevalence appears to decrease with increasing age (2)(3)(4)(5).
The current recommended diagnostic criteria for IBS are the Rome IV criteria: abdominal pain (≥1 day per week for ≥3 months) associated with defecation or a change in bowel habits (1,6). Irritable bowel syndrome is then subtyped according to the abnormality of stool consistency, including constipation-predominant (IBS-C, >25% hard stools and <25% loose stools), diarrhea-predominant (IBS-D, >25% loose stools and <25% hard stools), mixed bowel habits (IBS-M, >25% loose stools and >25% hard stools); and unclassified (IBS-U <25% loose stools and <25% hard stools) (1). However, the available randomized clinical trials (RCTs) have used a variety of criteria, including Manning, Rome I, II, III, IV or questionnaire-defined. Therefore, for this consensus, IBS was pragmatically defined as abdominal pain associated with change in bowel habit for at least three months, and studies were included if they met this definition, regardless of criteria used. When diagnosing IBS, a full history and relevant examination are recommended, with limited use of diagnostic tests as discussed in the recommendations section of this consensus.
There have been guidelines on the management of IBS (7,8), but there has been an emergence of new therapies and new RCTs on current therapies because these guidelines have been published. The purpose of this guideline is to critically review the literature relating to diagnostic testing and the psychological and pharmacological treatment of IBS and to develop a consensus on specific recommendations for patients with any IBS, IBS-C or IBS-D.
# METHODS
# Scope and Purpose
These consensus statements focused on specific questions, identified and discussed by the participants, regarding the management of IBS. The development of this clinical practice guideline began in January 2017, with the full consensus group participating in a face-to-face meeting in May 2017; supplementary statements on breath testing were added after the meeting.
# Sources and Searches
The editorial office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University performed a systematic literature search of MEDLINE (1946to March 2017, EMBASE (1980to March 2017, and CENTRAL (Cochrane Central Register of Controlled Trials). Evidence was first gathered from the most recently published, high-quality systematic reviews (primarily from the American College of Gastroenterology monograph published in 2014 (7), on which PM was a co-author). These meta-analyses were then updated with any further data identified in the literature searches up to March 2017. The updated search strategies are described in Appendix 1 online. Study inclusion criteria were parallel group RCTs (crossover studies were included if the data were available from the first period such that parallel group data could be obtained), using any definition of IBS, including a dichotomous outcome measure relating to global IBS symptom improvement, human studies, and English publications. Further details regarding the search strategies used for preparing the initial consensus statements can be found in Appendix 1 online. Two additional systematic searches (up to May 2017) were performed after the consensus meeting to address statements eight and nine, with key search terms including irritable bowel syndrome, breath tests, and lactose intolerance.
# Review and Grading of Evidence
A methodologist (PM) used the GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach (9) to assess the risk of bias (of individual studies and overall across studies), indirectness, inconsistency, imprecision and other considerations (including publication bias) to determine the overall quality of evidence for each statement. The quality of evidence (QoE) for the individual statements was classified as high, moderate, low or very low as described in GRADE methodology (9,10) and used in prior Canadian Association of Gastroenterology (CAG) consensus documents (11)(12)(13)(14)(15)(16). GRADE assessments were validated by a second, nonparticipating methodologist, then reviewed and agreed upon by voting members of the consensus group at the meeting.
Approved product labeling from government regulatory agencies varies from country to country, and though not ignored, recommendations are based on evidence from the literature and consensus discussion and may not fully reflect the product labeling for a given country.
# Consensus Process
This Canadian consensus group consisted of 12 voting participants with experience in the area of IBS, including the chair (PM), gastroenterologists, general practitioners, a psychiatrist, a psychologist, a patient representative, and the moderator (also a gastroenterologist, WP).
The CAG web-based consensus platform (ECD solutions, Atlanta, Georgia, USA) was used to initiate the consensus process before the face-to-face consensus meeting held in Chicago, Illinois, USA in May 2017. The meeting chair (PM) and the steering committee (CA, GM, CK and the patient-representative [MM]) developed the initial questions. The voting members then used the web-based platform to vote on their level of agreement and provide comments on the questions which were to be used to develop the recommendation statements during the meeting. A summary report of the literature search results was provided to the participants before the meeting.
At the meeting, the methodologist/chair (PM) presented the data and provided the group with a review of the GRADE evaluations which informed the quality of evidence determination for each of the questions. Recommendation statements were developed that were subsequently voted on anonymously via touchpads. A statement achieved consensus and was accepted if ≥75% of participants voted four (agree) or five (strongly agree) on a scale of one to five (with one, two, and three indicating disagree strongly, disagree, and neutral, respectively). Following acceptance of a statement, participants voted on the strength of the recommendation. A level of agreement of ≥75% of participants was needed to classify a statement as 'strong' (we recommend); if this threshold was not met, the statement defaulted to 'conditional' (we suggest). The strength of the recommendation considered risk-benefit balance, patients' values and preferences, cost and resource allocation, and the quality of the evidence. Therefore, it was possible for a recommendation to be classified as strong despite having low-quality evidence or conditional despite the existence of high-quality evidence (17). A strong recommendation is indicative of a more broadly applicable statement ('most patients should receive the recommended course of action'), whereas a conditional recommendation suggests that clinicians should 'recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences' (17).
At the meeting, the group did not reach consensus on three of the initial 31 statements (no recommendation A-C); thus, these statements were rejected. The evidence has been discussed in the text, but the consensus group did not make a recommendation (neither for nor against) offering these treatments to IBS patients.
The initial manuscript was drafted by the meeting chair/ methodologist (PM) and was then reviewed and revised by the remaining members of the consensus group. The manuscript was made available to all CAG members for comments for a two-week period before submission for publication, as per CAG policy for all clinical practice guidelines.
In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months before the consensus meeting were provided by all participants and made available to all group members.
# Role of the Funding Sources
Funding for the consensus meeting was provided by unrestricted, arms-length grants to the CAG by Allergan Canada Inc. and Proctor & Gamble Canada. The CAG administered all aspects of the meeting, and the funding sources had no involvement in the process at any point nor were they made aware of any part of the process from the development of search strings and the statements to the drafting and approval of these guidelines. (20). The main role for CRP is to identify inflammatory disease such as IBD in patients with IBS symptoms; however, the performance of this marker is insufficient to be clinically useful. For example, a CRP of ≤0.5 mg/dL predicted a ≤1% probability of having IBD. Thus, it would appear that CRP has a good negative predictive value, but because the underlying risk of having IBD among the general population with symptoms is also <1%, it is unclear what additional value CRP testing would have in IBS patients. The evidence for this statement was graded as very-low quality due to the observational nature of the data, indirectness and heterogeneity in the studies assessed. Discussion: The consensus group concluded that CRP was unlikely to have value for the diagnosis of IBS or to effectively rule out IBD. Patients with IBS appear to have only a mildly elevated risk of IBD compared with the individuals without IBS, but the absolute risk remains low (see statements four and five). Therefore, CRP testing is likely not warranted on the basis of an IBS diagnosis alone and should be performed only in patients in whom there is a high suspicion of IBD.
# RECOMMENDATIONS
# Key evidence:
There was very-low quality evidence on the value of testing for fecal calprotectin (FC) in patients with IBS. The systematic review of biomarkers included eight case-control studies (n=259 IBS patients, n=565 IBD patients and n=238 healthy controls) evaluating FC (20). Neither a low nor high level of FC was predictive of IBS. In comparison with healthy controls, the highest predictive value for IBS was only 18.8% at 280 µg/g (however, this level also predicted a 17.1% chance of IBD). In contrast, a low FC level could exclude IBD (<40 µg/g predicted a ≤1% chance of IBD), and the likelihood of IBD increased with increasing FC levels (1000 μ/g predicted a 78.7% of IBD) (20). The evidence for this statement was graded as very low-quality due to indirectness and the case-control study designs because this design overestimates the diagnostic accuracy of the test. *The strength of each recommendation was assigned by the consensus group, per the GRADE system, as strong ('we recommend . . . ') or conditional ('we suggest . . . '). A recommendation could be classified as strong despite low quality evidence to support it, or conditional despite the existence of high-quality evidence due to the four components considered in each recommendation (risk:benefit balance, patients' values and preferences, cost and resource allocation, and quality of evidence). (20). Although levels <50 µg/g suggest an absence of IBD, levels between 50 and 250 µg/g are equivocal and would not be helpful. In addition, as was the case for CRP, although FC levels are predictive of IBD, the consensus group agreed that because IBS is associated with only a mildly elevated risk of IBD, FC testing should be performed only in patients in whom there is a high suspicion of IBD. Key evidence: A systematic review was conducted for these consensus guidelines to evaluate the prevalence of other diagnoses (e.g., IBD or microscopic colitis) in IBS patients undergoing colonoscopy. Among patients with IBS symptoms, the rate of IBD diagnosis was 4% (95% CI, 1-9; nine studies, n=5603) (21)(22)(23)(24)(25)(26)(27)(28)(29), and the rate of microscopic colitis was 4.5% (95% CI, 2.4-7.3; nine studies, n=3344) (21,22,25,27,(29)(30)(31)(32)(33). In patients with IBS-D only, the rate of microscopic colitis was higher at 10% (95% CI, 3-19; six studies, n=841) (23,(29)(30)(31)(32)34). While this data might suggest colonoscopy is useful, there was no age limit in these studies, and all suffered from referral bias. There was significant heterogeneity. In addition, in the majority of studies that included a control group without IBS symptoms, there was no significant difference in the frequency of colonoscopic findings in the IBS group compared with the control groups (21,22,24,27), with the exception of microscopic colitis in females with diarrhea over the age of 45 years (23,31,33,34).
A longitudinal, case-control study using data from a national health insurance database in Taiwan compared the 10-year risk of organic diseases among patients with IBS (n=1225) with age-and sex-matched controls (n=4900) (35) Unexpectedly, no cases of celiac disease were reported in the IBS group. Although significantly higher in the IBS group than in the non-IBS group, with the exception of microscopic colitis (59.8% versus 43.6%), the absolute incidence rates of IBD (7% versus 3.8%) and CRC (4.6% versus 1.3%) remained low (35). This study did not stratify by age; therefore, the rates in patients under 50 years could not be determined.
The utility of alarm features in predicting CRC was evaluated in a systematic review of 15 studies (n=19,443) in unselected adults (36). Using a positive likelihood ratio (LR) of 10, which usually signifies a diagnostically useful test (37), most of the included alarm features performed poorly (36). A positive LR was noted for rectal bleeding (unspecified) (LR 1.32' 95% CI, 1.19-1.47), change in bowel habit (LR 1.29; 95% CI, 1.05-1.59), anemia (LR 1.43; 95% CI, 0.75-2.74), and weight loss (LR 1.96; 95% CI, 1.25-3.08). The only two symptoms with sufficient specificity to rule in the diagnosis of CRC (therefore suggesting that colonoscopy would be appropriate) were abdominal mass (97%; 95% CI, 96-98) and dark red rectal bleeding (96%; 95% CI, [93][94][95][96][97][98].
Discussion: Data were conflicting, and while some evidence suggested that IBS patients are at increased risk for organic disease over the long-term compared with individuals in the general population, absolute rates remain low.
With respect to CRC, the risk is low in the general population <50 years of age (38), and IBS is not a recognized risk factor for CRC (39,40). There appears to be little or no evidence that IBS increases the risk of CRC over the short-term compared with the general population (41,42), with the exception of the study from Taiwan that suggested a 3.6 times higher 10-year risk in the IBS group compared with the non-IBS group (35).
Data in the general population suggested that the diagnostic accuracy of alarm symptoms for CRC was poor. Alarm features are usually defined as vomiting, gastrointestinal bleeding, abdominal mass, dysphagia, unexplained weight loss and anemia (43). Only abdominal mass and dark red rectal bleeding were associated with an increased risk of CRC (36).
An observational study of the predictive value of alarm features, specifically in IBS patients, did suggest a significantly higher prevalence of organic diseases (including Crohn's disease, celiac disease, and microscopic colitis) among those with alarm features compared with those without (27.7% versus 15.4%, P=0.002) (44). There was a trend toward a higher rate of CRC among IBS patients with alarm features, but this was not significant. The likelihood of organic disease increased with increasing numbers of alarm features. Importantly, the prevalence of organic diseases was significantly higher in patients with IBS-D compared with those with IBS-C.
Finally, data do not support the idea that patients may be reassured by a normal colonoscopy. A retrospective study in patients with IBS aged <50 years found no difference in the proportions of patients that were 'reassured' (defined as a negative response to the question 'Do you think something serious is wrong with your body?') by negative colonoscopy compared with no colonoscopy (45)
# Statement 4: We recommend AGAINST IBS patients <50 years of age without alarm features ROUTINELY having a colonoscopy to exclude alternate diagnoses.
Therefore, the consensus group concluded that routine colonoscopy is generally not warranted in IBS patients <50 years of age, and alarm symptoms do not appear to increase the risk of CRC sufficiently to warrant routine colonoscopy. However, clinical judgement is important, and colonoscopy and flexible sigmoidoscopy would continue to play a role to investigate specific indications such as a high clinical suspicion of IBD or microscopic colitis or for patients with a combination of alarm features or a pronounced alarm feature such as dramatic weight loss.
# Key evidence:
The support for this statement is extrapolated from evidence-based guidelines on screening for CRC (39,40,46). Colonoscopy is regarded as the gold-standard screening test for CRC, and while some guidelines (40) do not recommend this approach in the average-risk population, the opportunistic screening of patients ≥50 years of age with recently onset IBS symptoms that have not had investigation within five years would involve fewer individuals than a general population screening program. Therefore, this would likely be less costly and the benefits would be likely to outweigh the risks. There is moderate-quality evidence that flexible sigmoidoscopy is associated with a decreased incidence of CRC, which when extrapolated to colonoscopy is reduced to low quality because of indirectness (46). Additional, low-quality, observational data have shown that screening colonoscopy in individuals at average risk can reduce the relative risk of CRC incidence but not CRC mortality (47).
Discussion: An estimated 50% of patients with IBS report having first had symptoms before the age of 35 years (48), and the odds of IBS in individuals over 50 years were significantly lower than in those younger than 50 years (OR, 0.75; 95% CI, 0.62-0.92) (2). Therefore, the new onset of IBS symptoms in older patients may warrant colonoscopy to exclude other diagnoses (e.g., CRC or IBD).
Guidelines recommend that individuals 50 years or above at average risk for CRC undergo screening with fecal occult blood testing or colonoscopy (39,40). As mentioned (see statements four and five), there appears to be little evidence that IBS symptoms alone increase the risk of CRC (41,42); therefore, the consensus group agreed that adults 50 years or older with an established history of IBS should be screened for CRC according to average risk guidelines (39,40).
The consensus group emphasized that colonoscopy is just one method of screening for CRC, and patients should be made aware and educated about the efficacy of fecal immunochemical tests (FITs) in reducing CRC incidence and mortality (39). This is particularly important in light of the greater resource requirements associated with colonoscopy (40). Patient should be engaged in informed decision-making about screening, and preferences for colonoscopy or FIT should be considered (39).
# Key evidence:
The efficacy of food allergy testing has been evaluated in one RCT, in which 150 patients were randomized to exclude all foods that they were intolerant of according to an IgG antibody test or to a sham diet where patients were asked to avoid the same number of foods to which they exhibited IgG antibodies but not those particular foods (49). The trial had an unclear risk of bias. At 12 weeks, a greater proportion of patients in the active intervention group reported a 'significantly improved' global impact score versus those in the sham diet group (28% versus 17%, number needed to treat [NNT] 9). But this was not statistically significant (P=0.14). This was higher among patients who fully adhered to their diets (54.1% versus 15%, NNT 2.5).
Discussion: Food adverse reactions include food allergy and food intolerance. While food allergies are mediated by immunologic reactions, food intolerance is not and may be due to factors within foods, such as chemical agents (e.g., caffeine or tyramine), enzyme deficiency of the host (e.g., lactase deficiency) or idiosyncratic responses related to an unknown mechanism (50,51). Although patients with IBS self-report food allergies more often than the general population, evidence suggests that true food allergies are relatively uncommon. True food allergies are reported in about 1% to 4% of adults in the general population, with 50% to 90% of presumed food allergies being food intolerances (51). In a study in patients with GI symptoms, food allergy was confirmed by endoscopic allergen provocation or elimination diet and rechallenged in only 3.2% of patients, despite 32% of patients with GI symptoms reporting adverse reactions to food (52). Another study found no difference in the frequency of positive skin prick tests in IBS patients with and without self-reported adverse reactions to food, and symptoms correlated with the foods identified by allergy testing in only 14% of cases (53).
In contrast, food triggers are common, with more than half of IBS patients having self-reported food intolerances (54,55). The most common food triggers include those with incompletely absorbed carbohydrates (e.g., dairy products, beans/lentils, apple and flour), foods rich in biogenic amines (e.g., wine/ beer, salami and cheese), histamine-releasing foods (e.g., milk, wine/beer and pork), and fried and fatty foods (54,56).
# Statement 6: We recommend patients with new-onset IBS symptoms at ≥50 years of age have colonoscopy to exclude alternative diagnoses.
GRADE: Strong recommendation, low-quality evidence. Vote: strongly agree, 50%; agree, 50% Journal of the Canadian Association of Gastroenterology, 2019, Vol. XX, No. XX 7
The consensus group concluded that true food allergies are likely to be rare in IBS patients, and there are little data to support the efficacy of avoiding foods as identified by allergy testing. Therefore, they strongly recommended against IBS patients undergoing allergy testing and encouraged patient education to discourage this practice. This suggestion does not preclude encouraging patients to avoid specific foods that have been associated with symptom exacerbations, but allergy testing is unlikely to provide any additional benefit. Key evidence: A systematic review was conducted for these consensus guidelines to evaluate the prevalence of lactose malabsorption in patients with IBS. In a meta-analysis of 34 case series including 9041 patients with all subtypes of IBS evaluated with a lactose H 2 breath test, the prevalence of lactose malabsorption was 47% (95% CI, 41%-53%) with significant heterogeneity between studies. The prevalence was 50% (95% CI, 43%-56%) in European studies, 21% (95% CI, 14%-29%) in US studies, and 56% (95% CI, 43%-69%) in South Asian studies. Heterogeneity persisted in these subanalyses, suggesting that the variability in results could not be explained by different genetic populations with different underlying risks of lactase deficiency but was likely due to variations in patient selection, doses of lactose used and cutoffs to define malabsorption.
In 10 case control studies, including 2008 subjects, there was no significant difference in the prevalence of lactose malabsorption in IBS patients compared with controls with no GI symptoms (OR 1.68; 95% CI, 0.95-2.94, P=0.07) (Figure 1). Again, there was significant heterogeneity between studies.
Discussion: While lactose malabsorption is common, there appears to be no significant difference in its prevalence in patients with IBS compared with the general population. Furthermore, the few studies that have assessed the efficacy of lactose avoidance in improving symptoms in IBS patients show conflicting results (57)(58)(59)(60)(61)(62).
The data do not exclude lactose malabsorption as the explanation for IBS symptoms in a minority of patients, but they do not support the routine use of lactose breath testing in IBS patients.
# Key evidence:
A systematic review of studies evaluating the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with IBS was conducted for these consensus guidelines. In a meta-analysis of 24 case series, including 2698 patients with all subtypes of IBS evaluated with a glucose H 2 breath test, the prevalence of SIBO was 25% (95% CI, 19%-32%) with significant heterogeneity between studies and use of a variety of nonvalidated cutoffs. This analysis excluded studies evaluating the lactulose H 2 breath test, which may be less specific (63).
In 13 case-control studies, including a total of 2682 participants, there was a statistically significant difference in the prevalence of SIBO in patients with IBS compared with controls without GI symptoms (OR 6.29; 95% CI, 4.55-8.68) (Figure 2). There was no significant heterogeneity between studies. Discussion: Although a strong difference in the prevalence of SIBO was found between patients with IBS and healthy controls, clinicians do not require a test to differentiate between those with IBS and those who are asymptomatic. Studies have rarely evaluated other control groups, but those that did found that SIBO was either just as or more prevalent in those with functional diarrhea (63) and functional dyspepsia (64), with the latter finding not explained by proton pump inhibitor use.
Furthermore, there is a paucity of studies of antibiotic therapy for improving symptoms in patients with a positive glucose breath test (versus negative breath test), and most have focused on only those that are breath test positive (65,66). This approach does not define the value of a positive test.
The consensus group concluded that although SIBO may be an explanation for IBS symptoms for some patients, the data do not support the routine use of glucose breath testing in IBS patients. (72). GRADE analysis found all trials to be at high-risk of bias, with significant clinical and statistical heterogeneity between studies.
Discussion: The interest in a low FODMAP diet stems from the fact that FODMAPs are carbohydrates that are largely indigestible in the small intestine because of the absence of suitable hydrolase enzymes or incomplete absorption (73). This leads to an increase in fluid in the small bowel, which may be one of the underlying mechanisms for diarrhea in IBS. In addition, fermentation of FODMAPs by colonic microbiota results in production of gas, short chain fatty acids, and possibly other metabolites (73)(74)(75)(76).
There was a trend toward a beneficial effect of low FODMAP diet, but the data were very low in quality. Patients will often want to explore dietary changes (77), and the low FODMAP appears to be the most studied and perhaps the most likely to improve overall symptoms (see also statement 11). Most studies also showed significant improvements in individual symptoms of abdominal pain, bloating, frequency and urgency (68)(69)(70)(71). Increases in dietary FODMAP content were associated with increasing symptoms, demonstrating the importance of adherence to the diet (70). The low FODMAP diet has potential drawbacks. Of concern is the fact that the low FODMAP diet can have a substantial effect on the colonic microbiota. Studies have shown a reduction in the relative proportion of Bifidobacteria and other changes that may negatively affect gastrointestinal health (70)(71)(72)78). The included RCTs were all short-term (three to four weeks) (68-71), and long-term use is generally not recommended due to the risk of dietary inadequacy related to the exclusion of many nutrient-rich foods (73). From a patient's perspective, the low FODMAP diet can be difficult to adhere to, costly, and restricting for social events such as dining out (73,79).
The consensus group concluded that there were some data to suggest that a low FODMAP diet may be helpful for some patients. However, if a low-FODMAP diet is suggested, it should be implemented under the guidance of a dietician, and a strict diet should be implemented for as short a term as possible (e.g., four weeks).
# Key evidence:
Two RCTs evaluated a gluten-free diet in 111 patients with IBS in whom celiac disease had been rigorously excluded (67,80,81). In these rechallenge trials, IBS patients who reported symptom control with a gluten-free diet were then randomized to a gluten challenge or continued a gluten-free diet. This provides indirect data because withdrawing a significant food group from the diet and then introducing it may induce symptoms even in an individual without IBS. In the pooled analysis, there was no statistically significant impact on IBS symptoms in the gluten challenge versus gluten-free diet groups (RR 0.46; 95% CI, 0.16-1.28; P=0.14), with significant heterogeneity between studies. A randomized trial suggested that the benefit of a gluten-free diet in patients without celiac disease may relate to the accompanying reduction in FODMAPs (82).
Discussion: Nearly two-thirds of IBS patients have reported that their GI symptoms were related to meals (56). Patients commonly associate certain foods with exacerbations of their symptoms, and more than one-half have self-reported food intolerances (54 ,55, 77). As a result, patients will often try to explore dietary modifications to relieve their symptoms (77).
Perhaps based on the role of gluten in the pathogenesis of celiac disease, gluten has become associated with gastrointestinal symptoms. Conversely, the gluten-free diet is perceived as healthier and has become increasingly popular with the general population (83). However, a gluten-free diet overall is not necessarily healthier because it is associated with high sugar intake and low fibre and mineral intake (84). In addition, gluten-free foods can be difficult to obtain and are more expensive than their gluten-containing counterparts (85).
The consensus group suggested against a gluten-free diet, concluding that it has an uncertain effect on IBS symptoms and places an unnecessary burden on IBS patients.
# Key evidence:
For this consensus, a prior systematic review and meta-analysis ( 86) was updated with one additional RCT (87) for a total of 15 RCTs (n=946). Most trials did not differentiate between patients according to IBS subtype, and few used Rome criteria to diagnose IBS. Risk of bias was unclear in the majority of studies.
Overall, there was a statistically significant effect in favour of fibre supplementation versus placebo or no treatment (RR of IBS not improving 0.87; 95% CI, 0.80-0.94; P=0.0003). Bran (six studies, n=411) had no significant effect on treatment of IBS (RR of IBS not improving 0.90; 95% CI, 0.79-1.03; P=0.14); however, ispaghula husk (psyllium) (seven studies, n=499) was effective (RR of IBS not improving 0.83; 95% CI, 0.73-0.94; P=0.005; NNT 7; 95% CI, 4-25).
In the updated meta-analysis (seven studies, n=606), there was no increase in overall adverse events with fibre compared with placebo (36.6% versus 25.1%; RR 1.06; 95% CI, 0.92-1.22). There were insufficient data from individual studies to assess adverse events according to fibre type.
Discussion: The evidence suggests that only soluble (e.g., ispaghula husk/psyllium) but not insoluble (e.g., wheat bran) fibre had a significant effect for the treatment of IBS symptoms. It has been suggested that insoluble fibre may exacerbate symptoms (7). Psyllium has been shown to improve both constipation and diarrhea (88). The mechanisms are unlikely to be solely related to bulking of stool and may also include alterations in the production of gaseous fermentation products and changes to the composition of the gut microbiome (86,88).
While increasing fibre content in diet may also be helpful, this is more difficult to regulate and was not studied in the RCTs, which all used fibre supplements. Foods high in soluble fibre include oats, barley, flaxseeds, oranges, carrots, beans/legumes, and those high in insoluble fibre include wheat bran, whole grains, some vegetables (e.g., broccoli, cabbage), and fruits with skins (e.g., apples, grapes) (55).
Based on the evidence for efficacy and safety, the consensus group strongly recommended soluble fibre supplementation as a low-cost, safe treatment option that is acceptable to patients and has moderate-quality evidence that it improves IBS symptoms.
# Key evidence:
Evidence for herbal remedies in IBS was available from three systematic reviews (89)(90)(91). One systematic review of 72 RCTs concluded that traditional Chinese medicine (TCM) combined with conventional Western medicine improved IBS symptoms (RR 1.21; 95% CI, 1.18-1.24) compared with Western medicine alone using indirect comparisons. However, the authors noted the methodological quality of the included RCTs was very low (89). A second systematic review including 27 studies on a wide variety of herbal therapies found the most evidence for efficacy in IBS for essential oil of Mentha piperita and the compound preparation STW 5, a formula containing hydroethanolic extract of nine herbs. Aloe vera, Curcuma xanthorriza and Fumaria officinalis showed no benefit in IBS. However, the authors did not synthesize the results from different preparations and were unable to reach a definitive conclusion as to the value of herbal therapies in IBS (90).
The third systematic review evaluated 22 RCTs including 25 different TCM or Western herbal therapies compared with placebo or conventional medicines. Eight studies (using nine herbals) showed global improvement of IBS symptoms, four studies (using three herbals) found efficacy in IBS-D, and two studies (using two herbals) showed efficacy in IBS-C. However, 18 of 22 trials were determined to be of poor quality, and there was evidence of publication bias (91).
Discussion: Overall, the evidence for herbal treatments, most of which is derived from studies of TCMs, is very low-quality. Many herbal products are not regulated, and the amount of 'active ingredient' can vary among the different products or batches of products. Products that are licensed by Health Canada's Natural and Non-prescription Health Products Directorate (NNHPD) include an eight-digit natural product number (NPN) or homeopathic medicine number (DIN-HM) on the label. In addition, although the published studies report low rates of adverse events, herbal treatments are not without side effects.
The consensus group concluded that while some studies suggest a benefit of some herbal therapies, there is insufficient evidence for any particular herbal product that would warrant recommending any individual therapy. Conversely, it cannot be ruled out that some products may be effective, and more high-quality studies are needed. Key evidence: A Cochrane systematic review identified six RCTs evaluating acupuncture in IBS. Pooled results from the only two trials providing data for the dichotomous outcome (the proportion of responders with clinically recognized improvement in symptoms) showed no statistically significant effect of acupuncture versus sham acupuncture (RR 1.28; 95% CI, 0.83-1.98; n=109) (92). However, most of the trials were of poor quality and were heterogeneous in terms of interventions, controls and outcomes measured.
An update to the Cochrane systematic review included 17 RCTs (n=1806), but this review did not fulfill our inclusion criteria because it provided no dichotomous data for the acupuncture versus sham comparisons. However, there was no evidence of an improvement with acupuncture relative to sham (placebo) acupuncture for symptom severity (standard mean difference [SMD] −0.11; 95% CI, −0.35 to 0.13; four RCTs; 281 patients) or quality of life (SMD −0.03; 95% CI, −0.27 to 0.22; three RCTs; 253 patients) (93). The overall quality of the evidence in the sham controlled trials was rated moderate due to sparse data.
The proportion of patients with symptom improvement was significantly higher in the acupuncture group compared with pharmacological therapy (84% versus 63%; RR 1.28; 95% CI, 1.12 to 1.45; five studies; 449 patients) and compared with no specific therapy (63% versus 34%; RR 2.11; 95% CI, 1.18 to 3.79; two studies, 181 patients). The overall quality of evidence for this outcome was low due to a high risk of bias (no blinding) and sparse data (93).
Therefore, the current GRADE assessment concluded that there was very low-quality evidence suggesting that there were no benefits of acupuncture relative to a credible sham acupuncture control for proportion of responders or IBS symptom severity (92).
Discussion: Data did not show a significant benefit of acupuncture compared with sham acupuncture treatments in improving IBS symptoms overall. A recent RCT that postdated the search window for this consensus provided further support for a lack of efficacy (94).
Data are very low-quality, and it is unknown whether level of therapist training or different acupuncture techniques would impact results. Although generally well tolerated, adverse events of acupuncture can include bleeding, pain and aggravation of symptoms, and rare, serious complications can include tissue or nerve injury and infections (95)(96)(97).
# Statement 15: We recommend AGAINST offering acupuncture to IBS patients to improve IBS symptoms.
Overall, probiotics were statistically significantly superior to placebo (RR of IBS not improving 0.81; 95% CI, 0.74-0.89; P<0.00001; NNT 7; 95% CI, 5-12.5) (Table 2). There was significant heterogeneity between studies. Subanalyses according to type of probiotic demonstrated significant effects only for combination probiotics (20 Overall probiotics had a statistically significant effect in reducing global symptom or abdominal pain scores (33 studies; SMD -0.21; 95% CI, -0.31 to -0.10; P=0.0001), bloating scores (24 studies; SMD -0.13; 95% CI, -0.24 to -0.02; P=0.02) and flatulence scores (11 studies; SMD -0.23; 95% CI, -0.38 to -0.08; P=0.003) but not urgency scores (8 studies; SMD -0.11; 95% CI, -0.26 to 0.05) compared with placebo.
Data on overall adverse events were reported in 36 of the RCTs. The pooled incidence of adverse events was not significantly greater among patients who received probiotics versus those who received placebo (19.4% versus 17.0%; RR 1.09; 95% CI, 0.91-1.29).
Discussion: Probiotics overall and combination products have demonstrated efficacy in improving IBS symptoms. However, trials assessed a variety of combination and specific-species products (but widely variable strains). Significant benefits were seen with combination products (most of which contain Lactobacillus but different species) and a trend but no significant benefit with single-species Lactobacillus products.
Similar to herbal products, many probiotic products are not regulated. They may have limited shelf life, making the content of live bacteria questionable. Probiotic products can be an economic burden, and patients should be encouraged to select products that are licensed by Health Canada's NNHPD.
The consensus group concluded that while studies suggest benefits with probiotic therapies overall, and with combination probiotics, there is insufficient evidence for any particular species. Although some products may be helpful, others may not. Therefore, if probiotics are to be used, the consensus group suggested a limited therapeutic trial (e.g., one month). Probiotics can be expensive for patients but are often viewed as a more 'natural', low-risk approach to improving IBS symptoms (120).
# No recommendation A: The consensus group does not make a recommendation (neither for nor against) offering IBS patients relaxation techniques to improve IBS symptoms.
No recommendation B: The consensus group does not make a recommendation (neither for nor against) offering IBS patients shortterm psychodynamic psychotherapy to improve IBS symptoms. (125). There was significant heterogeneity between studies.
Subanalyses according to type of psychological therapy demonstrated significant effects for cognitive behavioural therapy (CBT) (nine studies; RR 0.60; 95% CI, 0.44-0.83; NNT 3; 95% CI, 2-6), hypnotherapy (four studies; RR 0.74; 95% CI, 0.63-0.87; NNT 4; 95% CI, 3-8), multicomponent psychological therapy (five studies; RR 0.72; 95% CI, 0.62-0.83; NNT 4; 95% CI, 3-7) and dynamic psychotherapy (two studies: RR 0.60; 95% CI, 0.39-0.93; NNT 3; 95% CI, 2-25). Multi-component psychological therapy administered via the telephone and contingency management were each studied in 1 trial, and each appeared to have beneficial effects.
No significant benefit was seen with relaxation therapy (seven studies: RR 0.78; 95% CI, 0.62-1.00), stress management (three studies; RR 0.68; 95% CI, 0.39-1.20), self-administered CBT (three studies; RR 0.53; 95% CI, 0.17-1.66), mindfulness meditation training (two studies; RR 0.78; 95% CI, 0.44-1.41) or CBT delivered via the internet (two studies; RR 0.75; 95% CI, 0.48-1.17).
In the four trials (126-129) (n=233) that used 'sham' or 'control' psychological interventions, there was a statistically significant effect of 'active' psychological therapy (RR 0.56; 95% CI, 0.38-0.84; NNT 3; 95% CI, 2-9).
Adverse event data were poorly reported in the individual RCTs, precluding any meaningful analysis.
Discussion: There was evidence to suggest that psychological therapies overall, as well as CBT, hypnotherapy, and multi-component psychological therapies can be effective for the management of IBS symptoms. However, the data were of very low quality, with evidence of publication bias or other small study effects that may result in overestimates of the effects of psychological therapies. The majority of studies were small, the control group was often usual care or wait list, and blinding is generally not feasible.
Cognitive behavioural therapy was the most widely studied psychological therapy and was found to be effective. Therapistadministered CBT appears to be necessary because internet-based, self-administered or minimal contact CBT did not have significant benefits overall. In small studies, gut-directed hypnotherapy was also found to be effective overall. The mechanism of action is not simply through improvement of distress or mental health symptoms, as the largest effect sizes were found for gastrointestinal symptoms (130). The consensus group concluded that psychotherapy with CBT or hypnotherapy may be effective for some patients, and while it was suggested as a management option, it was recognized that in clinical practice, availability can be a problem.
Relaxation techniques are generally elements of other types of psychological therapies, such as CBT. Clinical trial results with relaxation therapy only were inconsistent and may depend on the techniques that were used. Relaxation therapy was not statistically significantly different than control, but the 95% confidence intervals did include a clinically important benefit. However, because of the inconsistent results, the consensus group could not make a recommendation for or against this option. Some consensus participants had concerns that if a patient fails relaxation therapy, they may not be willing to try another more effective psychotherapeutic option. Although evidence suggested significant effects for dynamic psychotherapy, the findings of the two studies came from the same lab, the therapy can be difficult to replicate, and the data do not reflect techniques commonly used in current clinical practice. The studies were short-term (e.g., eight sessions), while in clinical practice, this type of psychotherapy is usually administered over a longer period. Unlike therapies such as CBT that are manualized with a specific protocol, psychodynamic therapies are less structured. The consensus group concluded that the data may not reflect a psychotherapy that is clinically available and were unable to make a recommendation for or against this option.
Overall, the consensus group concluded that while access in Canada may be a problem, psychological therapies-particularly CBT or hypnotherapy-may be a beneficial treatment option for some patients.
# Key evidence:
For this consensus, a prior systematic review and meta-analysis (98), was updated with three new studies (131)(132)(133) for a total of 26 RCTs (n=2811). The quality of the trials was generally poor with the majority having small sample sizes and high risk of bias. Most trials pre-dated Rome criteria, and the majority used author-defined criteria to diagnose IBS. The majority of trials did not differentiate between the type of IBS patients.
The trials evaluated a total of 13 different antispasmodics, and overall antispasmodic therapy was significantly superior to placebo (RR of IBS symptoms not improving 0.65; 95% CI, 0.56-0.76; P<0.00001; NNT 5; 95% CI, 4-8). There was significant heterogeneity between studies.
Subanalyses of individual antispasmodics demonstrated significant benefits compared with placebo for otilonium ( . The most common adverse events were dry mouth, dizziness, and blurred vision. No serious adverse events were reported in either treatment arm in any of the trials.
Discussion: Antispasmodics have anticholinergic or calcium-channel blocking properties, which may help in IBS by relaxing smooth muscles in the gut (134). Although the quality of evidence is very low, antispasmodics have been used in IBS in primary care for a long time and there is some evidence for efficacy in improving IBS symptoms. However, there are a wide variety of medications, and not all were effective. Of the four antispasmodics available in Canada, hyoscine, pinaverium, and dicyclomine (dicylcoverine), were shown to be effective, while trimebutine was not. Therefore, the consensus group suggested the use of only these three antispasmodics. In light of the fact that the evidence was very weak, the potential for anticholinergic side effects, and the higher quality evidence for other alternative treatments, the consensus group suggested that these agents generally be reserved for use in patients who fail other treatments or whose symptoms are best served by an agent taken as needed for abdominal pain. not improving 0.66; 95% CI, 0.57-0.76; P<0.00001; NNT 4; 95% CI, 3-6) (125). There was a trend toward heterogeneity between studies, but this was not statistically significant.
Subanalyses according to type of antidepressant class demonstrated significant effects on IBS symptoms with both tricyclic antidepressants (TCAs) (12 studies; RR of IBS not improving 0.65; 95% CI, 0.55-0.77; P<0.00001; NNT 4; 95% CI, 3-6) and selective serotonin reuptake inhibitors (SSRIs) (7 studies, RR 0.68; 95% CI, 0.51-0.91; P=0.01; NNT 4; 95% CI, 2.5-20) compared with placebo.
Overall adverse event data were available from seven RCTs. The pooled incidence of adverse events was significantly greater among patients who received antidepressants versus those who received placebo (31.3% versus 16.5%; RR 1.63; 95% CI, 1.18-2.25; NNH 9; 95% CI, 5-111). No serious adverse events were reported in any of the trials. Drowsiness and dry mouth were more common in patients who received TCAs than those who received placebo.
Discussion: There was good-quality evidence demonstrating that antidepressants overall, TCAs, and SSRIs are effective in improving IBS symptoms and abdominal pain. Possible mechanisms of action of antidepressants in gastrointestinal disorders may include effects on gut transit times, and central and peripheral pain sites, as well as antiinflammatory and analgesic properties (136,137). TCAs have been extensively studied and have demonstrated efficacy in multiple chronic pain conditions (e.g., neuropathic pain, headaches, low back pain, fibromyalgia), while there is much less support for SSRIs for the treatment of pain (136).
In the clinical trials the TCAs studied included amitriptyline, desipramine, doxepin, imipramine, and trimipramine, and the SSRIs included citalopram, fluoxetine, paroxetine (121,135). However, the choice of antidepressant should consider a number of disease and medication factors. TCAs have been shown to prolong gut transit times and constipation is a common adverse event, whereas SSRIs may decrease transit time (138). Therefore, TCAs may be more effective in IBS-D (139), and SSRIs in IBS-C (140). However, most of the RCTs did not analyze results according to IBS type. In addition, because TCAs have demonstrated benefits for chronic pain (136), they may be useful in patients with IBS-C once constipation is controlled with other treatments. Because antidepressants in IBS may be used as a short-term treatment trial, the choice of SSRIs should consider that discontinuation syndrome can be more frequent or severe with paroxetine (141,142).
The effect of antidepressant treatment on coexistent depression or anxiety in IBS patients is controversial. No significant correlations between depression scores and improvements in IBS symptoms have been demonstrated (121). In IBS trials, the doses of SSRIs were similar to those used to treat depression, whereas the doses of TCAs were considerably lower than therapeutic antidepressant doses (121). It has been suggested that the benefits of SSRIs in IBS may be related to improvements in overall well-being ( 143), but improvements in IBS have been independent of change in mood (121,143).
From the patient perspective, patients may interpret the prescription of an antidepressant as a dismissal of their symptoms as psychological, or those experiencing mood symptoms, may expect the antidepressant to improve these symptoms (143). Therefore, patient education on the nature of IBS, and the potential effects of antidepressants is crucial for adherence.
The consensus group suggested that SSRIs may be preferred over TCAs for patients with IBS-C and comorbid depression, because of the adverse event profile of TCAs and the fact that SSRIs are used at therapeutic antidepressant doses; however, there is little specific evidence for this. For gastroenterologists who do not feel comfortable prescribing antidepressants, they may want to consider referring patients back to their primary care providers for treatment. Key evidence: Data were available from two double-blind RCTs including 42 patients with clinically defined IBS-M or IBS-D and compared loperamide with placebo for three to 13 weeks (144,145). Pooled results showed no significant improvement with loperamide over placebo for global IBS symptoms (RR of IBS not improving 0.44; 95% CI, 0.14-1.42; P=0.17) (Figure 4). Loperamide was associated with a significant effect on stool frequency (RR of stool frequency not improving was 0.2 (95% CI, 0.05-0.90; p=0.01) and stool consistency (100% of patients improved versus 20-45%, P=0.006) compared with placebo. Beneficial effects on stool frequency, stool consistency, and urgency were also demonstrated in two other RCTs that were not included in the GRADE analysis because of lack of adequate global symptom results (146,147).
Overall incidence of adverse events with loperamide was similar to placebo in the two included trials (144,145).
Discussion: Loperamide is an opioid receptor agonist that has been shown to decrease peristalsis and fluid secretion, resulting in delayed intestinal transit and decreased loss of fluids and electrolytes (146,148). Loperamide significantly improved diarrheal symptoms, but has not been shown to consistently improve global IBS symptoms or abdominal pain
# Statement 23: We suggest AGAINST offering diarrhea-predominant IBS patients continuous loperamide use to improve IBS symptoms.
GRADE: Conditional recommendation, very low-quality evidence. Vote: strongly agree, 17%; agree, 83% (144)(145)(146)(147). In addition, common side effects of loperamide can include abdominal pain, bloating, nausea, vomiting, and constipation) ( 149).
Patients will sometimes use loperamide prophylactically when social situations or travel make it inconvenient to have diarrhea, or when participating in a stressful situation that is known to exacerbate diarrhea. Although there is no data on intermittent use, the consensus group acknowledged that some patients may find this strategy useful, and therefore, suggested against continuous loperamide use only.
# Key evidence:
There is little evidence for the use of cholestyramine in unselected patients with IBS-D. A systematic review, of data on the use of cholestyramine in IBS-D patients also included patients with chronic diarrhea, and only reported response rates in patients with evidence of bile acid malabsorption (BAM) as identified by 7-day SeHCAT scanning (tauroselcholic [ 75 selenium] acid) retention rates (150). Pooled data from 15 studies showed a dose-response to cholestyramine according to severity of malabsorption: severe BAM 96%, (<5% retention), moderate BAM 80% at (<10% retention) and mild BAM 70% (<15% retention) (P=0.007 for trend). Data were not reported for patients with a negative SeHCAT, who were generally not given a therapeutic trial of cholestyramine.
A systematic review conducted for this consensus identified 15 case-series' studies in patients with IBS-D (n =1223), but did not identify any RCTs. None of the case-series reported dichotomous data on the proportion of patients responding to cholestyramine with a clear definition of response in unselected IBS-D patients.
Discussion: While there was some evidence of symptomatic response in a select group of patients with IBS-D or chronic diarrhea who had idiopathic BAM, efficacy rates decreased with decreasing severity of BAM. The data were very low quality, and may not be generalizable to IBS patients without BAM.
Therefore, based on the lack of data in unselected patients with IBS-D, the consensus group suggested against this treatment.
# No recommendation C: The consensus group does not make a recommendation (neither for nor against) offering diarrhea-predominant IBS patients one course of rifaximin therapy to improve IBS symptoms.
Key evidence: For this consensus, a prior systematic review of antibiotics in IBS ( 7) was updated with two additional RCTs (151,152) for a total of seven RCTs (n=2654) (119). Patients had non-constipated IBS (predominantly IBS-D).
Overall, rifaximin was significantly more effective than placebo in treating IBS (RR of IBS symptoms not improving 0.82; 95% CI, 0.72-0.95, P=0.006; NNT 9; 95% CI, 6-12.5); however, there was significant heterogeneity between trials. The effect remained significant in an analysis that included only the four RCTs with low risk of bias (n=1996; RR 0.87; 95% CI, 0.82-0.93; NNT 11; 95% CI, 8-20) with no significant heterogeneity (153)(154)(155).
The incidence of overall adverse events was not significantly greater among patients in the rifaximin group compared with the placebo group (three studies; RR 0.70; 95% CI, 0.42-1.16).
Discussion: Rifaximin is a non-systemic broad-spectrum antibiotic derived from rifamycin, which targets the gut (156,157). Rifaximin has been associated with a low risk of development of bacterial resistance, or cross-resistance with rifampin (157). The mechanisms of action of rifaximin in IBS have not been clearly identified, but may alter the microbiome thus reducing gas production (157,158).
There was moderate-quality evidence of a beneficial effect of rifaximin over placebo, which continued to be apparent at the end of follow up (three to six months). In addition, one trial suggested efficacy with a repeat course in IBS patients who had relapsed after previously responding to rifaximin (152).
There were a number of concerns around recommending the widespread use of an antibiotic for the management of IBS. Rifamycins are important in the treatment of serious infections, and the potential for antibiotic resistance and cross-resistance with rifaximin is a serious issue. There were also concerns around the poorly defined mechanism of action in IBS, the cost, and the potential for overuse. In addition, although rifaximin has been FDA approved for the treatment of IBS-D in US (156), it has not been approved by Health Canada for this use.
As a result there is little experience in Canada with this agent for IBS. From a patient's perspective, the use of an antibiotic can be confusing, because it may lead patients to believe that they have an infection that will be 'cured' after the course of therapy. Because of these concerns, the consensus group was unable to recommend for or against rifaximin treatment at this time, despite data demonstrating efficacy in IBS. To minimize over use, the consensus group suggested that if this strategy is to be tried, patient should be referred to a gastroenterologist for treatment.
# Key evidence:
The efficacy of eluxadoline in IBS has been reported in three RCTs (n=3235) (159,160). All three of the included trials used Rome III criteria to define IBS-D, and all were at low risk of bias. In the pooled analysis, eluxadoline was significantly more effective than placebo (RR of IBS not improving 0.91; 95% CI, 0.85-0.97; P=0.004; NNT 12.5; 95% CI, 8-33) (Figure 5); however, there was significant heterogeneity between trial results. Eluxadoline had no statistically significant effect on abdominal pain (RR of no improvement 0.95; 95% CI, 0.89-1.02; p=0.06) although there was a trend to benefit, but did improve stool consistency (RR of no improvement 0.88; 95% CI, 0.80-0.96; p<0.01; NNT 10; 95% CI, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].
Overall adverse event data were provided in all three RCTs. The pooled incidence of patients reporting at least one adverse event in the two RCTs reported by Lembo et al was 59% with eluxadoline and 56% with placebo (160). In the other RCT, the rates of adverse events were 48% with eluxadoline and 49% with placebo (159). The most common adverse events with eluxadoline were constipation, nausea, and vomiting (159,160). Serious adverse reactions of pancreatitis and sphincter of Oddi spasm have been reported (<1% of patients).
Discussion: Eluxadoline is a synthetic opioid receptor modulator, with high-affinity for the μ-opioid receptors, and the δ-opioid receptors in the GI tract only. In contrast, loperamide is only active at the μ-opioid receptor (161). The drug was approved by Health Canada in January 2017 for the treatment of IBS-D ( 162), but only became available in late April, therefore, at the time of this consensus there was little or no clinical experience with this agent in Canada.
There was moderate-quality evidence that eluxadoline had a beneficial effect over placebo, for overall IBS symptoms. Effects were modest with response rates at 26 weeks of about 30% with eluxadoline compared with 20% with placebo (160). The treatment effect of eluxadoline over placebo was observed within the first week and was maintained throughout the 26-week trials (160).
There are a number of safety concerns with eluxadoline, and the drug is contraindicated in patients with biliary duct obstruction, cholecystectomy, alcoholism, pancreatitis, hepatic impairment, and chronic or severe constipation (162). In the clinical trials the majority of serious adverse events (pancreatitis and sphincter of Oddi spasm) occurred in patients with pre-existing conditions including absence of a gallbladder or excessive alcohol consumption (160).
However, among patients with IBS this is an important contraindication because these patients are at 2-to-3-times higher risk of cholecystectomy (4.6% to 12.4%) compared with the general population (2.4% to 4.1%) (163,164).
Although there was moderate-quality evidence for efficacy, the potential safety issues and the lack of clinical experience with the drug led the consensus group to make only a conditional suggestion in favour of this treatment at this time. In addition, they suggested that if this treatment is to be used, the patient should be referred to a gastroenterologist, and the treatment trial should be of limited duration (e.g., three months).
# Key evidence:
Two RCTs that fulfilled inclusion criteria for this consensus, compared polyethylene glycol 3350 (PEG) and placebo in a total of 181 patients with Rome (II or III) diagnosed IBS-C (165,166). Compared with placebo, there was a statistically significant increase in the number of bowel movements in one study (166), but not in the other (165), and there was no significant improvement in abdominal pain in either (165,166). Discussion: PEG is a large polymer that acts as an osmotic laxative. In the study meeting inclusion criteria for this consensus there was no evidence of benefit of PEG in IBS-C patients (165). Another larger RCT (n=139) using a PEG plus electrolytes formulation, found an improvement in the number of bowel movements but no effect on abdominal discomfort/pain. In addition, there is evidence that PEG is effective in chronic idiopathic constipation (CIC) (7).
While there is little evidence that osmotic laxatives (e.g., PEG) will improve overall IBS symptoms, some evidence suggests it has beneficial effects on constipation. Therefore, the consensus group suggested against the use of osmotic laxatives for overall symptoms. However, as was the case with loperamide for diarrhea (see statement 23), the consensus group acknowledged that these agents may be useful in some IBS-C patients, particularly as adjunctive therapy in patients who have improved on other treatments but continue to have constipation.
# Key evidence:
A systematic review including eight RCTs, provided high-quality evidence that prucalopride, a 5-HT 4 agonist, was effective in patients with CIC (71.1% of patients failed to respond to prucalopride versus 87.4% with placebo; NNT 5; 95% CI, 4-8) (7). However, it has not been evaluated in RCTs in IBS-C patients. A less selective 5-HT 4 agonist, tegaserod, which has been withdrawn from the market for safety reasons, demonstrated efficacy in IBS-C in a meta-analysis of 11 RCTs (167). There was evidence of publication bias or other small study effects.
Discussion: While prucalopride has demonstrated improvements in constipation symptoms in patients with CIC, there is currently no evidence that it will improve overall symptoms in IBS-C patients. In addition, adverse events were more common with prucalopride compared with placebo, including headache, nausea, and diarrhea (7).
Based on the lack of evidence of benefits in IBS patients, the consensus group suggested against this treatment for overall IBS symptoms, but this does not preclude the targeted use of this agent for constipation symptoms. Key evidence: Evidence for lubiprostone is available from three RCTs in IBS-C patients (n=1366) (168,169). All three of the trials used Rome II criteria to define IBS-C, and all were at low risk of bias. One trial was a dose-ranging, phase IIb study that assessed lubiprostone 8-24 µg bid, and the other two were phase III studies using a dose of eight µg bid. In the pooled analysis, lubiprostone was significantly more effective than placebo (RR of IBS not improving 0.91; 95% CI, 0.87-0.95; P<0.0001; NNT 12.5; 95% CI, 8-25). (Figure 6), Data on overall adverse events were provided in all three of the trials (168,169), but were pooled only for the two phase III studies (169). In the phase IIb study and the pooled phase III studies, there were no significant differences in the incidences of overall adverse events between lubiprostone and placebo (168,169). The phase IIb study reported significantly higher rates of gastrointestinal adverse events (e.g., diarrhea and nausea) particularly at higher doses (168), but this was not seen in the pooled phase III studies using the eight µg bid only (169).
Discussion: Although there was moderate-quality evidence that lubiprostone significantly improved overall IBS symptoms, the effect on abdominal pain was significant for the first two months, but not the third month of treatment in the phase IIb study (168). Lubiprostone activates a specific chloride channel (ClC-2) in the GI tract, and thus enhances intestinal fluid secretion and increases GI transit, which may mediate its beneficial effects on constipation symptoms (170). In light of the fact that this treatment is expensive (171), and there are no comparative studies to evaluate whether it will be more effective than other less expensive treatments, the consensus group made a Discussion: There was high-quality evidence that linaclotide was effective in improving overall IBS symptoms for IBS-C patients. Linaclotide also significantly improved abdominal pain, abdominal bloating, and bowel symptoms (172)(173)(174)(175). Linaclotide is a minimally-absorbed, synthetic peptide that acts on the guanylate cyclase C receptors locally in the gut. It stimulates fluid secretion, increases colonic transit, and modulates afferent pain sensors (171,176). Although there was a relatively high incidence of diarrhea (10-20%), it infrequently resulted in treatment discontinuation. Over 4000 patients were treated with linaclotide in RCTs, including over 2000 patients treated for one year or longer; most adverse events were mild to moderate in intensity, and the incidence of serious adverse events was low (177).
Although, linaclotide is a relatively expensive treatment (171), the high-quality evidence for improvements in multiple IBS symptoms, and the likely low risk of long-term serious adverse events, led the consensus group to make a strong recommendation in favour of using linaclotide in IBS-C patients.
# FUTURE RESEARCH
The heterogeneous nature of IBS and the lack of specific treatments makes the management challenging. Further research is needed on identifying treatments that will manage both specific and global IBS symptoms. Previous studies have evaluated symptom subgroups according to Rome criteria but studies should evaluate objective parameters such as inflammatory markers, microbiome or metabolomics profiles that might better identify IBS patients that will respond to a specific therapy.
Because IBS symptoms may be related in part to alterations in the microbiota, more research is needed to assess the benefits of altering the microbiome for therapeutic benefit. The antibiotic rifaximin, probiotics, and certain dietary modifications have shown some efficacy in relieving IBS symptoms, which may be related to changes in the colonic microbiota. Further research is needed on the pathogenic changes and strategies to target these changes.
While CBT demonstrated significant beneficial effects on IBS symptoms, self-administered CBT, or CBT delivered via the internet did not. Strategies are need to improve delivery and access to therapist administered CBT. In addition, research is needed to find ways to increase the effectiveness of self-administered or online CBT, which will improve access to less costly, less resource intensive therapy.
# SUMMARY
These guidelines present recommendations for the diagnosis and management of patients with IBS. Consensus was reached on 28 of 31 statements pertaining to the diagnosis and management of IBS (Table 1). An algorithm summarizing the consensus-guided approach to management of patients with IBS is shown in Figure 8.
IBS is diagnosed based on symptoms, with limited use of diagnostic tests; however, serological testing is suggested to exclude celiac disease. Journal of the Canadian Association of Gastroenterology, 2019, Vol. XX, No. XX Initial treatment may include a trial of psyllium, but not wheat bran, supplementation to help reduce symptoms. Patients with any IBS whose main symptoms include pain or bloating may benefit from the use of peppermint oil or antispasmodics. A short-term trial of a low FODMAP diet, probiotics, or TCAs, may be useful for patients with IBS-D or IBS-M/U. In addition, patients with IBS-D may benefit from eluxadoline therapy. Pharmacological therapies that may help relieve symptoms for patients with IBS-C include linaclotide, SSRIs, and lubiprostone. Patients with any IBS may also benefit from CBT or hypnotherapy.
These guidelines should help to optimize the use and proper positioning of existing medical therapies and thus improve outcomes in patients with IBS. However, the heterogeneous nature of IBS and the lack of specific treatments continues to make the management challenging. Additional research is needed to identify better treatments for IBS symptoms, and the conclusions of this consensus may subject to change as further data become available and practice patterns evolve. contributions: Paul Sinclair and Lesley Marshall (CAG representatives, administrative and technical support, and logistics assistance), and Pauline Lavigne and Steven Portelance (unaffiliated, editorial assistance). We are grateful to Cathy Yuan for conducting the search strategies, assessing eligibility and extracting the data with PM. We are also grateful to Alex Ford for double checking GRADE assessments with Dr. Paul Moayyedi. Finally, we would like to thank our patient advocate, Megan Marsiglio, for invaluable insights. Canadian Association of Gastroenterology Statement: This clinical practice guideline (CPG) on the management of irritable bowel syndrome was developed under the direction of Dr. Paul Moayyedi, in accordance with the policies and procedures of the Canadian Association of Gastroenterology (CAG) and under the direction of CAG Clinical Affairs. It has been reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors. The CPG was developed following a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian panel with expertise on this topic. The CPG aims to provide a reasonable and practical approach to care for specialists, and allied health professionals are charged with the duty of providing optimal care to patients and families and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The CPG is not intended to be a substitute for physicians using their individual judgment in managing clinical care in consultation with the patient, with appropriate regard to all the individual
# 20
Journal of the Canadian Association of Gastroenterology, 2019, Vol. XX, No. XX circumstances of the patient, diagnostic and treatment options available, and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.
Grant Support: This guideline was supported through unrestricted grants to the Canadian Association of Gastroenterology by Allergan Canada Inc. and Proctor & Gamble Canada, who had no involvement in any aspect of the guideline development.
# Conflicts of
# Acknowledgments
The CAG would like to thank Allergan Canada Inc. and Proctor & Gamble Canada for their generous support of the guideline process. The consensus group would like to thank the following people for their | None | None |
0a2360ab3d2812fbf01a613cc6cf8820a0e53c6e | cma | None | Safe and effective vaccines provide the first hope for mitigating the devastating health and economic impacts resulting from COVID-19 and related public health orders. Both the Pfizer-BioNTech and Moderna products are currently approved in Canada, and further vaccines will likely become available in the coming months. A high rate of vaccine uptake across all sectors of Canadian society is a priority public health goal. Recent case reports of reactions to COVID-19 vaccines have raised questions about their safety for use in individuals with allergies and those who are immunocompromised. In this document, we aim to address these concerns and provide guidance for CSACI members. Suggested approach to vaccination for allergists/immunologists in individuals with confirmed or suspected allergic contraindications to receiving COVID-19 vaccines.#
- Assessment by an allergist is warranted in any individual with a suspected allergy to a COVID-19 vaccine or any of its components. This includes anyone who has experienced a suspected allergic reaction after receiving the first dose of a COVID-19 vaccine, or someone with a suspected or confirmed allergy to a component of the vaccine. Proper assessment will help to clarify whether and how a COVID-19 vaccine can be (re)administered and, if necessary, can help in the selection of an alternative COVID-19 vaccine when one becomes available.
- Assessment by an allergist is NOT required for individuals with a history of unrelated allergies, including to allergies to foods, drugs, insect venom or environmental allergens. In these individuals, the available COVID-19 vaccines can be administered without any special precautions. As for the routine administration of all vaccines, they should be administered in a healthcare setting capable of managing anaphylaxis, and individuals should be observed for a minimum of 15-30 minutes following vaccination.
- These recommendations will be updated as appropriate.
# Summary:
- There is a low risk for allergic reactions associated with vaccines. Non-allergic reactions to vaccines are much more frequent than allergic reactions. a. Vaccines activate the immune system, which will commonly result in minor side effects, including mild fever and local inflammatory reactions at the site of the injection. b. Non-allergic reactions to vaccines also include anxiety-related adverse events that can mimic allergic reactions. 2. The nature and cause of the reactions to the Pfizer-BioNTech and Moderna COVID- 19 vaccines remains unclear, including how many have been due to allergic reactions. 3. The feasibility of allergy testing for the COVID-19 vaccines is not yet known. 4. The Pfizer-BioNTech and Moderna COVID-19 vaccines contain polyethylene glycol (PEG), which has been identified as potentially allergenic, but it is not yet known whether allergy to PEG is responsible for the reported adverse reactions to these vaccines. 5. It is unknown whether allergy testing for PEG compounds will be relevant to the investigation of possible allergy to the Pfizer-BioNTech and Moderna COVID-19 vaccines. 6. Chlorhexidine hypersensitivity should be considered in relevant cases. 7. Graded administration of these vaccines in someone with a suspected or confirmed allergy to the vaccine or one of its components can be considered if further doses are required.
- There is a low risk for allergic reactions associated with vaccines. Non-allergic reactions to vaccines are much more frequent than allergic reactions.
Vaccines activate the immune system, which will commonly result in minor side effects, including mild fever and local inflammatory reactions at the site of the injection. This may include redness, swelling, pain, and warmth at the injection sites. (1) These reactions are not a contraindication to receiving the same vaccine in the future, as they do not pose a risk for future allergic reactions to the vaccine.
Non-allergic reactions to vaccines also include anxiety-related adverse events that can mimic allergic reactions, and may include breath-holding, hyperventilation, and vasovagal syncope (fainting) (see Table 1 in the Canadian Immunization Guide: Anaphylaxis and other Acute Reactions following Vaccination). (2)
Acute localized allergic reactions at the site of the injection, consisting of urticaria and angioedema, are also possible, but the risk of systemic allergic reactions, including anaphylaxis, is considered extremely rare. Studies suggest that the estimated annual rate of anaphylaxis in Canada is approximately 0.4 to 1.8 cases per 1,000,000 doses of vaccine administration (2)(3)(4)
- The nature and cause of the reactions to the Pfizer-BioNTech and Moderna COVID-19 vaccines remains unclear, including how many have been due to allergic reactions.
A recent publication suggests that "the rate of anaphylaxis associated with the Pfizer SARS-CoV-2 mRNA vaccine appears to be approximately 10 times as high as the incidence reported with all previous vaccines";(5) however, we must be cautious not to repeat history. Previous experience with the pandemic H1N1 (pH1N1) vaccine has educated us that although the pH1N1 vaccine was initially reported to have caused a "rate of anaphylaxis 20 times greater than the historical average", subsequent careful investigation revealed that a striking 96% of those initially reported to have experienced anaphylaxis after receiving the vaccine had no evidence of allergy to that vaccine. Polyethylene glycol, commonly known as PEG, has been identified as the most likely potentially allergenic component of both Pfizer-BioNTech and Moderna COVID-19 vaccines, (8) though it is not yet known whether the PEG component of these vaccines is responsible for the reactions that have been reported to date. The other components of these vaccines, including the active mRNA components of both vaccines, are unlikely to be allergenic.
- It is unknown whether allergy testing for PEG compounds will be relevant to the investigation of possible allergy to the Pfizer-BioNTech and Moderna COVID-19 vaccines.
Allergy to PEG has previously been reported. PEG compounds have a range of molecular weights, and allergic sensitization to PEG has mainly been documented for PEG with higher molecular weight and when present in higher concentration. (9)(10)(11)(12)(13)( 14) However, PEG is found in multiple products that are tolerated safely on a daily basis by many individuals in Canada, including bowel preparation products for surgical procedures, certain laxatives and other medications, certain skin care products and cosmetics, and some food and drinks.
A recent publication has suggested a possible role for allergy testing to PEG within the context of evaluation of allergy to these vaccines. (15) Although both epicutaneous and intradermal skin testing for PEG has been described within the context of case reports and research, (10)(12)(13) such testing has not been standardized and its validity is not well established. In addition, systemic reactions, including anaphylaxis, has been described as a result of both epicutaneous and intradermal testing to PEG. (11)( 13) Furthermore, although cross-reactivity between different types of PEG has been suggested, (10)(11)( 14) the Pfizer-BioNTech and Moderna COVID-19 vaccines contain different forms of PEG, and the degree of cross-reactivity between these PEG molecules has not yet been established. The Oxford-AstraZeneca COVID-19 vaccine has been approved by the UK and contains polysorbate 80 (which may cross-react with PEG), but the clinical implications of this are also unknown. ( 15)
- Chlorhexidine hypersensitivity should be considered in relevant cases.
Other exposures should also be considered as a possible source of adverse reactions during vaccination with these vaccines. Localized irritation and contact reactions have been described to compounds used to prepare the injection site. More specifically chlorhexidine, used to sterilize vaccine injection sites, may elicit allergic reactions. Skin testing for chlorhexidine allergy may be used to make a diagnosis but is not standardized. (16)
- Graded administration of these vaccines in someone with a suspected or confirmed allergy to the vaccine or one of its components can be considered if further doses are required.
In summary, for a higher-risk patient who has previously experienced a suspected or confirmed severe allergic reaction to a COVID-19 vaccine or any of its components, allergy testing to the vaccine or its components is not required for the vast majority of these patients. A reasonable and safe option for consideration as part of shared decision-making is the administration of the COVID-19 vaccine using a graded vaccine administration protocol. For higher-risk patients who are hesitant to proceed with graded vaccine administration, allergy testing remains an option after education that the predictive value of such testing is unknown. Allergy testing for lowerrisk patients is NOT recommended to prevent delay in administration of COVID-19 vaccines.
Guidance for the cautious graded administration of a vaccine in someone with a confirmed IgEmediated allergy to that vaccine or one of its components has previously been published: administer 0.05 mL 1:10 dilution, 10%, 20%, 30%, and 40% of the full dose incrementally in alternate arms at 15-minute intervals, followed by a minimum 30-minute observation period.
Suggested approach to vaccination for allergists/immunologists in immunocompromised individuals.
- COVID-19 vaccines should be offered to immunocompromised patients if the benefit is deemed to outweigh any potential risks of vaccination.
Immunocompromised individuals are at high risk for severe COVID-19 and should be considered a priority group for intervention that will reduce their risk of this disease. The NACI currently recommends that "COVID-19 vaccine should not be routinely offered to individuals who are immunosuppressed due to disease or treatment until further evidence is available" However, they further state that these vaccines "may be offered… in this population if a risk assessment deems that the benefits outweigh the potential risks for the individual". (8)
In the UK, immunosuppressed individuals are considered a priority group to receive COVID-19 vaccines (see Table 3 in the referenced document). (20) The European Society for Immunodeficiency (ESID) currently recommends that "patients with PID receive COVID-19 vaccinations provided that they are not live vaccines". (21) The European League Against Rheumatism (EULAR) recommends that immunocompromised patients be vaccinated against COVID-19 ( 22) Accordingly, the CSACI suggests that COVID-19 vaccines should be offered to immunocompromised patients following a careful risk assessment if the benefit is deemed to outweigh any potential risks of vaccination. We recognize that this is a rapidly evolving area and will be following this closely, with updates made to this recommend as necessary. | Safe and effective vaccines provide the first hope for mitigating the devastating health and economic impacts resulting from COVID-19 and related public health orders. Both the Pfizer-BioNTech and Moderna products are currently approved in Canada, and further vaccines will likely become available in the coming months. A high rate of vaccine uptake across all sectors of Canadian society is a priority public health goal. Recent case reports of reactions to COVID-19 vaccines have raised questions about their safety for use in individuals with allergies and those who are immunocompromised. In this document, we aim to address these concerns and provide guidance for CSACI members. Suggested approach to vaccination for allergists/immunologists in individuals with confirmed or suspected allergic contraindications to receiving COVID-19 vaccines.#
• Assessment by an allergist is warranted in any individual with a suspected allergy to a COVID-19 vaccine or any of its components. This includes anyone who has experienced a suspected allergic reaction after receiving the first dose of a COVID-19 vaccine, or someone with a suspected or confirmed allergy to a component of the vaccine. Proper assessment will help to clarify whether and how a COVID-19 vaccine can be (re)administered and, if necessary, can help in the selection of an alternative COVID-19 vaccine when one becomes available.
• Assessment by an allergist is NOT required for individuals with a history of unrelated allergies, including to allergies to foods, drugs, insect venom or environmental allergens. In these individuals, the available COVID-19 vaccines can be administered without any special precautions. As for the routine administration of all vaccines, they should be administered in a healthcare setting capable of managing anaphylaxis, and individuals should be observed for a minimum of 15-30 minutes following vaccination.
• These recommendations will be updated as appropriate.
# Summary:
1. There is a low risk for allergic reactions associated with vaccines. Non-allergic reactions to vaccines are much more frequent than allergic reactions. a. Vaccines activate the immune system, which will commonly result in minor side effects, including mild fever and local inflammatory reactions at the site of the injection. b. Non-allergic reactions to vaccines also include anxiety-related adverse events that can mimic allergic reactions. 2. The nature and cause of the reactions to the Pfizer-BioNTech and Moderna COVID- 19 vaccines remains unclear, including how many have been due to allergic reactions. 3. The feasibility of allergy testing for the COVID-19 vaccines is not yet known. 4. The Pfizer-BioNTech and Moderna COVID-19 vaccines contain polyethylene glycol (PEG), which has been identified as potentially allergenic, but it is not yet known whether allergy to PEG is responsible for the reported adverse reactions to these vaccines. 5. It is unknown whether allergy testing for PEG compounds will be relevant to the investigation of possible allergy to the Pfizer-BioNTech and Moderna COVID-19 vaccines. 6. Chlorhexidine hypersensitivity should be considered in relevant cases. 7. Graded administration of these vaccines in someone with a suspected or confirmed allergy to the vaccine or one of its components can be considered if further doses are required.
# -----------------------------------------------------------------------------------------
• There is a low risk for allergic reactions associated with vaccines. Non-allergic reactions to vaccines are much more frequent than allergic reactions.
Vaccines activate the immune system, which will commonly result in minor side effects, including mild fever and local inflammatory reactions at the site of the injection. This may include redness, swelling, pain, and warmth at the injection sites. (1) These reactions are not a contraindication to receiving the same vaccine in the future, as they do not pose a risk for future allergic reactions to the vaccine.
Non-allergic reactions to vaccines also include anxiety-related adverse events that can mimic allergic reactions, and may include breath-holding, hyperventilation, and vasovagal syncope (fainting) (see Table 1 in the Canadian Immunization Guide: Anaphylaxis and other Acute Reactions following Vaccination). (2)
Acute localized allergic reactions at the site of the injection, consisting of urticaria and angioedema, are also possible, but the risk of systemic allergic reactions, including anaphylaxis, is considered extremely rare. Studies suggest that the estimated annual rate of anaphylaxis in Canada is approximately 0.4 to 1.8 cases per 1,000,000 doses of vaccine administration (2)(3)(4)
• The nature and cause of the reactions to the Pfizer-BioNTech and Moderna COVID-19 vaccines remains unclear, including how many have been due to allergic reactions.
A recent publication suggests that "the rate of anaphylaxis associated with the Pfizer SARS-CoV-2 mRNA vaccine appears to be approximately 10 times as high as the incidence reported with all previous vaccines";(5) however, we must be cautious not to repeat history. Previous experience with the pandemic H1N1 (pH1N1) vaccine has educated us that although the pH1N1 vaccine was initially reported to have caused a "rate of anaphylaxis 20 times greater than the historical average", subsequent careful investigation revealed that a striking 96% of those initially reported to have experienced anaphylaxis after receiving the vaccine had no evidence of allergy to that vaccine. Polyethylene glycol, commonly known as PEG, has been identified as the most likely potentially allergenic component of both Pfizer-BioNTech and Moderna COVID-19 vaccines, (8) though it is not yet known whether the PEG component of these vaccines is responsible for the reactions that have been reported to date. The other components of these vaccines, including the active mRNA components of both vaccines, are unlikely to be allergenic.
• It is unknown whether allergy testing for PEG compounds will be relevant to the investigation of possible allergy to the Pfizer-BioNTech and Moderna COVID-19 vaccines.
Allergy to PEG has previously been reported. PEG compounds have a range of molecular weights, and allergic sensitization to PEG has mainly been documented for PEG with higher molecular weight and when present in higher concentration. (9)(10)(11)(12)(13)( 14) However, PEG is found in multiple products that are tolerated safely on a daily basis by many individuals in Canada, including bowel preparation products for surgical procedures, certain laxatives and other medications, certain skin care products and cosmetics, and some food and drinks.
A recent publication has suggested a possible role for allergy testing to PEG within the context of evaluation of allergy to these vaccines. (15) Although both epicutaneous and intradermal skin testing for PEG has been described within the context of case reports and research, (10)(12)(13) such testing has not been standardized and its validity is not well established. In addition, systemic reactions, including anaphylaxis, has been described as a result of both epicutaneous and intradermal testing to PEG. (11)( 13) Furthermore, although cross-reactivity between different types of PEG has been suggested, (10)(11)( 14) the Pfizer-BioNTech and Moderna COVID-19 vaccines contain different forms of PEG, and the degree of cross-reactivity between these PEG molecules has not yet been established. The Oxford-AstraZeneca COVID-19 vaccine has been approved by the UK and contains polysorbate 80 (which may cross-react with PEG), but the clinical implications of this are also unknown. ( 15)
• Chlorhexidine hypersensitivity should be considered in relevant cases.
Other exposures should also be considered as a possible source of adverse reactions during vaccination with these vaccines. Localized irritation and contact reactions have been described to compounds used to prepare the injection site. More specifically chlorhexidine, used to sterilize vaccine injection sites, may elicit allergic reactions. Skin testing for chlorhexidine allergy may be used to make a diagnosis but is not standardized. (16)
• Graded administration of these vaccines in someone with a suspected or confirmed allergy to the vaccine or one of its components can be considered if further doses are required.
In summary, for a higher-risk patient who has previously experienced a suspected or confirmed severe allergic reaction to a COVID-19 vaccine or any of its components, allergy testing to the vaccine or its components is not required for the vast majority of these patients. A reasonable and safe option for consideration as part of shared decision-making is the administration of the COVID-19 vaccine using a graded vaccine administration protocol. For higher-risk patients who are hesitant to proceed with graded vaccine administration, allergy testing remains an option after education that the predictive value of such testing is unknown. Allergy testing for lowerrisk patients is NOT recommended to prevent delay in administration of COVID-19 vaccines.
Guidance for the cautious graded administration of a vaccine in someone with a confirmed IgEmediated allergy to that vaccine or one of its components has previously been published: administer 0.05 mL 1:10 dilution, 10%, 20%, 30%, and 40% of the full dose incrementally in alternate arms at 15-minute intervals, followed by a minimum 30-minute observation period.
[see Table V in the referenced document] (17)
Suggested approach to vaccination for allergists/immunologists in immunocompromised individuals.
• COVID-19 vaccines should be offered to immunocompromised patients if the benefit is deemed to outweigh any potential risks of vaccination.
Immunocompromised individuals are at high risk for severe COVID-19 and should be considered a priority group for intervention that will reduce their risk of this disease. The NACI currently recommends that "COVID-19 vaccine should not be routinely offered to individuals who are immunosuppressed due to disease or treatment until further evidence is available" However, they further state that these vaccines "may be offered… in this population if a risk assessment deems that the benefits outweigh the potential risks for the individual". (8)
In the UK, immunosuppressed individuals are considered a priority group to receive COVID-19 vaccines (see Table 3 in the referenced document). (20) The European Society for Immunodeficiency (ESID) currently recommends that "patients with PID receive COVID-19 vaccinations provided that they are not live vaccines". (21) The European League Against Rheumatism (EULAR) recommends that immunocompromised patients be vaccinated against COVID-19 ( 22) Accordingly, the CSACI suggests that COVID-19 vaccines should be offered to immunocompromised patients following a careful risk assessment if the benefit is deemed to outweigh any potential risks of vaccination. We recognize that this is a rapidly evolving area and will be following this closely, with updates made to this recommend as necessary. | None | None |
5c119dfb9e4f19b5aaa16f29ba6db02cc1dbfae8 | cma | None | These recommendations are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. They should be used as an adjunct to sound clinical decision making.To provide guidance to health care providers when they receive notification a newborn in their care is a sickle cell trait carrier. Providers will be responsible for communicating results with the family and arranging necessary follow-up in accordance with this guide.# IMPLEMENTATION CONSIDERATIONS SUMMARY
There are no immediate health concerns for an infant who carries SCT. No urgent action is required and referral to a hematologist is generally not necessary. However, there may be implications for other family members. See Appendix B for frequently asked questions to help guide your discussions with the family.
# IMPLICATIONS FOR OTHER FAMILY MEMBERS
When a child is found to carry SCT, at least one parent is also expected to carry SCT. Given how common SCT is, there is a chance that both parents carry SCT. These couples have a 1 in 4 probability of having a child with SCD (see Figure 1).
If the parents of an infant carrying SCT are planning more pregnancies, the following hemoglobinopathy investigations are recommended: hemoglobin electrophoresis, CBC and ferritin. Genetic counselling is recommended if both parents are found to be carriers for any thalassemia or other hemoglobinopathy.
# APPENDIX B SICKLE CELL TRAIT FREQUENTLY ASKED QUESTIONS
This resource can be used by health care providers when talking with parents about their child's sickle cell trait status.
# WHAT IS SICKLE CELL TRAIT?
Sickle cell trait (SCT) is not a disease, but an inherited blood condition. This occurs when a person inherits a sickle hemoglobin gene from one parent and a standard (fully working) hemoglobin gene from the other parent. Therefore, a person with one sickle hemoglobin gene is said to 'carry' SCT.
# WHAT IS THE DIFFERENCE BETWEEN SCT AND SICKLE CELL DISEASE (SCD)?
SCT is NOT a milder form of SCD. SCD results from the inheritance of two sickle hemoglobin genes, one from each parent, which causes normally round red blood cells to become curved or "sickle" shape. When the sickled red blood cells travel through small blood vessels, they are more likely to become stuck and clog the blood flow to organs in the body. Since individuals with SCT have only one sickle hemoglobin gene, they still make enough standard hemoglobin to prevent the cells from sickling. Without sickling, red blood cells are able to transport oxygen to tissues and organs in the body without becoming stuck in the small blood vessels. Individuals with SCT are at no higher risk for symptoms of SCD than anyone else.
# WHO IS AFFECTED BY SCT?
SCT can occur in any ethnic group, but it is more common in certain populations such as African, Mediterranean, Middle Eastern and Asian groups. Worldwide, an estimated 300 million people carry SCT, with a prevalence ranging from 2% to 30% in more than 40 countries (1). The carrier frequency is estimated to be approximately 1/100 overall in the Alberta population.
# WHAT HEALTH COMPLICATIONS ARE ASSOCIATED WITH SCT?
Most people with SCT will rarely have any associated health problems as a result of being a carrier and will not develop SCD. However, people with SCT are at increased chance of experiencing blocked blood vessels should they become significantly dehydrated, particularly during times of extremely strenuous activity. In rare cases, people who carry SCT may have some health issues such as blood in the urine, presence of excess proteins in the urine, or chronic kidney disease.
# WHY IS IT IMPORTANT TO KNOW THAT MY CHILD HAS SCT?
Your child and their future partner may want to know this information before they plan to have children of their own. Should your child's partner also have SCT, then their children (your grandchildren) would be at an increased risk of having SCD (see Figure 1).
Hemoglobin is a protein in red blood cells that carries oxygen throughout the body.
# Appendix B WHAT DOES HAVING A CHILD WITH SCT MEAN FOR ME, MY PARTNER AND FOR FUTURE PREGNANCIES?
If both members of a couple carry SCT, they can have a child who has SCD. Each child born to a couple where both parents carry SCT has a: 1 in 2 (50%) chance of carrying SCT. 1 in 4 (25%) chance of having SCD. 1 in 4 (25%) chance that they will neither have SCT or SCD.
# Figure 1: Autosomal Recessive Inheritance Pattern of SCT
If the parents of an infant with SCT are planning more pregnancies, carrier testing is recommended. Genetic counselling is also recommended if both parents are found to be carriers in order to review the different options available to the parents during pregnancy.
# SHOULD MY OTHER CHILDREN BE TESTED?
If your other children were born outside of Alberta, or within Alberta but before April 1, 2019 they may not have been screened for SCD. Therefore, we suggest you talk with your family doctor about additional screening for SCD. | These recommendations are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. They should be used as an adjunct to sound clinical decision making.To provide guidance to health care providers when they receive notification a newborn in their care is a sickle cell trait carrier. Providers will be responsible for communicating results with the family and arranging necessary follow-up in accordance with this guide.# IMPLEMENTATION CONSIDERATIONS SUMMARY
There are no immediate health concerns for an infant who carries SCT. No urgent action is required and referral to a hematologist is generally not necessary. However, there may be implications for other family members. See Appendix B for frequently asked questions to help guide your discussions with the family.
# IMPLICATIONS FOR OTHER FAMILY MEMBERS
When a child is found to carry SCT, at least one parent is also expected to carry SCT. Given how common SCT is, there is a chance that both parents carry SCT. These couples have a 1 in 4 probability of having a child with SCD (see Figure 1).
If the parents of an infant carrying SCT are planning more pregnancies, the following hemoglobinopathy investigations are recommended: hemoglobin electrophoresis, CBC and ferritin. Genetic counselling is recommended if both parents are found to be carriers for any thalassemia or other hemoglobinopathy.
# APPENDIX B SICKLE CELL TRAIT FREQUENTLY ASKED QUESTIONS
This resource can be used by health care providers when talking with parents about their child's sickle cell trait status.
# WHAT IS SICKLE CELL TRAIT?
Sickle cell trait (SCT) is not a disease, but an inherited blood condition. This occurs when a person inherits a sickle hemoglobin gene from one parent and a standard (fully working) hemoglobin gene from the other parent. Therefore, a person with one sickle hemoglobin gene is said to 'carry' SCT.
# WHAT IS THE DIFFERENCE BETWEEN SCT AND SICKLE CELL DISEASE (SCD)?
SCT is NOT a milder form of SCD. SCD results from the inheritance of two sickle hemoglobin genes, one from each parent, which causes normally round red blood cells to become curved or "sickle" shape. When the sickled red blood cells travel through small blood vessels, they are more likely to become stuck and clog the blood flow to organs in the body. Since individuals with SCT have only one sickle hemoglobin gene, they still make enough standard hemoglobin to prevent the cells from sickling. Without sickling, red blood cells are able to transport oxygen to tissues and organs in the body without becoming stuck in the small blood vessels. Individuals with SCT are at no higher risk for symptoms of SCD than anyone else.
# WHO IS AFFECTED BY SCT?
SCT can occur in any ethnic group, but it is more common in certain populations such as African, Mediterranean, Middle Eastern and Asian groups. Worldwide, an estimated 300 million people carry SCT, with a prevalence ranging from 2% to 30% in more than 40 countries (1). The carrier frequency is estimated to be approximately 1/100 overall in the Alberta population.
# WHAT HEALTH COMPLICATIONS ARE ASSOCIATED WITH SCT?
Most people with SCT will rarely have any associated health problems as a result of being a carrier and will not develop SCD. However, people with SCT are at increased chance of experiencing blocked blood vessels should they become significantly dehydrated, particularly during times of extremely strenuous activity. In rare cases, people who carry SCT may have some health issues such as blood in the urine, presence of excess proteins in the urine, or chronic kidney disease.
# WHY IS IT IMPORTANT TO KNOW THAT MY CHILD HAS SCT?
Your child and their future partner may want to know this information before they plan to have children of their own. Should your child's partner also have SCT, then their children (your grandchildren) would be at an increased risk of having SCD (see Figure 1).
Hemoglobin is a protein in red blood cells that carries oxygen throughout the body.
# Appendix B WHAT DOES HAVING A CHILD WITH SCT MEAN FOR ME, MY PARTNER AND FOR FUTURE PREGNANCIES?
If both members of a couple carry SCT, they can have a child who has SCD. Each child born to a couple where both parents carry SCT has a: 1 in 2 (50%) chance of carrying SCT. 1 in 4 (25%) chance of having SCD. 1 in 4 (25%) chance that they will neither have SCT or SCD.
# Figure 1: Autosomal Recessive Inheritance Pattern of SCT
If the parents of an infant with SCT are planning more pregnancies, carrier testing is recommended. Genetic counselling is also recommended if both parents are found to be carriers in order to review the different options available to the parents during pregnancy.
# SHOULD MY OTHER CHILDREN BE TESTED?
If your other children were born outside of Alberta, or within Alberta but before April 1, 2019 they may not have been screened for SCD. Therefore, we suggest you talk with your family doctor about additional screening for SCD. | None | None |
2d172b6c0cdf6ade94f3aff7ff2aabaa77779360 | cma | None | This work is licensed under a Creative Commons Attribution 4.0 International License.- It can take at least 7-14 days, and sometimes longer, after symptom onset for antibodies to develop, therefore the use of serology POC tests in the early phase of infection can result in a false negative COVID-19 diagnosis at a time when patients are most infectious (i.e. a negative result does not rule out infection). - False negative interpretations may occur in elderly and immunocompromised patients, who are unable to mount an adequate antibody response. - Since serology POC tests do not detect virus, a positive or negative result does not determine whether a person is infectious. - Positive results may be due to past or recent infection with SARS-CoV-2 or from COVID-19 vaccination. - Most POC serology tests are unable to differentiate antibodies developed from previous infection from those generated in response to COVID-19 vaccination. Given the rapid expansion of COVID-19 vaccination, this further limits the use of serology POC tests. - As with other COVID-19 serological platforms, false positive results may occur if these kits cross-react with antibodies from recent or past exposure to other coronaviruses, including human coronaviruses. - Other infections, as well as non-infectious conditions (e.g. rheumatoid factor-positive diseases), may also cause false positive results. - False positive results are more likely in areas of low prevalence and low vaccine uptake. The local epidemiology and pretest probability of the individual (i.e. clinical and epidemiological risk factors) need to be taken into consideration when interpreting POC serology results.# Introduction
Point-of-care (POC) serology tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), detect the human antibody response to infection or vaccination and not the virus itself. Most are qualitative immunochromatographic (lateral-flow)-based assays that detect IgG+/-IgM from a finger prick blood sample and can provide results in less than 30 minutes. While there is widespread interest in adopting POC serology tests for COVID-19, there are currently significant limitations to this testing modality, including the incomplete understanding of the immunological response in COVID-19, suboptimal clinical validation data, uncertain correlation (or lack thereof) with clinical laboratorybased serology tests and wide variability in performance among different POC tests. Many of the key points outlined below also apply to laboratory-based COVID-19 serology testing.
# Current position for acute diagnostics
Serology POC tests for COVID-19 are not recommended for use as a diagnostic tool for acute infection and only three products are approved by Health Canada to date. In general, these tests are not able to detect antibodies until at least a week or more after symptoms have started, and therefore are not suitable for diagnosis of acute SARS-CoV-2 infection at this time. We recommend that nucleic acid detection (e.g. real-time polymerase chain reaction) remain the first line test for the diagnosis of acute SARS-CoV-2 infection, as advised by the World Health Organization (1).
# ADVISORY COMMITTEE STATEMENT
- Due to the visual interpretations of most POC serology tests, false positive and negative results may arise from incorrect or subjective reading. - As per recommendations from the National Advisory Committee on Immunization, there is no indication for serology prior to or after COVID-19 vaccination. - Any kits used need to be thoroughly evaluated for performance characteristics (sensitivity, specificity) before being used clinically, including in-field use conditions.
An evolving and exceptional use for POC serology testing may be considered when laboratory-based serology testing is not available or is unable to meet the necessary rapid turnaround times to help identify COVID-19 patients most likely to benefit from anti-SARS-CoV-2 monoclonal antibody therapy.
Serology testing currently has limited clinical utility; however, some jurisdictions have recommended its use to help inform treatment decisions for COVID-19 patients, as early clinical trial data showed that some monoclonal antibody therapies (e.g. casirivimab + imdevimab) were most effective in seronegative patients. Even in this context, we recommend that serology POC tests be performed in a laboratory setting to help mitigate some of the risks outlined above and validated before use as described below. When possible, laboratory-based SARS-CoV-2 serology testing is preferred.
# Current position for use as "immunity certificates or passports"
There has been ongoing discussion around the use of antibody testing as evidence of immunity to facilitate individual movement in public areas and to permit international travel. The knowledge around immunity to SARS-CoV-2 is rapidly evolving; however, at this time, the correlates of protection and duration of immunity are not well understood. As such, we do not recommend using serology, including POC tests, for determining individual immunity or for establishing exemptions from public health measures.
# Key points
- Since there is currently no correlate of protection, it is unknown if the levels of antibodies detected by serology POC tests are sufficient for protection. - Since POC tests do not provide a quantitative result, their utility may be limited even once a correlate of protection is established. - COVID-19 antibodies may persist for at least six months; however, the rate at which antibodies decline over time varies by age, immune status of the individual and severity of disease. - Binding antibodies detected by serology POC tests may not correlate with neutralizing (i.e. protective) antibodies.
- Since it takes at least 7-14 days (longer in some individuals) to mount an antibody response, a negative result does not exclude an active infection or rule out infectiousness; therefore, it does not confirm that an individual cannot transmit SARS-CoV-2. Serology tests should not replace molecular (or antigen) testing for travel or other screening purposes. - Although reinfection or infection after vaccination is relatively rare, a positive serology result does not guarantee protection from infection, especially with intense exposures and the emergence of SARS-CoV-2 variants that have immune escape potential. - Since serology POC tests do not detect T-cell mediated immunity to SARS-CoV-2, which is also important for long-term protection, a negative result is not proof that an individual is not immune. - Modelling has shown that public health measures, such as masking and physical distancing, will be required to control the spread of SARS-CoV-2 until the time that population vaccine coverage and adequate population immunity are achieved. Thus, a positive serology result, including from POC testing, may provide a false sense of protection from SARS-CoV-2 infection at the individual level.
# Important considerations is implementing point-of-care testing
The role of serology in the diagnosis of SARS-CoV-2 infection, patient management and immunity testing is of limited utility.
Once the dynamics of the serological response in COVID-19 are better understood and a correlate of protection is identified, serology may play an important role in the population-based public health response. If serology POC testing is implemented for a specific purpose (e.g. testing for monoclonal antibody treatment), the following should be considered:
- Extensive validation of the test(s) against a gold standard (viral neutralization assays or another laboratory-based serological assay). Performance characteristics (sensitivity, specificity, positive and negative predictive values, crossreaction to other coronaviruses) should be established using sera from patients infected with SARS-CoV-2 (ancestral and variants), other respiratory viruses, including seasonal coronaviruses, and healthy controls. - Provide adequate training to healthcare/laboratory workers to perform the test and interpret the result. - Performing a risk assessment for infection with SARS-CoV-2 and bloodborne infections for the operator. We recommend that universal protective measures to prevent bloodborne pathogen transmission (at a minimum, gloves and gowns) be used when running POC assays until the risk to the operator can be formally assessed. - Establishing an ongoing quality control/quality assurance program prior to implementation.
- Establishing provisions to ensure the capture of testing data for individual patient records and surveillance purposes and the requirement for participation in external quality assessment to maintain high-quality testing.
Based on currently available information, the Canadian Public Health Laboratory Network recommends that COVID-19 POC serological assays not be used for routine clinical or immunity testing at this time. In line with recommendations by the National Advisory Committee on Immunization (2), serology testing should not be used to document vaccination status or to assess response to COVID-19 vaccination. As more information becomes available on immunological correlates of protection, duration of immunity, test performance and assays are validated against gold standard serological methods, clinical application of POC assays will be re-evaluated. Molecular testing, such as real-time polymerase chain reaction, remains the primary test method for laboratory confirmation of acute SARS-CoV-2 infection and diagnosis of COVID-19. | This work is licensed under a Creative Commons Attribution 4.0 International License.• It can take at least 7-14 days, and sometimes longer, after symptom onset for antibodies to develop, therefore the use of serology POC tests in the early phase of infection can result in a false negative COVID-19 diagnosis at a time when patients are most infectious (i.e. a negative result does not rule out infection). • False negative interpretations may occur in elderly and immunocompromised patients, who are unable to mount an adequate antibody response. • Since serology POC tests do not detect virus, a positive or negative result does not determine whether a person is infectious. • Positive results may be due to past or recent infection with SARS-CoV-2 or from COVID-19 vaccination. • Most POC serology tests are unable to differentiate antibodies developed from previous infection from those generated in response to COVID-19 vaccination. Given the rapid expansion of COVID-19 vaccination, this further limits the use of serology POC tests. • As with other COVID-19 serological platforms, false positive results may occur if these kits cross-react with antibodies from recent or past exposure to other coronaviruses, including human coronaviruses. • Other infections, as well as non-infectious conditions (e.g. rheumatoid factor-positive diseases), may also cause false positive results. • False positive results are more likely in areas of low prevalence and low vaccine uptake. The local epidemiology and pretest probability of the individual (i.e. clinical and epidemiological risk factors) need to be taken into consideration when interpreting POC serology results.# Introduction
Point-of-care (POC) serology tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), detect the human antibody response to infection or vaccination and not the virus itself. Most are qualitative immunochromatographic (lateral-flow)-based assays that detect IgG+/-IgM from a finger prick blood sample and can provide results in less than 30 minutes. While there is widespread interest in adopting POC serology tests for COVID-19, there are currently significant limitations to this testing modality, including the incomplete understanding of the immunological response in COVID-19, suboptimal clinical validation data, uncertain correlation (or lack thereof) with clinical laboratorybased serology tests and wide variability in performance among different POC tests. Many of the key points outlined below also apply to laboratory-based COVID-19 serology testing.
# Current position for acute diagnostics
Serology POC tests for COVID-19 are not recommended for use as a diagnostic tool for acute infection and only three products are approved by Health Canada to date. In general, these tests are not able to detect antibodies until at least a week or more after symptoms have started, and therefore are not suitable for diagnosis of acute SARS-CoV-2 infection at this time. We recommend that nucleic acid detection (e.g. real-time polymerase chain reaction) remain the first line test for the diagnosis of acute SARS-CoV-2 infection, as advised by the World Health Organization (1).
# ADVISORY COMMITTEE STATEMENT
• Due to the visual interpretations of most POC serology tests, false positive and negative results may arise from incorrect or subjective reading. • As per recommendations from the National Advisory Committee on Immunization, there is no indication for serology prior to or after COVID-19 vaccination. • Any kits used need to be thoroughly evaluated for performance characteristics (sensitivity, specificity) before being used clinically, including in-field use conditions.
An evolving and exceptional use for POC serology testing may be considered when laboratory-based serology testing is not available or is unable to meet the necessary rapid turnaround times to help identify COVID-19 patients most likely to benefit from anti-SARS-CoV-2 monoclonal antibody therapy.
Serology testing currently has limited clinical utility; however, some jurisdictions have recommended its use to help inform treatment decisions for COVID-19 patients, as early clinical trial data showed that some monoclonal antibody therapies (e.g. casirivimab + imdevimab) were most effective in seronegative patients. Even in this context, we recommend that serology POC tests be performed in a laboratory setting to help mitigate some of the risks outlined above and validated before use as described below. When possible, laboratory-based SARS-CoV-2 serology testing is preferred.
# Current position for use as "immunity certificates or passports"
There has been ongoing discussion around the use of antibody testing as evidence of immunity to facilitate individual movement in public areas and to permit international travel. The knowledge around immunity to SARS-CoV-2 is rapidly evolving; however, at this time, the correlates of protection and duration of immunity are not well understood. As such, we do not recommend using serology, including POC tests, for determining individual immunity or for establishing exemptions from public health measures.
# Key points
• Since there is currently no correlate of protection, it is unknown if the levels of antibodies detected by serology POC tests are sufficient for protection. • Since POC tests do not provide a quantitative result, their utility may be limited even once a correlate of protection is established. • COVID-19 antibodies may persist for at least six months; however, the rate at which antibodies decline over time varies by age, immune status of the individual and severity of disease. • Binding antibodies detected by serology POC tests may not correlate with neutralizing (i.e. protective) antibodies.
• Since it takes at least 7-14 days (longer in some individuals) to mount an antibody response, a negative result does not exclude an active infection or rule out infectiousness; therefore, it does not confirm that an individual cannot transmit SARS-CoV-2. Serology tests should not replace molecular (or antigen) testing for travel or other screening purposes. • Although reinfection or infection after vaccination is relatively rare, a positive serology result does not guarantee protection from infection, especially with intense exposures and the emergence of SARS-CoV-2 variants that have immune escape potential. • Since serology POC tests do not detect T-cell mediated immunity to SARS-CoV-2, which is also important for long-term protection, a negative result is not proof that an individual is not immune. • Modelling has shown that public health measures, such as masking and physical distancing, will be required to control the spread of SARS-CoV-2 until the time that population vaccine coverage and adequate population immunity are achieved. Thus, a positive serology result, including from POC testing, may provide a false sense of protection from SARS-CoV-2 infection at the individual level.
# Important considerations is implementing point-of-care testing
The role of serology in the diagnosis of SARS-CoV-2 infection, patient management and immunity testing is of limited utility.
Once the dynamics of the serological response in COVID-19 are better understood and a correlate of protection is identified, serology may play an important role in the population-based public health response. If serology POC testing is implemented for a specific purpose (e.g. testing for monoclonal antibody treatment), the following should be considered:
• Extensive validation of the test(s) against a gold standard (viral neutralization assays or another laboratory-based serological assay). Performance characteristics (sensitivity, specificity, positive and negative predictive values, crossreaction to other coronaviruses) should be established using sera from patients infected with SARS-CoV-2 (ancestral and variants), other respiratory viruses, including seasonal coronaviruses, and healthy controls. • Provide adequate training to healthcare/laboratory workers to perform the test and interpret the result. • Performing a risk assessment for infection with SARS-CoV-2 and bloodborne infections for the operator. We recommend that universal protective measures to prevent bloodborne pathogen transmission (at a minimum, gloves and gowns) be used when running POC assays until the risk to the operator can be formally assessed. • Establishing an ongoing quality control/quality assurance program prior to implementation.
• Establishing provisions to ensure the capture of testing data for individual patient records and surveillance purposes and the requirement for participation in external quality assessment to maintain high-quality testing.
Based on currently available information, the Canadian Public Health Laboratory Network recommends that COVID-19 POC serological assays not be used for routine clinical or immunity testing at this time. In line with recommendations by the National Advisory Committee on Immunization (2), serology testing should not be used to document vaccination status or to assess response to COVID-19 vaccination. As more information becomes available on immunological correlates of protection, duration of immunity, test performance and assays are validated against gold standard serological methods, clinical application of POC assays will be re-evaluated. Molecular testing, such as real-time polymerase chain reaction, remains the primary test method for laboratory confirmation of acute SARS-CoV-2 infection and diagnosis of COVID-19. | None | None |
35ffe54ddd54f1eee2c284c54273ff04e50f4b33 | cma | None | This guideline provides recommendations for the diagnosis and management of adults aged ≥ 19 years with chronic obstructive pulmonary disease (COPD).- Use spirometry to confirm airflow obstruction in all patients suspected of having COPD. - Promote smoking cessation or reduction (even in long-term smokers) to improve symptom control and slow the progression of COPD, among other benefits. - Refer patients with moderate to severe COPD to pulmonary rehabilitation. - Implement pharmacologic therapy in a stepwise approach and use the lowest step that achieves optimal control based on the patient's severity of COPD. - Develop an exacerbation action plan with the patient for pharmacologic therapies including short-acting bronchodilators, oral corticosteroids, and antibiotics. - Use routine follow-ups to evaluate the patient's inhaler technique and adherence regularly. Evaluating inhaler technique is particularly important in patients who are older, frail, or cognitively impaired. COPD is characterized by persistent airflow limitation that is typically progressive, not fully reversible, and associated with an abnormal inflammatory response of the lungs to noxious particles or gases (e.g., exposure to cigarette smoke). The two most common conditions that contribute to COPD are emphysema (destruction of alveoli) and chronic bronchitis (inflammation of bronchioles). COPD may present with comorbidities and exacerbations which contribute to overall symptom severity affecting the patient's daily activities and quality of life. These features are most prominent in patients with moderate to severe COPD, but even patients with mild COPD can experience exacerbations. 1 Acute exacerbation of COPD (AECOPD) is characterized by an increase in dyspnea, cough and/or sputum that is beyond normal day-to-day variation. It may be acute in onset, but can also have a more indolent onset and result in a change in regular medication. 1 Patients who experience an acute exacerbation have a significantly higher mortality rate than those with stable COPD. 2 This mortality risk increases as the number of exacerbations increases.Approximately 138,500 individuals aged ≥ 45 years in BC have been diagnosed with COPD (approximately 6% of British Columbians aged ≥ 45 years). 3 Many individuals have unrecognized COPD and remain undiagnosed. 4COPD patients commonly present with comorbidities which reduce quality of life. In patients with mild to moderate COPD, cardiovascular diseases are the leading cause of hospitalizations and the second leading cause of mortality after lung cancer. In severe and very severe COPD, respiratory failure and pneumonia are the leading causes of morbidity and mortality. However, even in these patients, cardiovascular diseases remain a major concern. 5# Diagnosis
While a diagnosis is based on a combination of medical history and physical examination, it is the documentation of airflow limitation using spirometry that confirms the diagnosis.
Consider a COPD diagnosis for a patient ≥ 40 years of age who has:
1) Respiratory symptoms, including:
- dyspnea (progressive, persistent and worse with exercise); - chronic cough; and - increased sputum production.
AND 2) One of the following:
- history of exposure to cigarette smoke;
- history of environmental/occupational exposure to smoke, dust or gas/fumes; - frequent respiratory infections; or - family history of COPD.
Consider alternative diagnoses. Asthma and asthma-COPD overlap syndrome (ACOS) are the two primary differential diagnoses to rule out (see Table 1 for features). Other alternative diagnoses include:
- heart failure (e.g., older patients, when breathlessness is out of proportion to spirometry results; measuring B-type natriuretic peptide (BNP) levels may help in diagnosing heart failure); and - tuberculosis (e.g., high risk populations -aboriginal, foreign born).
# Investigations or Tests
# Spirometry
Send ALL patients suspected of having COPD for confirmation of the diagnosis by spirometry. A COPD diagnosis is confirmed when a post-bronchodilator spirometry measurement indicates that there is airflow limitation which is not fully reversible (FEV 1 / FVC ratio < 0.7 or FEV 1 / FVC < lower limit of normal values). A FEV 1 predicted measurement is not needed for diagnosis, but is useful in the assessment of severity.
Timely access to spirometry may be a challenge in rural and remote communities, but should remain a reasonable goal.
Assuming access to spirometry can occur in a reasonable time frame, a referral to a specialist should not be done before objectively confirming the diagnosis of COPD.
# Borderline Spirometry Results
There is some controversy regarding the fixed cut-off of < 0.7 for FEV 1 / FVC ratio versus using < lower limit of normal values.
There is some evidence that a fixed ratio can lead to over diagnosis in older populations, under diagnosis in young people, and a gender difference. 6 Recent evidence also suggests that some current or former smokers may have symptoms of COPD without meeting spirometric criteria for a COPD diagnosis. 7 For borderline results, repeat spirometry after a few months.
Consider alternative diagnoses for all patients with borderline spirometry results or if breathlessness is out of proportion to spirometry results. If FEV 1 response to bronchodilator is:
- ≥ 400 mL, strongly consider asthma or ACOS.
- < 400 mL (but ≥ 200 mL and ≥ 12% of FEV 1 ), consider asthma or ACOS depending on the history and pattern of symptoms (see Table 1 above).
? Chest X-ray A chest x-ray is not helpful in diagnosing COPD. A chest x-ray that shows hyperinflation may suggest COPD, but the diagnosis requires objective confirmation with spirometry. A chest x-ray may be useful, and should be documented, if there are concerns about other significant comorbidities (e.g., heart failure, tuberculosis, pneumonia).
# ? Other Pulmonary Function Tests
Other pulmonary function tests (e.g., body plethysmography, diffusing capacity, arterial blood gas measurement) are not required for a COPD diagnosis, but may be helpful in assessing the severity of COPD or when considering alternative diagnoses. For example, a body plethysmography may help in the assessment of severity of COPD, but is not essential.
Peak flow meter readings may help rule out asthma, but their usefulness in assessing COPD remains unclear.
# Assessment of COPD Severity
Once the diagnosis is confirmed, determine the level of COPD severity (see Table 2) by using the patient's:
- current level of symptoms;
- FEV 1 predicted; - risk of exacerbation; and - presence of comorbidities.
# Assessment Tools
To assist in determining the current level of a patient's symptoms, use a tool such as the COPD Assessment Test (CAT) (website: www.catestonline.org). The MRC Breathlessness/Dyspnea Scale (website: www.mrc.ac.uk/research/facilities-and-resources-forresearchers/mrc-scales) may also be useful.
# Management
The therapeutic goals of COPD management include: 8 - to alleviate breathlessness and other respiratory symptoms that affect daily activities;
- to prevent and reduce the frequency and severity of acute exacerbations;
- to minimize disease progression and reduce the risk of morbidity/mortality; and - to optimally manage comorbidities (if present) to reduce exacerbations and COPD symptoms related to comorbidities.
When developing the patient's therapeutic goals and a management plan, consider:
- using a shared decision-making approach with the patient, taking into account patient preferences and capabilities (e.g. cognitive ability, language barriers); - including a chronic disease and self-management approach facilitated by health professionals, as it can significantly improve health status and reduce hospital admissions for exacerbations by 40%; 9 - using non-pharmacological and pharmacological interventions based on the individual patient's level of severity, - simplifying the medication regime in the context of other conditions and treatments, particularly in the elderly; and - reviewing the treatment approach regularly to eliminate medications that are not improving symptoms or reducing exacerbations.
# Lifestyle and Self-Management
The patient's understanding of, and participation in, optimal care may improve coping skills and quality of life and reduce the likelihood of hospitalization from COPD. Educate the patient and their family or caregiver about lifestyle and self-management strategies -refer to Associated Documents: Resource Guide for Patients.
# Smoking Cessation
Promote smoking cessation or reduction (even in long-term smokers) and avoidance of second-hand smoke. Smoking is the main cause of COPD and the main contributing factor for disease progression. Smoking cessation has immediate benefits including: 1) improving symptom control, 2) slowing progression of disease, 3) improving cardiovascular outcomes, and 4) reducing long-term risk of lung cancer.
- For assistance in quitting smoking, refer patients to QuitNow at HealthLinkBC by telephone at 8-1-1 or website: www.quitnow.ca. - For more information on effective pharmacological aids for smoking cessation, refer to the BC Smoking Cessation program website: www2.gov.bc.ca/gov/content/health/health-drug-coverage/pharmacare-for-bc-residents/what-we-cover/drugcoverage/bc-smoking-cessation-program.
# Physical Activity
Encourage exercise and a more active lifestyle. Remaining active despite symptoms of shortness of breath must remain a priority for all patients with COPD.
# Pulmonary Rehabilitation and Respiratory Services
Moderate to severe COPD patients should be referred to a pulmonary rehabilitation program (where available) and to community respiratory services. Home and Community Care programs offered by health authorities include home visits by a respiratory therapist for COPD patients, among other things.
- To find a program in BC, contact HealthLink BC at 8-1-1, refer to the Referral Resources section below, or contact health authorities regarding local services. - A list of pulmonary rehabilitation programs in BC is available at prrl.rehab.med.ubc.ca/bc-pulmonary-rehabilitationprograms-contacts/.
# Diet Considerations
Ensure adequate diet to maintain body mass index in the "normal" range (20 to 25 kg/m 2 ), as it is essential in limiting disease progression and reducing morbidity and mortality related to COPD. Reduced body mass index (and in particular anorexia) is one of the most important risk factors for COPD progression.
# Air Quality
Encourage patients to stay indoors when air quality is poor, as air quality may have a significant effect on COPD symptoms and the risk of exacerbations.
# Oxygen Therapy
The goal of oxygen therapy is to maintain PaO 2 ≥ 60 mmHg or SpO 2 ≥ 90% at rest, on exertion and during sleep. (PaO 2 = partial pressure of oxygen in arterial blood, SpO 2 = % oxygen saturation). Oxygen therapy may be a useful addition to increase exercise capacity. Refer to Appendix C: BC Home Oxygen Program Medical Eligibility, or to health authorities for local criteria regarding coverage.
# Immunization
Individuals with COPD are at higher risk of complications of influenza and pneumococcal infection. While the polysaccharide pneumococcal vaccine may provide some protection against morbidity for patients with COPD, the evidence remains limited. 10 Encourage an annual influenza vaccine, which is provided free of charge in BC to adults with COPD -refer to website: www.healthlinkbc.ca/healthlinkbc-files/inactivated-influenza-vaccine.
The pneumococcal polysaccharide vaccine is recommended, and provided free of charge in BC, for adults with COPD. Some patients with specific comorbidities or undergoing certain treatments (e.g., chemotherapy) may also benefit from the pneumococcal conjugate vaccine. Some international COPD guidelines also suggest a booster of the pneumococcal polysaccharide vaccine at 5-10 years. Refer to HealthLink BC (website: www.healthlinkbc.ca/healthlinkbc-files/pneumococcalpolysaccharide-vaccine) and Immunize Canada (website: www.immunize.ca/en/diseases-vaccines/pneumococcal.aspx).
# Advance Care Planning
Initiate advance care planning discussions for all patients with a diagnosis of COPD. Advance care planning should be tailored to the needs of the patient along the disease trajectory, and should incorporate the patient's values and goals, indicate potential outcomes, and identify health care professionals involved in care. The advanced care plan is also an opportunity to identify the patient's alternate substitute decision maker or representative.
- For assistance, the Ministry of Health's advance care planning guide My Voice -Expressing My Wishes for Future Health Care Treatment is available at website: gov.bc.ca/advancecare.
# Pharmacologic Management
When developing the patient's therapeutic goals and pharmacologic management plan, individualize the plan based on the patient's symptoms, exacerbation history, response to treatment and their risk of adverse effects. For more information on specific medications, refer to Appendix A: Prescription Medication Table for COPD.
# Inhaled Medications
Many new inhaled medications, including fixed dose combinations, have been introduced in recent years. It is recommended to:
- Ensure that drug classes are not duplicated when initiating or modifying drug therapy.
- Evaluate the patient's inhaler technique and adherence regularly, as up to 90% of patients use their device incorrectly. Evaluating inhaler technique is particularly important in patients who are older, frail, or cognitively impaired. For information on how to use different inhalers, refer patients to website: www.lung.ca/lung-health/get-help/how-useyour-inhaler. - Consider prescribing a spacer for metered dose inhalers; however it should be noted that spacers require regular maintenance and cleaning to ensure optimal use.
Bronchodilator medications are central to symptom management in COPD, and should be prescribed on an as-needed or regular basis to prevent or reduce symptoms. 1
Stepwise Approach to Pharmacologic Therapy Implement pharmacologic therapy in a stepwise approach and use the lowest step that achieves optimal control based on the patient's severity of COPD (see Figure 1). When assessing for the next step, consider exertional dyspnea, functional status, history of exacerbations, complexity of medicines or devices, patient preference (e.g., cost and ability to adhere to treatment plan) and occurrence of adverse effects. Refer to Appendix A: Prescription Medication Table for COPD for information on dosing, drug costs, Pharmacare coverage, and therapeutic considerations.
# S T E P W IS E A P P R O A C H : U s e t h e lo w e s t s t e p t h a t a c h ie v e s o p t im a l c o n t r o l b a s e d o n t h e s e v e r it y o f C O P D
Abbreviations: COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid; LABA = long-acting beta 2 -agonist; LAMA = long-acting antimuscarinic antagonist; SABA = short-acting beta 2 -agonist; SAMA = short-acting muscarinic antagonist.
Step 1: SAMA or SABA Therapy -For symptom relief - For all symptomatic patients, prescribe a short-acting inhaled bronchodilator (short-acting beta 2 -agonist (SABA) or shortacting muscarinic antagonist (SAMA) for acute, short-term relief of shortness of breath. 6 - For those with moderate to severe COPD, SAMA or SABA monotherapy is recommended. Limited evidence suggests that SAMA reduces the risk of AECOPD, improves quality of life and lung function, and may be better tolerated, as compared to SABA monotherapy. 10,11 - If symptoms are not well controlled with monotherapy, consider combination therapy of SAMA + SABA. 10 Step 2: Additional LAMA or LABA Therapy -For symptom relief and to prevent exacerbations
- At the next step in symptom management, consider monotherapy with a long-acting beta 2 -agonist (LABA) or a long-acting antimuscarinic antagonist (LAMA). Limited evidence suggests LAMA may reduce the number of moderate and severe exacerbations compared to LABA therapy. 12,13 Given the limited evidence, consider a substantial trial of LAMA, followed by a LABA (or vice versa), then continue with the patient's preferred therapy. 13 - If monotherapy does not provide adequate relief of symptoms, consider a combination of LABA + LAMA, which provides slightly better quality life and lung function over either therapy alone, and reduces exacerbations compared to LABA alone. 14 Fixed dose combination inhalers of LABA with a LAMA are available, 8 and have been shown to be superior to inhaled corticosteroid (ICS) + LABA combination in reducing symptoms and preventing exacerbations in COPD. 15 - Ipratropium bromide/Atrovent® (a SAMA) and a LAMA should not be used concurrently. 6,10 Step 3: Triple Therapy -To prevent exacerbations
- For those with moderate to severe COPD and repeated exacerbations (e.g., FEV 1 < 50% predicted and ≥ 2 exacerbations in the past 12 months), a triple combination therapy of a LABA + ICS and LAMA is recommended. 6 - Fixed dose combination inhalers of an ICS with a LABA are available; if a combination inhaler is initiated, discontinue the use of the single agent LABA inhaler. 6 - The use of ICS with COPD remains controversial (see Controversies in Care section below). ICS monotherapy is not recommended, and if used in combination therapy, use the lowest possible dose.
# Treatment of Acute Exacerbations of COPD (AECOPD)
Acute exacerbations are characterized by sustained (e.g., 48 hours or more) worsening of shortness of breath and coughing, usually with increasing sputum volume. The most common cause of AECOPD is a viral or bacterial infection; however, there are a number of non-infectious causes of exacerbations including: pleural effusion, heart failure, pulmonary embolism, and pneumothorax.
Severe AECOPD complicated by acute respiratory failure is a medical emergency and the patient should seek immediate treatment. However, more than 80% of exacerbations can be managed on an outpatient basis with pharmacologic therapies including short-acting bronchodilators, oral corticosteroids, and antibiotics. 1 Develop an exacerbation action plan with the patient (see Associated Document: COPD Flare-up Action Plan). Note that there are some populations for which a written action plan may not be appropriate, including patients with cognitive disabilities, patients who cannot adequately follow instructions, and patients with significant comorbidities that might increase the risk of steroid-adverse effects. 16 Pharmacologic therapies may include:
1) short-acting bronchodilator for initial treatment of acute exacerbations - Adequate doses of bronchodilator (e.g., salbutamol 400 to 800 mcg ) delivered via metered dose inhaler with a spacer is equivalent to 2.5 mg by nebulizer and is as effective. Administer salbutamol frequently (up to every couple of hours) and titrate to response. 6 2) oral corticosteroids in most moderate to severe COPD patients 1 - A dose of 40 mg of prednisone per day for 5 days is an appropriate dose. 17 However, a dose of 50 mg of prednisone per day is often used in Canada because of its availability in a single tablet. Lower doses may need to be used, especially in the presence of diabetes mellitus.
- Evidence suggests that systemic corticosteroids in AECOPD shorten recovery time, improve lung function, improve arterial hypoxemia, and reduce the risk of early relapse, treatment failure, and duration of hospitalization. 1 - There is a well-powered randomized controlled trial comparing 5 versus 14 days of oral corticosteroids showing similar efficacy. 17 - For most patients, tapering of the corticosteroid dose should not be necessary. 1,6 - Systemic corticosteroids have not been shown to reduce AECOPD beyond the initial 30 days of an exacerbation and the long-term use of systemic corticosteroids is not recommended as the risk of adverse events far outweighs any potential benefits.
Bronchodilators and corticosteroids may be administered by nebulizer, metered-dose inhaler, or dry powder inhaler. While all of these devices are appropriate for treating COPD exacerbations, each has advantages and disadvantages. In choosing a drug/ device combination, take into account the patient's cognitive and physical ability, ease of use, convenience, cost, and patient preferences. 18 3) antibiotic treatment - Patients presenting with symptoms and risk factors for bacterial infection may benefit from antibiotic treatment. While studies have shown large and consistent benefit from antibiotic use among COPD patients admitted to the ICU, the evidence for their use in patients with mild to moderate exacerbations is less clear. 19 However, the totality of data suggests that for patients with moderate to severe exacerbations, antibiotics are effective in reducing relapse rates in COPD. 20 - Refer to Appendix B: Antibiotic Treatment Recommendations for Acute Exacerbations of COPD.
# Controversies in Care Cardiovascular Risk and Ipratropium
A small increase in cardiovascular events has been reported with the regular use of ipratropium in COPD patients. 1 However, this result has not been validated by a large randomized controlled trial (RCT) and further study is required. 21
# Cardiovascular Risk and Tiotropium
One large, long-term clinical trial showed no evidence of cardiovascular risk when tiotropium was added to other standard therapies. 21
# Mortality Risk and Tiotropium
A meta-analysis suggested that tiotropium delivered via the Respimat® inhaler was associated with a significantly increased risk of mortality when compared to placebo. However, in a large RCT comparing tiotripium via Respimat® to tiotropium via HandiHaler (dry powder inhaler), no differences in mortality or exacerbation rates were shown. 22
# Use of Inhaled Corticosteroid
The effects of ICS on pulmonary and systemic inflammation in COPD remain controversial, 1 and the use of ICS in COPD management is limited to specific indications:
- ICS monotherapy has very modest effects on symptoms and exacerbations and its limited benefits are outweighed by potential adverse effects, including increased risk of pneumonia. As such, ICS monotherapy is not recommended. - Triple therapy of a LABA, ICS and a LAMA has limited evidence to suggest it improves lung function and quality of life. 1 However, triple combination may be useful for the management of patients with moderate to severe COPD who continue to experience repeated exacerbations despite use of LABA/LAMA combination therapy or who have been recently hospitalized with severe COPD exacerbation. 23 As such, triple therapy is recommended for this indication.
# Use of Methylxanthines
The exact physiologic benefits of methylxanthines (xanthine derivatives, such as theophylline) remain unknown. There is limited data on the duration of action for both conventional release and extended release xanthine preparations. In the studies that have shown efficacy of theophylline in COPD, extended release formulations were used. 1 The use of theophylline in select patients with persistent symptoms was recommended in the previous version of this guideline (2011), and continues to be recommended by a number of international guidelines. 1,6 However, a Cochrane Review recommended against the use of methylxanthines for COPD exacerbations given that the evidence of potential benefit was modest and inconsistent, while potential adverse effects were significant. 24 Use of Oral N-acetylcysteine (NAC)
The routine use of NAC in the management of COPD remains controversial due to conflicting evidence and methodological issues in the trials. 25
# Indications for Referral
Refer patient to a specialist in cases where:
- the diagnosis is uncertain;
- a patient is < 40 years with COPD and limited smoking history, or has severe symptoms and disability which is disproportionate to their lung function; - there is evidence of an alpha-1 antitrypsin (A1AT) deficiency (e.g. early onset of emphysema or COPD, unexplained liver disease, family history); - there are signs and symptoms of hypoxemic or hypercarbic respiratory failure; - there are severe or recurrent exacerbations and treatment failure;
- the patient has severe COPD and disability requiring more intensive interventions;
- a more intensive comorbidity assessment and management is required; - a patient is frail and may benefit from multidisciplinary or comprehensive geriatric assessment, and/or - there is difficulty in assessing home oxygen or sleep disorders.
Family physicians and nurse practitioners in participating areas may consider contacting the Rapid Access to Consultative Expertise (RACE) phone line to speak directly with a specialist, including respirologists, or accessing referral services through PathwaysBC.ca. Refer to the Referral Resources section below.
# Ongoing Management
Follow-up Care Modify therapeutic goals and management plans as appropriate. Use routine follow-ups to ask about and monitor the patient's key clinical indicators, including:
- lung function;
- changes in symptoms (e.g. any improvement since starting/changing treatment; changes in level of breathlessness, activity level, sleep quality, etc.); - exacerbation history (frequency, severity) and review of the Flare-Up Action Plan (website: www2.gov.bc.ca/assets/gov/ health/practitioner-pro/bc-guidelines/copd_action_plan.pdf); - management of comorbidities (if present); and - pharmacologic therapy adherence and inhaler technique.
# Palliative Care
Making decisions about the intensity of palliative care is a highly individualized process and requires continuous review as COPD progresses. Once the decision to initiate palliative care is made, the goal of therapy is to manage symptoms, reduce treatment burden, and maximize comfort and quality of life. This may include providing support for the patient's family and caregivers. Consider referral to palliative care/hospice teams, if available.
Assess the need for home oxygen, non-pharmacologic therapies, and pharmacologic options for severe dyspnea (e.g., systemic opioids, anxiolytics).
For more information, refer to BCGuidelines.ca -Palliative Care for the Patient with Incurable Cancer or Advanced Disease and BC Pharmacare's Palliative Care Benefits Program (website: www2.gov.bc.ca/gov/content/health/practitioner-professionalresources/pharmacare/prescribers/plan-p-bc-palliative-care-benefits-program).
# Referral Resources - RACE -Rapid Access to Consultative Expertise Program
A telephone advice line from a selection of specialty services for general practitioners. - Pathways, pathwaysbc.ca An online resource that allows GPs and nurse practitioners and their office staff to quickly access current and accurate referral information, including wait times and areas of expertise, for specialists and specialty clinics. In addition, Pathways makes available hundreds of patient and physician resources that are categorized and searchable.
# Additional Resources
- BC Ministry of Health -Advance Care Planning, www.health.bc.ca In addition, each health authority also has an Advance Care Planning website.
- This guideline is based on scientific evidence current as of the effective date.
The guideline was developed by the Guidelines and Protocols Advisory Committee, approved by Doctors of BC and adopted by the Medical Services Commission.
# The principles of the Guidelines and Protocols Advisory Committee are to:
- encourage appropriate responses to common medical situations - recommend actions that are sufficient and efficient, neither excessive nor deficient - permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: [email protected] Website: www.BCGuidelines.ca | This guideline provides recommendations for the diagnosis and management of adults aged ≥ 19 years with chronic obstructive pulmonary disease (COPD).• Use spirometry to confirm airflow obstruction in all patients suspected of having COPD. [Amended, 2017] • Promote smoking cessation or reduction (even in long-term smokers) to improve symptom control and slow the progression of COPD, among other benefits. [2011] • Refer patients with moderate to severe COPD to pulmonary rehabilitation. [2011] • Implement pharmacologic therapy in a stepwise approach and use the lowest step that achieves optimal control based on the patient's severity of COPD. [New, 2017] • Develop an exacerbation action plan with the patient for pharmacologic therapies including short-acting bronchodilators, oral corticosteroids, and antibiotics. [Amended, 2017] • Use routine follow-ups to evaluate the patient's inhaler technique and adherence regularly. Evaluating inhaler technique is particularly important in patients who are older, frail, or cognitively impaired. [New, 2017]COPD is characterized by persistent airflow limitation that is typically progressive, not fully reversible, and associated with an abnormal inflammatory response of the lungs to noxious particles or gases (e.g., exposure to cigarette smoke). The two most common conditions that contribute to COPD are emphysema (destruction of alveoli) and chronic bronchitis (inflammation of bronchioles). COPD may present with comorbidities and exacerbations which contribute to overall symptom severity affecting the patient's daily activities and quality of life. These features are most prominent in patients with moderate to severe COPD, but even patients with mild COPD can experience exacerbations. 1 Acute exacerbation of COPD (AECOPD) is characterized by an increase in dyspnea, cough and/or sputum that is beyond normal day-to-day variation. It may be acute in onset, but can also have a more indolent onset and result in a change in regular medication. 1 Patients who experience an acute exacerbation have a significantly higher mortality rate than those with stable COPD. 2 This mortality risk increases as the number of exacerbations increases.Approximately 138,500 individuals aged ≥ 45 years in BC have been diagnosed with COPD (approximately 6% of British Columbians aged ≥ 45 years). 3 Many individuals have unrecognized COPD and remain undiagnosed. 4COPD patients commonly present with comorbidities which reduce quality of life. In patients with mild to moderate COPD, cardiovascular diseases are the leading cause of hospitalizations and the second leading cause of mortality after lung cancer. In severe and very severe COPD, respiratory failure and pneumonia are the leading causes of morbidity and mortality. However, even in these patients, cardiovascular diseases remain a major concern. 5# Diagnosis
While a diagnosis is based on a combination of medical history and physical examination, it is the documentation of airflow limitation using spirometry that confirms the diagnosis.
Consider a COPD diagnosis for a patient ≥ 40 years of age who has:
1) Respiratory symptoms, including:
• dyspnea (progressive, persistent and worse with exercise); • chronic cough; and • increased sputum production.
AND 2) One of the following:
• history of exposure to cigarette smoke;
• history of environmental/occupational exposure to smoke, dust or gas/fumes; • frequent respiratory infections; or • family history of COPD.
Consider alternative diagnoses. Asthma and asthma-COPD overlap syndrome (ACOS) are the two primary differential diagnoses to rule out (see Table 1 for features). Other alternative diagnoses include:
• heart failure (e.g., older patients, when breathlessness is out of proportion to spirometry results; measuring B-type natriuretic peptide (BNP) levels may help in diagnosing heart failure); and • tuberculosis (e.g., high risk populations -aboriginal, foreign born).
# Investigations or Tests
# Spirometry
Send ALL patients suspected of having COPD for confirmation of the diagnosis by spirometry. A COPD diagnosis is confirmed when a post-bronchodilator spirometry measurement indicates that there is airflow limitation which is not fully reversible (FEV 1 / FVC ratio < 0.7 or FEV 1 / FVC < lower limit of normal values). A FEV 1 predicted measurement is not needed for diagnosis, but is useful in the assessment of severity.
Timely access to spirometry may be a challenge in rural and remote communities, but should remain a reasonable goal.
Assuming access to spirometry can occur in a reasonable time frame, a referral to a specialist should not be done before objectively confirming the diagnosis of COPD.
# Borderline Spirometry Results
There is some controversy regarding the fixed cut-off of < 0.7 for FEV 1 / FVC ratio versus using < lower limit of normal values.
There is some evidence that a fixed ratio can lead to over diagnosis in older populations, under diagnosis in young people, and a gender difference. 6 Recent evidence also suggests that some current or former smokers may have symptoms of COPD without meeting spirometric criteria for a COPD diagnosis. 7 For borderline results, repeat spirometry after a few months.
Consider alternative diagnoses for all patients with borderline spirometry results or if breathlessness is out of proportion to spirometry results. If FEV 1 response to bronchodilator is:
• ≥ 400 mL, strongly consider asthma or ACOS.
• < 400 mL (but ≥ 200 mL and ≥ 12% of FEV 1 ), consider asthma or ACOS depending on the history and pattern of symptoms (see Table 1 above).
? Chest X-ray A chest x-ray is not helpful in diagnosing COPD. A chest x-ray that shows hyperinflation may suggest COPD, but the diagnosis requires objective confirmation with spirometry. A chest x-ray may be useful, and should be documented, if there are concerns about other significant comorbidities (e.g., heart failure, tuberculosis, pneumonia).
# ? Other Pulmonary Function Tests
Other pulmonary function tests (e.g., body plethysmography, diffusing capacity, arterial blood gas measurement) are not required for a COPD diagnosis, but may be helpful in assessing the severity of COPD or when considering alternative diagnoses. For example, a body plethysmography may help in the assessment of severity of COPD, but is not essential.
Peak flow meter readings may help rule out asthma, but their usefulness in assessing COPD remains unclear.
# Assessment of COPD Severity
Once the diagnosis is confirmed, determine the level of COPD severity (see Table 2) by using the patient's:
• current level of symptoms;
• FEV 1 predicted; • risk of exacerbation; and • presence of comorbidities.
# Assessment Tools
To assist in determining the current level of a patient's symptoms, use a tool such as the COPD Assessment Test (CAT) (website: www.catestonline.org). The MRC Breathlessness/Dyspnea Scale (website: www.mrc.ac.uk/research/facilities-and-resources-forresearchers/mrc-scales) may also be useful.
# Management
The therapeutic goals of COPD management include: 8 • to alleviate breathlessness and other respiratory symptoms that affect daily activities;
• to prevent and reduce the frequency and severity of acute exacerbations;
• to minimize disease progression and reduce the risk of morbidity/mortality; and • to optimally manage comorbidities (if present) to reduce exacerbations and COPD symptoms related to comorbidities.
When developing the patient's therapeutic goals and a management plan, consider:
• using a shared decision-making approach with the patient, taking into account patient preferences and capabilities (e.g. cognitive ability, language barriers); • including a chronic disease and self-management approach facilitated by health professionals, as it can significantly improve health status and reduce hospital admissions for exacerbations by 40%; 9 • using non-pharmacological and pharmacological interventions based on the individual patient's level of severity, • simplifying the medication regime in the context of other conditions and treatments, particularly in the elderly; and • reviewing the treatment approach regularly to eliminate medications that are not improving symptoms or reducing exacerbations.
# Lifestyle and Self-Management
The patient's understanding of, and participation in, optimal care may improve coping skills and quality of life and reduce the likelihood of hospitalization from COPD. Educate the patient and their family or caregiver about lifestyle and self-management strategies -refer to Associated Documents: Resource Guide for Patients.
# Smoking Cessation
Promote smoking cessation or reduction (even in long-term smokers) and avoidance of second-hand smoke. Smoking is the main cause of COPD and the main contributing factor for disease progression. Smoking cessation has immediate benefits including: 1) improving symptom control, 2) slowing progression of disease, 3) improving cardiovascular outcomes, and 4) reducing long-term risk of lung cancer.
• For assistance in quitting smoking, refer patients to QuitNow at HealthLinkBC by telephone at 8-1-1 or website: www.quitnow.ca. • For more information on effective pharmacological aids for smoking cessation, refer to the BC Smoking Cessation program website: www2.gov.bc.ca/gov/content/health/health-drug-coverage/pharmacare-for-bc-residents/what-we-cover/drugcoverage/bc-smoking-cessation-program.
# Physical Activity
Encourage exercise and a more active lifestyle. Remaining active despite symptoms of shortness of breath must remain a priority for all patients with COPD.
# Pulmonary Rehabilitation and Respiratory Services
Moderate to severe COPD patients should be referred to a pulmonary rehabilitation program (where available) and to community respiratory services. Home and Community Care programs offered by health authorities include home visits by a respiratory therapist for COPD patients, among other things.
• To find a program in BC, contact HealthLink BC at 8-1-1, refer to the Referral Resources section below, or contact health authorities regarding local services. • A list of pulmonary rehabilitation programs in BC is available at prrl.rehab.med.ubc.ca/bc-pulmonary-rehabilitationprograms-contacts/.
# Diet Considerations
Ensure adequate diet to maintain body mass index in the "normal" range (20 to 25 kg/m 2 ), as it is essential in limiting disease progression and reducing morbidity and mortality related to COPD. Reduced body mass index (and in particular anorexia) is one of the most important risk factors for COPD progression.
# Air Quality
Encourage patients to stay indoors when air quality is poor, as air quality may have a significant effect on COPD symptoms and the risk of exacerbations.
# Oxygen Therapy
The goal of oxygen therapy is to maintain PaO 2 ≥ 60 mmHg or SpO 2 ≥ 90% at rest, on exertion and during sleep. (PaO 2 = partial pressure of oxygen in arterial blood, SpO 2 = % oxygen saturation). Oxygen therapy may be a useful addition to increase exercise capacity. Refer to Appendix C: BC Home Oxygen Program Medical Eligibility, or to health authorities for local criteria regarding coverage.
# Immunization
Individuals with COPD are at higher risk of complications of influenza and pneumococcal infection. While the polysaccharide pneumococcal vaccine may provide some protection against morbidity for patients with COPD, the evidence remains limited. 10 Encourage an annual influenza vaccine, which is provided free of charge in BC to adults with COPD -refer to website: www.healthlinkbc.ca/healthlinkbc-files/inactivated-influenza-vaccine.
The pneumococcal polysaccharide vaccine is recommended, and provided free of charge in BC, for adults with COPD. Some patients with specific comorbidities or undergoing certain treatments (e.g., chemotherapy) may also benefit from the pneumococcal conjugate vaccine. Some international COPD guidelines also suggest a booster of the pneumococcal polysaccharide vaccine at 5-10 years. Refer to HealthLink BC (website: www.healthlinkbc.ca/healthlinkbc-files/pneumococcalpolysaccharide-vaccine) and Immunize Canada (website: www.immunize.ca/en/diseases-vaccines/pneumococcal.aspx).
# Advance Care Planning
Initiate advance care planning discussions for all patients with a diagnosis of COPD. Advance care planning should be tailored to the needs of the patient along the disease trajectory, and should incorporate the patient's values and goals, indicate potential outcomes, and identify health care professionals involved in care. The advanced care plan is also an opportunity to identify the patient's alternate substitute decision maker or representative.
• For assistance, the Ministry of Health's advance care planning guide My Voice -Expressing My Wishes for Future Health Care Treatment is available at website: gov.bc.ca/advancecare.
# Pharmacologic Management
When developing the patient's therapeutic goals and pharmacologic management plan, individualize the plan based on the patient's symptoms, exacerbation history, response to treatment and their risk of adverse effects. For more information on specific medications, refer to Appendix A: Prescription Medication Table for COPD.
# Inhaled Medications
Many new inhaled medications, including fixed dose combinations, have been introduced in recent years. It is recommended to:
• Ensure that drug classes are not duplicated when initiating or modifying drug therapy.
• Evaluate the patient's inhaler technique and adherence regularly, as up to 90% of patients use their device incorrectly. Evaluating inhaler technique is particularly important in patients who are older, frail, or cognitively impaired. For information on how to use different inhalers, refer patients to website: www.lung.ca/lung-health/get-help/how-useyour-inhaler. • Consider prescribing a spacer for metered dose inhalers; however it should be noted that spacers require regular maintenance and cleaning to ensure optimal use.
Bronchodilator medications are central to symptom management in COPD, and should be prescribed on an as-needed or regular basis to prevent or reduce symptoms. 1
Stepwise Approach to Pharmacologic Therapy Implement pharmacologic therapy in a stepwise approach and use the lowest step that achieves optimal control based on the patient's severity of COPD (see Figure 1). When assessing for the next step, consider exertional dyspnea, functional status, history of exacerbations, complexity of medicines or devices, patient preference (e.g., cost and ability to adhere to treatment plan) and occurrence of adverse effects. Refer to Appendix A: Prescription Medication Table for COPD for information on dosing, drug costs, Pharmacare coverage, and therapeutic considerations.
# S T E P W IS E A P P R O A C H : U s e t h e lo w e s t s t e p t h a t a c h ie v e s o p t im a l c o n t r o l b a s e d o n t h e s e v e r it y o f C O P D
Abbreviations: COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid; LABA = long-acting beta 2 -agonist; LAMA = long-acting antimuscarinic antagonist; SABA = short-acting beta 2 -agonist; SAMA = short-acting muscarinic antagonist.
Step 1: SAMA or SABA Therapy -For symptom relief • For all symptomatic patients, prescribe a short-acting inhaled bronchodilator (short-acting beta 2 -agonist (SABA) or shortacting muscarinic antagonist (SAMA) for acute, short-term relief of shortness of breath. 6 • For those with moderate to severe COPD, SAMA or SABA monotherapy is recommended. Limited evidence suggests that SAMA reduces the risk of AECOPD, improves quality of life and lung function, and may be better tolerated, as compared to SABA monotherapy. 10,11 • If symptoms are not well controlled with monotherapy, consider combination therapy of SAMA + SABA. 10 Step 2: Additional LAMA or LABA Therapy -For symptom relief and to prevent exacerbations
• At the next step in symptom management, consider monotherapy with a long-acting beta 2 -agonist (LABA) or a long-acting antimuscarinic antagonist (LAMA). Limited evidence suggests LAMA may reduce the number of moderate and severe exacerbations compared to LABA therapy. 12,13 Given the limited evidence, consider a substantial trial of LAMA, followed by a LABA (or vice versa), then continue with the patient's preferred therapy. 13 • If monotherapy does not provide adequate relief of symptoms, consider a combination of LABA + LAMA, which provides slightly better quality life and lung function over either therapy alone, and reduces exacerbations compared to LABA alone. 14 Fixed dose combination inhalers of LABA with a LAMA are available, 8 and have been shown to be superior to inhaled corticosteroid (ICS) + LABA combination in reducing symptoms and preventing exacerbations in COPD. 15 • Ipratropium bromide/Atrovent® (a SAMA) and a LAMA should not be used concurrently. 6,10 Step 3: Triple Therapy -To prevent exacerbations
• For those with moderate to severe COPD and repeated exacerbations (e.g., FEV 1 < 50% predicted and ≥ 2 exacerbations in the past 12 months), a triple combination therapy of a LABA + ICS and LAMA is recommended. 6 • Fixed dose combination inhalers of an ICS with a LABA are available; if a combination inhaler is initiated, discontinue the use of the single agent LABA inhaler. 6 • The use of ICS with COPD remains controversial (see Controversies in Care section below). ICS monotherapy is not recommended, and if used in combination therapy, use the lowest possible dose.
# Treatment of Acute Exacerbations of COPD (AECOPD)
Acute exacerbations are characterized by sustained (e.g., 48 hours or more) worsening of shortness of breath and coughing, usually with increasing sputum volume. The most common cause of AECOPD is a viral or bacterial infection; however, there are a number of non-infectious causes of exacerbations including: pleural effusion, heart failure, pulmonary embolism, and pneumothorax.
Severe AECOPD complicated by acute respiratory failure is a medical emergency and the patient should seek immediate treatment. However, more than 80% of exacerbations can be managed on an outpatient basis with pharmacologic therapies including short-acting bronchodilators, oral corticosteroids, and antibiotics. 1 Develop an exacerbation action plan with the patient (see Associated Document: COPD Flare-up Action Plan). Note that there are some populations for which a written action plan may not be appropriate, including patients with cognitive disabilities, patients who cannot adequately follow instructions, and patients with significant comorbidities that might increase the risk of steroid-adverse effects. 16 Pharmacologic therapies may include:
1) short-acting bronchodilator for initial treatment of acute exacerbations • Adequate doses of bronchodilator (e.g., salbutamol 400 to 800 mcg [4 to 8 puffs]) delivered via metered dose inhaler with a spacer is equivalent to 2.5 mg by nebulizer and is as effective. Administer salbutamol frequently (up to every couple of hours) and titrate to response. 6 2) oral corticosteroids in most moderate to severe COPD patients 1 • A dose of 40 mg of prednisone per day for 5 days is an appropriate dose. 17 However, a dose of 50 mg of prednisone per day is often used in Canada because of its availability in a single tablet. Lower doses may need to be used, especially in the presence of diabetes mellitus.
• Evidence suggests that systemic corticosteroids in AECOPD shorten recovery time, improve lung function, improve arterial hypoxemia, and reduce the risk of early relapse, treatment failure, and duration of hospitalization. 1 • There is a well-powered randomized controlled trial comparing 5 versus 14 days of oral corticosteroids showing similar efficacy. 17 • For most patients, tapering of the corticosteroid dose should not be necessary. 1,6 • Systemic corticosteroids have not been shown to reduce AECOPD beyond the initial 30 days of an exacerbation and the long-term use of systemic corticosteroids is not recommended as the risk of adverse events far outweighs any potential benefits.
Bronchodilators and corticosteroids may be administered by nebulizer, metered-dose inhaler, or dry powder inhaler. While all of these devices are appropriate for treating COPD exacerbations, each has advantages and disadvantages. In choosing a drug/ device combination, take into account the patient's cognitive and physical ability, ease of use, convenience, cost, and patient preferences. 18 3) antibiotic treatment • Patients presenting with symptoms and risk factors for bacterial infection may benefit from antibiotic treatment. While studies have shown large and consistent benefit from antibiotic use among COPD patients admitted to the ICU, the evidence for their use in patients with mild to moderate exacerbations is less clear. 19 However, the totality of data suggests that for patients with moderate to severe exacerbations, antibiotics are effective in reducing relapse rates in COPD. 20 • Refer to Appendix B: Antibiotic Treatment Recommendations for Acute Exacerbations of COPD.
# Controversies in Care Cardiovascular Risk and Ipratropium
A small increase in cardiovascular events has been reported with the regular use of ipratropium in COPD patients. 1 However, this result has not been validated by a large randomized controlled trial (RCT) and further study is required. 21
# Cardiovascular Risk and Tiotropium
One large, long-term clinical trial showed no evidence of cardiovascular risk when tiotropium was added to other standard therapies. 21
# Mortality Risk and Tiotropium
A meta-analysis suggested that tiotropium delivered via the Respimat® inhaler was associated with a significantly increased risk of mortality when compared to placebo. However, in a large RCT comparing tiotripium via Respimat® to tiotropium via HandiHaler (dry powder inhaler), no differences in mortality or exacerbation rates were shown. 22
# Use of Inhaled Corticosteroid
The effects of ICS on pulmonary and systemic inflammation in COPD remain controversial, 1 and the use of ICS in COPD management is limited to specific indications:
• ICS monotherapy has very modest effects on symptoms and exacerbations and its limited benefits are outweighed by potential adverse effects, including increased risk of pneumonia. As such, ICS monotherapy is not recommended. • Triple therapy of a LABA, ICS and a LAMA has limited evidence to suggest it improves lung function and quality of life. 1 However, triple combination may be useful for the management of patients with moderate to severe COPD who continue to experience repeated exacerbations despite use of LABA/LAMA combination therapy or who have been recently hospitalized with severe COPD exacerbation. 23 As such, triple therapy is recommended for this indication.
# Use of Methylxanthines
The exact physiologic benefits of methylxanthines (xanthine derivatives, such as theophylline) remain unknown. There is limited data on the duration of action for both conventional release and extended release xanthine preparations. In the studies that have shown efficacy of theophylline in COPD, extended release formulations were used. 1 The use of theophylline in select patients with persistent symptoms was recommended in the previous version of this guideline (2011), and continues to be recommended by a number of international guidelines. 1,6 However, a Cochrane Review recommended against the use of methylxanthines for COPD exacerbations given that the evidence of potential benefit was modest and inconsistent, while potential adverse effects were significant. 24 Use of Oral N-acetylcysteine (NAC)
The routine use of NAC in the management of COPD remains controversial due to conflicting evidence and methodological issues in the trials. 25
# Indications for Referral
Refer patient to a specialist in cases where:
• the diagnosis is uncertain;
• a patient is < 40 years with COPD and limited smoking history, or has severe symptoms and disability which is disproportionate to their lung function; • there is evidence of an alpha-1 antitrypsin (A1AT) deficiency (e.g. early onset of emphysema or COPD, unexplained liver disease, family history); • there are signs and symptoms of hypoxemic or hypercarbic respiratory failure; • there are severe or recurrent exacerbations and treatment failure;
• the patient has severe COPD and disability requiring more intensive interventions;
• a more intensive comorbidity assessment and management is required; • a patient is frail and may benefit from multidisciplinary or comprehensive geriatric assessment, and/or • there is difficulty in assessing home oxygen or sleep disorders.
Family physicians and nurse practitioners in participating areas may consider contacting the Rapid Access to Consultative Expertise (RACE) phone line to speak directly with a specialist, including respirologists, or accessing referral services through PathwaysBC.ca. Refer to the Referral Resources section below.
# Ongoing Management
Follow-up Care Modify therapeutic goals and management plans as appropriate. Use routine follow-ups to ask about and monitor the patient's key clinical indicators, including:
• lung function;
• changes in symptoms (e.g. any improvement since starting/changing treatment; changes in level of breathlessness, activity level, sleep quality, etc.); • exacerbation history (frequency, severity) and review of the Flare-Up Action Plan (website: www2.gov.bc.ca/assets/gov/ health/practitioner-pro/bc-guidelines/copd_action_plan.pdf); • management of comorbidities (if present); and • pharmacologic therapy adherence and inhaler technique.
# Palliative Care
Making decisions about the intensity of palliative care is a highly individualized process and requires continuous review as COPD progresses. Once the decision to initiate palliative care is made, the goal of therapy is to manage symptoms, reduce treatment burden, and maximize comfort and quality of life. This may include providing support for the patient's family and caregivers. Consider referral to palliative care/hospice teams, if available.
Assess the need for home oxygen, non-pharmacologic therapies, and pharmacologic options for severe dyspnea (e.g., systemic opioids, anxiolytics).
For more information, refer to BCGuidelines.ca -Palliative Care for the Patient with Incurable Cancer or Advanced Disease and BC Pharmacare's Palliative Care Benefits Program (website: www2.gov.bc.ca/gov/content/health/practitioner-professionalresources/pharmacare/prescribers/plan-p-bc-palliative-care-benefits-program).
# Referral Resources • RACE -Rapid Access to Consultative Expertise Program
A telephone advice line from a selection of specialty services for general practitioners. • Pathways, pathwaysbc.ca An online resource that allows GPs and nurse practitioners and their office staff to quickly access current and accurate referral information, including wait times and areas of expertise, for specialists and specialty clinics. In addition, Pathways makes available hundreds of patient and physician resources that are categorized and searchable.
# Additional Resources
• BC Ministry of Health -Advance Care Planning, www.health.bc.ca In addition, each health authority also has an Advance Care Planning website.
• This guideline is based on scientific evidence current as of the effective date.
The guideline was developed by the Guidelines and Protocols Advisory Committee, approved by Doctors of BC and adopted by the Medical Services Commission.
# The principles of the Guidelines and Protocols Advisory Committee are to:
• encourage appropriate responses to common medical situations • recommend actions that are sufficient and efficient, neither excessive nor deficient • permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: [email protected] Website: www.BCGuidelines.ca
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
# Resources Appendix A: Prescription Medication
# Appendix C: BC Home Oxygen Program Medical Eligibility
Medical eligibility criteria may vary slightly between health authorities. Refer to health authorities for more details on local criteria and application forms. All Home Oxygen Program applicants are expected to seek and be compliant with optimal medical or adjunctive treatment prior to use of oxygen therapy.
# CRITERIA NOTES
# RESTING OXYGEN PaO 2 ≤ 55mmHg on room air
Client must be breathing room air and seated at rest for at least 10 minutes prior to taking an arterial blood gas sample or beginning to monitor oximetry. OR If the client is unable to walk one minute or more, ambulatory oxygen will not be useful and will not be funded. Ambulatory testing is to be performed on a flat surface only; no exercise equipment (e.g. treadmills) is permitted.
Clients should be tested with their usual mobility devices (e.g. walkers, canes, etc.).
# Long-Term ambulatory oxygen therapy criteria (outpatient portable oxygen applications):
SpO 2 < 88% sustained continuously for a minimum of one minute while breathing room air and a measured improvement within a 6-minute walk test as tolerated on oxygen compared to room air showing 1) the distance traveled increases by at least 25% AND 2) at least 30 meters (100 feet).
-OR-SpO 2 < 80% with ambulation for a minimum of one minute.
# NOCTURNAL OXYGEN
SpO 2 must be < 88% for > 30% of a minimum 4 hour nocturnal oximetry study while breathing room air.
In the absence of co-morbidities (heart failure, pulmonary hypertension), 3 daytime desaturation must be present at rest or with ambulation according to sections 1 or 2 for nocturnal oxygen therapy to be funded.
Sleep disordered breathing (i.e. sleep apnea) will only be treated with supplemental oxygen if the nocturnal criteria are met despite optimal CPAP treatment.
# PALLIATIVE
Palliative clients must have hypoxemia according to sections 1, 2, or 3 above to be funded. | None | None |
d14118de137f229c2792ef7a15ed88d16c0cb0b7 | cma | None | Some patients with significant autoimmune/inflammatory diseases of the neurologic system (including the brain, spinal cord, motor nerves, neuromuscular junction and muscles -referred to broadly as neuromuscular) require treatment with immunotherapies. 1 These diseases (including multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and inflammatory myopathy) result from immune tolerance dysfunction such that the patient's immune system attacks their own tissues. Patients with neuromuscular conditions who require treatment with immunosuppressive medications are at increased risk of hospitalization and mortality from People were generally excluded from COVID-19 vaccine trials if they were on immunosuppressant treatment. Therefore, there are still uncertainties as to whether COVID-19 vaccine is efficacious and safe in patients with autoimmune neuromuscular disorders on therapy, as well as to the timing of immunization in relation to their treatments. 1,3 Is COVID-19 immunization recommended for patients with neuromuscular disorders receiving immunosuppressive/immunomodulating therapy? COVID-19 immunization should be encouraged for patients with neuromuscular disorders receiving immunosuppressive/immunomodulating therapy and is not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review: - The National Advisory Committee on Immunization recommends that immunosuppressed individuals may be offered the vaccine if the benefits of vaccine outweigh the potential risks. 4 - Based on the GBS/CIDP Foundation Global Medical Advisory Board's statement on November 11, 2021: "We recommend vaccination for all GBS, CIDP, and MMN patients as soon as possible as per their provincial authorities… If a patient has developed their disease within 6 weeks after receiving a COVID-19 vaccination, the patient should make an informed consent after discussing the risks versus benefits with their healthcare professional about receiving a second dose of vaccine that is of a different type, preferentially mRNA, as per the NACI guidance." 5#
While data specific to the safety and efficacy of the Pfizer and Moderna COVID-19 vaccines in people who take immunosuppressant or immunomodulating therapies is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 7 The authors of this guidance agree that the benefits of vaccine-induced immunity against COVID-19 for this population outweigh any theoretical risks of immunization.
The risks of COVID-19 infection to neuromuscular patients treated with immunotherapy include the following factors:
- During the COVID-19 pandemic, patients with neuromuscular disorders may be at greater risk of worse outcomes than otherwise healthy people because of an immunocompromised state related to immunotherapy. Immunosuppressive therapies can limit immune competence. 6,8 This can affect the risk of infections 9,10 ; some therapies are associated with an increased risk from particular types of pathogens. o Patients with autoimmune neuromuscular disorders (such as myasthenia gravis) who are infected with SARS-CoV-2 are frequently admitted to hospitals, have disease exacerbations and a higher mortality than the general population with COVID-19. 11 o Patients must continue with immunotherapy to avoid increasing symptoms including weakness of respiratory and bulbar muscles; the risk of relapse may result in permanent disability. o Infections are a well-recognised trigger of symptom exacerbation in autoimmune conditions such as myasthenia gravis and multiple sclerosis. 12 o Individual considerations regarding the appropriateness of the vaccine in patients with neuromuscular disease include, but are not limited to: o Level of activity of virus in the patient's local community o Individual risk of severe disease or death in patient contracting SARS-CoV-2 due to their neuromuscular condition and independent of their neuromuscular diagnosis (e.g., age and other comorbidities) o Whether family, care providers, and close contacts of the patient can receive immunization if they have no contraindication.
Is COVID-19 immunization efficacious and safe for patients with neuromuscular disorders receiving immunosuppressive/immunomodulating therapy?
- GBS cases following COVID-19 vaccination have been identified in Canada and internationally, but rarely. 13 There does not appear to be an increase from baseline incidence with mRNA vaccines. - As per NACI, safety data in immunocompromised individuals, including those receiving immunosuppressive therapy, were available from observational studies in people who were taking immunosuppressive therapies. 4 The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that of non-immunocompromised individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available.
COVID-19 Vaccines for People with Autoimmune Neuromuscular Disorders Receiving Immunosuppressive/Immunomodulating Therapy Updated: April 18, 2023
- There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 17 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. The safety of a third dose is unknown at this time, but in these small studies reactions were found to be similar to that of prior doses. - Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the authorized COVID-19 vaccines, as well as a discussion about the emerging evidence on the safety of mRNA COVID-19 vaccines in these populations. The recommendations in this clinical guidance are based on these small observational studies, extrapolation of data from other viral infections, immunology of immunizations and from expert opinion. - There is limited information on the effectiveness of vaccines in individuals who are on immunosuppressive medications. 18 However, even reduced efficacy may confer benefits against COVID-19 infections. 1 - As immune response to COVID-19 immunization is unknown for those taking immunosuppressant or immunomodulating therapy, patients with neuroimmunological disease who receive the COVID-19 vaccine should continue to closely follow public health recommendations including social distancing, regular hand washing and/or disinfection. - An increased risk of developing autoimmune or inflammatory disorders was not observed in clinical trial participants who received an mRNA COVID-19 immunization compared to placebo. Rate of recurrent GBS is infrequent after mRNA COVID-19 vaccine. 15,16 Are there any specific contraindications or exceptions for patients with neuromuscular disorders receiving immunosuppressive/immunomodulating therapy?
# Allergy to vaccine components
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 19 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process. Guillain Barre Syndrome (GBS)
Individuals with past history of Guillain Barre Syndrome (GBS) unrelated to COVID-19 vaccination should receive an mRNA COVID-19 vaccine. When mRNA COVID-19 vaccines are contraindicated or inaccessible, individuals may receive a viral vector COVID-19 vaccine after weighing the risks and benefits in consultation with their health care provider.
Individuals who developed GBS after a previous dose of a COVID-19 vaccine may receive another dose of an mRNA COVID-19 vaccine, after consultation with their health care provider (i.e., if the benefits outweigh the risk and informed consent is provided).
- No instances of GBS were seen during clinical trials of the Pfizer and Moderna mRNA vaccines 20,21 , and neither the U.S. Centers for Disease Control and Prevention (CDC) nor the Food and Drug Administration (FDA) recommends against the vaccine due to GBS. 22 - The incidence of GBS in the United Kingdom decreased by 50% during the first wave of COVID-19, likely due to COVID-19 control measures put in place which reduced the incidence of viral infection generally, compared to the same period during the four years prior. 23 - An analysis of the genetic and protein structure of SARS-CoV-2 showed that it contains no additional immunogenic material known or proven to drive an immune response that would trigger GBS. 24 Bell's palsy
Cases of Bell's palsy were reported in participants in the mRNA COVID-19 vaccine clinical trials. However, there was not an excess of Bell's palsy in the COVID-19 vaccine arm and the FDA does not consider these to be above the rate expected in the general population. They have not concluded these cases were caused by immunization. Therefore, the U.S. CDC recommends that individuals who have previously had Bell's Palsy may receive an mRNA COVID-19 vaccine. 25 Multiple Sclerosis Systematic reviews have not shown that vaccines cause or worsen multiple sclerosis. 26 Other vaccinations COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. Are there specific recommendations or considerations for safe and/or most effective vaccine administration?
Aligned with the Canadian Rheumatology Association's guidelines, 31 our recommendations are:
1) For patients on the following medications, there is no need to adjust or delay the medication: o Hydroxychloroquine, 2) For patients on the following medications, there are two options: a) Do not change medication dosing or b) Adjust medication dosing to optimize the immune response to the vaccine: i. For patients on weekly methotrexate, an option is to skip the methotrexate dose the following week after each vaccine dose. ii.
For patients on intravenous cyclophosphamide, an option is to take each vaccine dose at least one week prior to the next cyclophosphamide infusion. iii.
For patients on rituximab or ocrelizumab, the COVID-19 vaccination should ideally be timed four to five months after their last infusion and two to four weeks prior to their next infusion, when possible, in order to optimize vaccine response. However, in patients who require immediate infusion or who are unable to optimize timing of infusion product and vaccine, it is likely more important to have the COVID-19 vaccine earlier than to delay based on timing of B-cell therapy. iv.
For MS patients who are requiring first or repeat dosing of cladribine or alemtuzumab a delay could be considered until after full vaccine course plus four weeks. If treatment with alemtuzumab is required because of active disease, then vaccination will need to be delayed for 12 weeks after treatment dose.
Bridging with natalizumab can be considered in order to give full vaccination before initiating alemtuzumab. Vaccination after cladribine can occur 4 weeks after treatment dose. 32 v.
For patients on mycophenolate mofetil, if the disease is stable, the medication may be held for one week following each COVID-19 dose. 33
# vi.
For patients on prednisone 20mg/d or higher, consider waiting until the prednisone dose is tapered to below 20mg/d to receive both vaccine doses. 34 (Note: for individuals with Duchenne's Muscular Dystrophy on deflazacort, Parent Project Muscular Dystrophy and Muscular Dystrophy Canada recommend vaccination on current prednisone dose) 35 Pediatric patients on high-dose steroids should consult with their pediatric rheumatologist to decide on the best time to receive the vaccine. 36 | Some patients with significant autoimmune/inflammatory diseases of the neurologic system (including the brain, spinal cord, motor nerves, neuromuscular junction and muscles -referred to broadly as neuromuscular) require treatment with immunotherapies. 1 These diseases (including multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and inflammatory myopathy) result from immune tolerance dysfunction such that the patient's immune system attacks their own tissues. Patients with neuromuscular conditions who require treatment with immunosuppressive medications are at increased risk of hospitalization and mortality from People were generally excluded from COVID-19 vaccine trials if they were on immunosuppressant treatment. Therefore, there are still uncertainties as to whether COVID-19 vaccine is efficacious and safe in patients with autoimmune neuromuscular disorders on therapy, as well as to the timing of immunization in relation to their treatments. 1,3 Is COVID-19 immunization recommended for patients with neuromuscular disorders receiving immunosuppressive/immunomodulating therapy? COVID-19 immunization should be encouraged for patients with neuromuscular disorders receiving immunosuppressive/immunomodulating therapy and is not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review: • The National Advisory Committee on Immunization recommends that immunosuppressed individuals may be offered the vaccine if the benefits of vaccine outweigh the potential risks. 4 • Based on the GBS/CIDP Foundation Global Medical Advisory Board's statement on November 11, 2021: "We recommend vaccination for all GBS, CIDP, and MMN patients as soon as possible as per their provincial authorities… If a patient has developed their disease within 6 weeks after receiving a COVID-19 vaccination, the patient should make an informed consent after discussing the risks versus benefits with their healthcare professional about receiving a second dose of vaccine that is of a different type, preferentially mRNA, as per the NACI guidance." 5#
While data specific to the safety and efficacy of the Pfizer and Moderna COVID-19 vaccines in people who take immunosuppressant or immunomodulating therapies is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 7 The authors of this guidance agree that the benefits of vaccine-induced immunity against COVID-19 for this population outweigh any theoretical risks of immunization.
The risks of COVID-19 infection to neuromuscular patients treated with immunotherapy include the following factors:
o During the COVID-19 pandemic, patients with neuromuscular disorders may be at greater risk of worse outcomes than otherwise healthy people because of an immunocompromised state related to immunotherapy. Immunosuppressive therapies can limit immune competence. 6,8 This can affect the risk of infections 9,10 ; some therapies are associated with an increased risk from particular types of pathogens. o Patients with autoimmune neuromuscular disorders (such as myasthenia gravis) who are infected with SARS-CoV-2 are frequently admitted to hospitals, have disease exacerbations and a higher mortality than the general population with COVID-19. 11 o Patients must continue with immunotherapy to avoid increasing symptoms including weakness of respiratory and bulbar muscles; the risk of relapse may result in permanent disability. o Infections are a well-recognised trigger of symptom exacerbation in autoimmune conditions such as myasthenia gravis and multiple sclerosis. 12 o Individual considerations regarding the appropriateness of the vaccine in patients with neuromuscular disease include, but are not limited to: o Level of activity of virus in the patient's local community o Individual risk of severe disease or death in patient contracting SARS-CoV-2 due to their neuromuscular condition and independent of their neuromuscular diagnosis (e.g., age and other comorbidities) o Whether family, care providers, and close contacts of the patient can receive immunization if they have no contraindication.
Is COVID-19 immunization efficacious and safe for patients with neuromuscular disorders receiving immunosuppressive/immunomodulating therapy?
• GBS cases following COVID-19 vaccination have been identified in Canada and internationally, but rarely. 13 There does not appear to be an increase from baseline incidence with mRNA vaccines. [14][15][16] • As per NACI, safety data in immunocompromised individuals, including those receiving immunosuppressive therapy, were available from observational studies in people who were taking immunosuppressive therapies. 4 The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that of non-immunocompromised individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available.
COVID-19 Vaccines for People with Autoimmune Neuromuscular Disorders Receiving Immunosuppressive/Immunomodulating Therapy Updated: April 18, 2023
3
• There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 17 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. The safety of a third dose is unknown at this time, but in these small studies reactions were found to be similar to that of prior doses. • Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the authorized COVID-19 vaccines, as well as a discussion about the emerging evidence on the safety of mRNA COVID-19 vaccines in these populations. The recommendations in this clinical guidance are based on these small observational studies, extrapolation of data from other viral infections, immunology of immunizations and from expert opinion. • There is limited information on the effectiveness of vaccines in individuals who are on immunosuppressive medications. 18 However, even reduced efficacy may confer benefits against COVID-19 infections. 1 • As immune response to COVID-19 immunization is unknown for those taking immunosuppressant or immunomodulating therapy, patients with neuroimmunological disease who receive the COVID-19 vaccine should continue to closely follow public health recommendations including social distancing, regular hand washing and/or disinfection. • An increased risk of developing autoimmune or inflammatory disorders was not observed in clinical trial participants who received an mRNA COVID-19 immunization compared to placebo. Rate of recurrent GBS is infrequent after mRNA COVID-19 vaccine. 15,16 Are there any specific contraindications or exceptions for patients with neuromuscular disorders receiving immunosuppressive/immunomodulating therapy?
# Allergy to vaccine components
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 19 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process. Guillain Barre Syndrome (GBS)
Individuals with past history of Guillain Barre Syndrome (GBS) unrelated to COVID-19 vaccination should receive an mRNA COVID-19 vaccine. When mRNA COVID-19 vaccines are contraindicated or inaccessible, individuals may receive a viral vector COVID-19 vaccine after weighing the risks and benefits in consultation with their health care provider.
Individuals who developed GBS after a previous dose of a COVID-19 vaccine may receive another dose of an mRNA COVID-19 vaccine, after consultation with their health care provider (i.e., if the benefits outweigh the risk and informed consent is provided).
• No instances of GBS were seen during clinical trials of the Pfizer and Moderna mRNA vaccines 20,21 , and neither the U.S. Centers for Disease Control and Prevention (CDC) nor the Food and Drug Administration (FDA) recommends against the vaccine due to GBS. 22 • The incidence of GBS in the United Kingdom decreased by 50% during the first wave of COVID-19, likely due to COVID-19 control measures put in place which reduced the incidence of viral infection generally, compared to the same period during the four years prior. 23 • An analysis of the genetic and protein structure of SARS-CoV-2 showed that it contains no additional immunogenic material known or proven to drive an immune response that would trigger GBS. 24 Bell's palsy
Cases of Bell's palsy were reported in participants in the mRNA COVID-19 vaccine clinical trials. However, there was not an excess of Bell's palsy in the COVID-19 vaccine arm and the FDA does not consider these to be above the rate expected in the general population. They have not concluded these cases were caused by immunization. Therefore, the U.S. CDC recommends that individuals who have previously had Bell's Palsy may receive an mRNA COVID-19 vaccine. 25 Multiple Sclerosis Systematic reviews have not shown that vaccines cause or worsen multiple sclerosis. 26 Other vaccinations COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. [27][28][29][30] Are there specific recommendations or considerations for safe and/or most effective vaccine administration?
Aligned with the Canadian Rheumatology Association's guidelines, 31 our recommendations are:
1) For patients on the following medications, there is no need to adjust or delay the medication: o Hydroxychloroquine, 2) For patients on the following medications, there are two options: a) Do not change medication dosing or b) Adjust medication dosing to optimize the immune response to the vaccine: i. For patients on weekly methotrexate, an option is to skip the methotrexate dose the following week after each vaccine dose. ii.
For patients on intravenous cyclophosphamide, an option is to take each vaccine dose at least one week prior to the next cyclophosphamide infusion. iii.
For patients on rituximab or ocrelizumab, the COVID-19 vaccination should ideally be timed four to five months after their last infusion and two to four weeks prior to their next infusion, when possible, in order to optimize vaccine response. However, in patients who require immediate infusion or who are unable to optimize timing of infusion product and vaccine, it is likely more important to have the COVID-19 vaccine earlier than to delay based on timing of B-cell therapy. iv.
For MS patients who are requiring first or repeat dosing of cladribine or alemtuzumab a delay could be considered until after full vaccine course plus four weeks. If treatment with alemtuzumab is required because of active disease, then vaccination will need to be delayed for 12 weeks after treatment dose.
Bridging with natalizumab can be considered in order to give full vaccination before initiating alemtuzumab. Vaccination after cladribine can occur 4 weeks after treatment dose. 32 v.
For patients on mycophenolate mofetil, if the disease is stable, the medication may be held for one week following each COVID-19 dose. 33
# vi.
For patients on prednisone 20mg/d or higher, consider waiting until the prednisone dose is tapered to below 20mg/d to receive both vaccine doses. 34 (Note: for individuals with Duchenne's Muscular Dystrophy on deflazacort, Parent Project Muscular Dystrophy and Muscular Dystrophy Canada recommend vaccination on current prednisone dose) 35 Pediatric patients on high-dose steroids should consult with their pediatric rheumatologist to decide on the best time to receive the vaccine. 36 | None | None |
417de9501cc93f10c112964a7f3d2a089371a96a | cma | None | # Guideline Resource Unit
Background There were an estimated 220,400 new diagnoses of cancer in Canada in 2018, and it is estimated that one in two Canadians will develop cancer in their lifetime. 1 For patients undergoing cancer treatment, chemotherapy-induced peripheral neuropathy (CIPN) is a common treatment-related side effect that can have a significant negative impact on quality of life 2 and is associated with higher healthcare costs and resource use. 3 CIPN is defined as the injury or degeneration of peripheral nerve fibers caused by exposure to a neurotoxic chemotherapy agent. Patients experiencing CIPN may experience sensory symptoms such as paresthesia, dysesthesia (numbness, tingling, abnormal touch sensations), cold sensitivity, hyperalgesia or allodynia in the hands or feet in a stocking-glove distribution, as well as pain. 4,5 Motor symptoms may include loss of strength, muscle cramps, and spontaneous movements. 6 The precise incidence and prevalence of CIPN varies according to the chemotherapeutic agent, dose, duration of exposure, and method of assessment, and there is likely significant underreporting. 5 Approximately two-thirds of patients experience CIPN in the first month following chemotherapy and half of these patients continue to experience CIPN after six months. 7,8 It is likely that the rate of CIPN will continue to rise as cancer treatments become more aggressive and patient survival rates improve. 9,10 The chemotherapy agents associated with the highest incidence are the platinum drugs (cisplatin, carboplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine) and bortezomib. 5,11,12 In addition, newer classes of medications, including molecular targeted chemotherapeutics and immune checkpoint inhibitors, continue to be associated with CIPN. 10 Management of CIPN can lead to chemotherapy dose reductions, modifications and/or premature treatment discontinuation, adversely affecting treatment outcomes.
The purpose of this guideline is to provide clinical practice recommendations to members of multidisciplinary healthcare teams who screen, assess, and manage adult patients with chemotherapy-induced peripheral neuropathy in their daily clinical practice.
# Search Strategy
The PubMed database was searched for relevant studies, guidelines and consensus documents published up to December 2018. The specific search strategy, search terms, and search results, are presented in Appendix A, and evidence tables are available upon request. Online resources from oncology-based health organizations and guideline developers were also systematically searched, and relevant guidelines from the following organizations were considered in the development of our recommendations: American Society of Clinical Oncology (ASCO), BC Cancer (BCC), and the National Comprehensive Cancer Network (NCCN).
# Target Population
The following recommendations apply to adult cancer patients with chemotherapy-induced peripheral neuropathy. 1.2 Prior to neurotoxic therapy, a baseline focused health assessment should be performed and recorded, identifying any pre-existing conditions that may predispose/exacerbate CIPN (see Table 1). 14,15 Since CIPN often progresses with dose accumulation, it is recommended that patients are actively assessed for signs and symptoms during chemotherapy, and intermittently thereafter. 5 The main goal of routine clinical assessment is to determine whether the patient is experiencing significant neuropathic symptoms that require intervention. 1.3 A valid quantitative measure should be used to assess the severity of motor symptoms, sensory symptoms, and pain. We recommend the use of the NCI-CTCAE v5 (Nervous System Disorders) and ESASr (Pain) tools regularly as needed at each appointment. Table 2 has been adapted from BC Cancer, 14 and summarizes these tools.
# Recommendations
# Prevention
Although several agents have been investigated for their efficacy in the prevention of CIPN, these studies have not demonstrated reliable or conclusive evidence of benefit to clinical practice. Limiting factors include small sample size, lack of placebo-controlled groups, un-blinded study designs, and the harms outweighing the benefits. 5,9,11,23,24 There are therefore currently no agents that can be recommended as a standard of care for the prevention of CIPN in patients with cancer undergoing treatment with neurotoxic agents.
2.1 Ensure patients are aware of the following before starting a chemotherapy regimen:
- Specific neurotoxic effects that can be expected from their chemotherapy regimen.
- Awareness of potential risk factors for CIPN, including prior chemotherapy, diabetes, folate/vitamin B12 deficiencies, history of smoking, and decreased creatinine clearance. 5,7 - There are certain chemotherapy drugs such as paclitaxel and nab-paclitaxel that are associated with worsening of CIPN symptoms after completion of the last course of therapy. 25 - Platinum neuropathy can progress for several months after completion of chemotherapy and can lead to permanent damage or limitations. 25,26 - Signs and symptoms of platinum neuropathy (sensory, motor, autonomic) that should be reported to a health care provider when they are first noticed. - Strategies for self-care and personal safety.
The following agents are not recommended for the prevention of CIPN: 23,24 - Acetyl-L-carnitine (ALC)
- Amifostine 3 The efficacy of the following agents for the prevention of CIPN is inconclusive: 23,24 - N-acetylcysteine
- Carbamazepine - Glutamate - GSH for patients receiving cisplatin/oxaliplatin chemotherapy - Goshajinkigan (GJG) - Omega-3 fatty acids - Oxcarbazepine - rhuLIF - Vitamin E - Venlafaxine 2.
# Exercise
- There is a growing body of evidence to suggest a protective effect of exercise and physical activity on CIPN, particularly for patients treated with taxanes, platinum drugs, or vinca alkaloids. 27-30 - More information is required regarding the optimal types of training (i.e., balance, strength, endurance) and recommended duration of exercise regimens; referral to a rehabilitation specialist is appropriate for patients who are experiencing changes in strength or mobility.
# Rehabilitation
Cancer patients with CIPN often present with significant functional deficits, particularly as their neuropathy worsens. The most common deficits include decreased balance, gait abnormalities, muscle weakness, fine motor difficulties, and sensory loss, which can lead to an increased risk of falls, difficulties with performing activities of daily living (ADL), and safety concerns. 4 Rehabilitation specialists such as occupational therapists and physical therapists have a critical role in providing therapeutic interventions, education, and practical advice to help patients correct and manage their symptoms and improve their quality of life. 4, Guideline Resource Unit
# CIPN rehabilitation referral criteria:
- Grade 2 CIPN according to NCI-CTCAE version 5 criteria (see Table 2; moderate pain and symptoms impacting instrumental ADLs such as preparing meals, shopping, managing money) and/or; - Subsequent to an unsuccessful trial of initial pharmacologic therapy options (see Figure 1).
# Assessments and outcome measures:
- General: quantitative sensory testing is a method of objectively quantifying and assessing sensory impairment. Is not sufficiently reliable to be used alone for decision making, but may be used as an adjunct to clinical assessment (monofilament protective sensation testing, reflex testing, vibration sensation testing, temperature testing, manual muscle testing of affected area). 4 - Upper extremity specific: grip strength, DASH, functional task assessment, fine motor outcome measure (e.g., Jebsen Hand Function Test). - Lower extremity specific: balance testing/assessment (Berg, TUG, FAB, mini-BEST), Gait assessment (Winters-Stone 2017). 35 - Canadian Occupational Performance Measure: 36 o Individualized measure of a patient's perception of problems encountered in occupational performance. Aims to provide high quality, occupation-focused, evidence-based, patientcentered practice. - General assessment of ADL.
# Pharmacological Management
Figure 1 outlines the recommended pharmacologic treatment approach for patients with painful established CIPN. The goals of pharmacologic therapy are:
- a reduction of pain by 30% or greater - improved function (e.g., increased tolerance for walking and standing), mood, and sleep - minimal or tolerable adverse effects Good Practice Point: Guiding Principles for Administering Pharmacologic Therapy
- Titrate each agent up to usual minimum effective dose; if well tolerated and helpful, continue to titrate to the optimal dose. - If an agent is ineffective and/or poorly tolerated, discontinue and consider an alternate agent.
- If an agent is only partially effective but well tolerated, continue it and add an additional agent or agents from a different class. - Intractable pain may require treatment with some combination of agents such as anticonvulsants, antidepressants, and opioid analgesics. Opioids should be used with caution in patients with cancer that has been cured or is under long-term control. - Individual patients and responses will vary, and every pain syndrome is unique, therefore the lack of evidence does not preclude reasonable attempts at symptom management.
4.1 For patients with CIPN symptoms that require pharmacological intervention, duloxetine is the only agent that has been shown in a well-designed randomized clinical trial to be effective in alleviating CIPN, 42 and is therefore the only recommended first-line medication. A subgroup analysis within the same trial suggested that duloxetine may be most effective for patients receiving platinum agents such as oxaliplatin compared to taxanes such as paclitaxel. 42 The recommended dosing is 30 mg per day for the first week, and 60 mg per day thereafter, if well tolerated.
The efficacy of the following agents is inconclusive for treatment of CIPN, but because their efficacy has been established for other forms of neuropathic pain and based on limited treatment options, it is reasonable to consider these agents either in addition to duloxetine, or if duloxetine is not effective or well-tolerated. Patients should be informed of the limited scientific evidence and counseled on the potential harms and benefits. 24 - Anticonvulsants (gabapentin or pregabalin)
- Tricyclic antidepressants (amitriptyline, nortriptyline, desipramine, or imipramine)
- Referral to a specialized pain management service is recommended for discussion of other add-on or alternative options not described above.
Additional Criteria: Review articles, case reports with <30 patients, and studies that did not report on the outcomes of interest were excluded from the final review were not included in the final review. | # Guideline Resource Unit
Background There were an estimated 220,400 new diagnoses of cancer in Canada in 2018, and it is estimated that one in two Canadians will develop cancer in their lifetime. 1 For patients undergoing cancer treatment, chemotherapy-induced peripheral neuropathy (CIPN) is a common treatment-related side effect that can have a significant negative impact on quality of life 2 and is associated with higher healthcare costs and resource use. 3 CIPN is defined as the injury or degeneration of peripheral nerve fibers caused by exposure to a neurotoxic chemotherapy agent. Patients experiencing CIPN may experience sensory symptoms such as paresthesia, dysesthesia (numbness, tingling, abnormal touch sensations), cold sensitivity, hyperalgesia or allodynia in the hands or feet in a stocking-glove distribution, as well as pain. 4,5 Motor symptoms may include loss of strength, muscle cramps, and spontaneous movements. 6 The precise incidence and prevalence of CIPN varies according to the chemotherapeutic agent, dose, duration of exposure, and method of assessment, and there is likely significant underreporting. 5 Approximately two-thirds of patients experience CIPN in the first month following chemotherapy and half of these patients continue to experience CIPN after six months. 7,8 It is likely that the rate of CIPN will continue to rise as cancer treatments become more aggressive and patient survival rates improve. 9,10 The chemotherapy agents associated with the highest incidence are the platinum drugs (cisplatin, carboplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine) and bortezomib. 5,11,12 In addition, newer classes of medications, including molecular targeted chemotherapeutics and immune checkpoint inhibitors, continue to be associated with CIPN. 10 Management of CIPN can lead to chemotherapy dose reductions, modifications and/or premature treatment discontinuation, adversely affecting treatment outcomes.
The purpose of this guideline is to provide clinical practice recommendations to members of multidisciplinary healthcare teams who screen, assess, and manage adult patients with chemotherapy-induced peripheral neuropathy in their daily clinical practice.
# Search Strategy
The PubMed database was searched for relevant studies, guidelines and consensus documents published up to December 2018. The specific search strategy, search terms, and search results, are presented in Appendix A, and evidence tables are available upon request. Online resources from oncology-based health organizations and guideline developers were also systematically searched, and relevant guidelines from the following organizations were considered in the development of our recommendations: American Society of Clinical Oncology (ASCO), BC Cancer (BCC), and the National Comprehensive Cancer Network (NCCN).
# Target Population
The following recommendations apply to adult cancer patients with chemotherapy-induced peripheral neuropathy. 1.2 Prior to neurotoxic therapy, a baseline focused health assessment should be performed and recorded, identifying any pre-existing conditions that may predispose/exacerbate CIPN (see Table 1). 14,15 Since CIPN often progresses with dose accumulation, it is recommended that patients are actively assessed for signs and symptoms during chemotherapy, and intermittently thereafter. 5 The main goal of routine clinical assessment is to determine whether the patient is experiencing significant neuropathic symptoms that require intervention. 1.3 A valid quantitative measure should be used to assess the severity of motor symptoms, sensory symptoms, and pain. We recommend the use of the NCI-CTCAE v5 (Nervous System Disorders) and ESASr (Pain) tools regularly as needed at each appointment. Table 2 has been adapted from BC Cancer, 14 and summarizes these tools.
# Recommendations
# Prevention
Although several agents have been investigated for their efficacy in the prevention of CIPN, these studies have not demonstrated reliable or conclusive evidence of benefit to clinical practice. Limiting factors include small sample size, lack of placebo-controlled groups, un-blinded study designs, and the harms outweighing the benefits. 5,9,11,23,24 There are therefore currently no agents that can be recommended as a standard of care for the prevention of CIPN in patients with cancer undergoing treatment with neurotoxic agents.
2.1 Ensure patients are aware of the following before starting a chemotherapy regimen:
• Specific neurotoxic effects that can be expected from their chemotherapy regimen.
• Awareness of potential risk factors for CIPN, including prior chemotherapy, diabetes, folate/vitamin B12 deficiencies, history of smoking, and decreased creatinine clearance. 5,7 • There are certain chemotherapy drugs such as paclitaxel and nab-paclitaxel that are associated with worsening of CIPN symptoms after completion of the last course of therapy. 25 • Platinum neuropathy can progress for several months after completion of chemotherapy and can lead to permanent damage or limitations. 25,26 • Signs and symptoms of platinum neuropathy (sensory, motor, autonomic) that should be reported to a health care provider when they are first noticed. • Strategies for self-care and personal safety.
# 2.2
The following agents are not recommended for the prevention of CIPN: 23,24 • Acetyl-L-carnitine (ALC)
• Amifostine 3 The efficacy of the following agents for the prevention of CIPN is inconclusive: 23,24 • N-acetylcysteine
• Carbamazepine • Glutamate • GSH for patients receiving cisplatin/oxaliplatin chemotherapy • Goshajinkigan (GJG) • Omega-3 fatty acids • Oxcarbazepine • rhuLIF • Vitamin E • Venlafaxine 2.
# Exercise
• There is a growing body of evidence to suggest a protective effect of exercise and physical activity on CIPN, particularly for patients treated with taxanes, platinum drugs, or vinca alkaloids. 27-30 • More information is required regarding the optimal types of training (i.e., balance, strength, endurance) and recommended duration of exercise regimens; referral to a rehabilitation specialist is appropriate for patients who are experiencing changes in strength or mobility.
# Rehabilitation
Cancer patients with CIPN often present with significant functional deficits, particularly as their neuropathy worsens. The most common deficits include decreased balance, gait abnormalities, muscle weakness, fine motor difficulties, and sensory loss, which can lead to an increased risk of falls, difficulties with performing activities of daily living (ADL), and safety concerns. 4 Rehabilitation specialists such as occupational therapists and physical therapists have a critical role in providing therapeutic interventions, education, and practical advice to help patients correct and manage their symptoms and improve their quality of life. 4,[31][32][33][34] Guideline Resource Unit
# CIPN rehabilitation referral criteria:
• Grade 2 CIPN according to NCI-CTCAE version 5 criteria (see Table 2; moderate pain and symptoms impacting instrumental ADLs such as preparing meals, shopping, managing money) and/or; • Subsequent to an unsuccessful trial of initial pharmacologic therapy options (see Figure 1).
# Assessments and outcome measures:
• General: quantitative sensory testing is a method of objectively quantifying and assessing sensory impairment. Is not sufficiently reliable to be used alone for decision making, but may be used as an adjunct to clinical assessment (monofilament protective sensation testing, reflex testing, vibration sensation testing, temperature testing, manual muscle testing of affected area). 4 • Upper extremity specific: grip strength, DASH, functional task assessment, fine motor outcome measure (e.g., Jebsen Hand Function Test). • Lower extremity specific: balance testing/assessment (Berg, TUG, FAB, mini-BEST), Gait assessment (Winters-Stone 2017). 35 • Canadian Occupational Performance Measure: 36 o Individualized measure of a patient's perception of problems encountered in occupational performance. Aims to provide high quality, occupation-focused, evidence-based, patientcentered practice. • General assessment of ADL.
# Pharmacological Management
Figure 1 outlines the recommended pharmacologic treatment approach for patients with painful established CIPN. The goals of pharmacologic therapy are:
• a reduction of pain by 30% or greater • improved function (e.g., increased tolerance for walking and standing), mood, and sleep • minimal or tolerable adverse effects Good Practice Point: Guiding Principles for Administering Pharmacologic Therapy
• Titrate each agent up to usual minimum effective dose; if well tolerated and helpful, continue to titrate to the optimal dose. • If an agent is ineffective and/or poorly tolerated, discontinue and consider an alternate agent.
• If an agent is only partially effective but well tolerated, continue it and add an additional agent or agents from a different class. • Intractable pain may require treatment with some combination of agents such as anticonvulsants, antidepressants, and opioid analgesics. Opioids should be used with caution in patients with cancer that has been cured or is under long-term control. • Individual patients and responses will vary, and every pain syndrome is unique, therefore the lack of evidence does not preclude reasonable attempts at symptom management.
4.1 For patients with CIPN symptoms that require pharmacological intervention, duloxetine is the only agent that has been shown in a well-designed randomized clinical trial to be effective in alleviating CIPN, 42 and is therefore the only recommended first-line medication. A subgroup analysis within the same trial suggested that duloxetine may be most effective for patients receiving platinum agents such as oxaliplatin compared to taxanes such as paclitaxel. 42 The recommended dosing is 30 mg per day for the first week, and 60 mg per day thereafter, if well tolerated.
# 4.2
The efficacy of the following agents is inconclusive for treatment of CIPN, but because their efficacy has been established for other forms of neuropathic pain and based on limited treatment options, it is reasonable to consider these agents either in addition to duloxetine, or if duloxetine is not effective or well-tolerated. Patients should be informed of the limited scientific evidence and counseled on the potential harms and benefits. 24 • Anticonvulsants (gabapentin or pregabalin)
• Tricyclic antidepressants (amitriptyline, nortriptyline, desipramine, or imipramine)
• Referral to a specialized pain management service is recommended for discussion of other add-on or alternative options not described above.
#
Additional Criteria: Review articles, case reports with <30 patients, and studies that did not report on the outcomes of interest were excluded from the final review were not included in the final review.
# Conflict of Interest Statements
Dean England has nothing to disclose.
Dr. Lyle Galloway has nothing to disclose.
# Kelsey Kenway has nothing to disclose.
Xanthoula Kostaras has nothing to disclose.
# Dr. Elizabeth Kurien has nothing to disclose.
Krista Rawson has nothing to disclose. | None | None |
a7614672b0061f857d44263b657a0816dcdef993 | cma | None | # Background
Myelofibrosis (MF) is a clonal myeloproliferative stem cell disorder characterized by reactive bone marrow fibrosis, extramedullary hematopoiesis, and abnormal cytokine expression leading to systemic symptoms. The purpose of this guideline is to provide a practical approach to diagnosis, investigation and management of myelofibrosis.
Primary myelofibrosis (PMF) is a "BCR-ABL1 negative MPN" categorized alongside polycythemia vera (PV) and essential thrombocytosis (ET) according to current 2016 World Health Organization (WHO) classification (Table 1) 1,2 . Myelofibrosis may arise de novo as primary myelofibrosis (PMF) or develop secondary to either PV or ET, post-PV and post-ET MF, respectively. Clinical manifestations of MF are heterogeneous including: cytopenias, hepatosplenomegaly, constitutional symptoms (night sweats, fevers, and weight loss), chronic fatigue and bone pain. Disease complications include: symptomatic portal hypertension, pulmonary hypertension, non-hepatosplenic extramedullary hematopoesis, bleeding and/or thrombosis and leukemic transformation 3 . Currently, the only curative treatment option is allogeneic stem cell transplant (alloSCT) which is an option in only a selection of patients. As a result, treatment options are to alleviate patient symptoms with novel therapy modalities being investigated.
# Epidemiology
The estimated incidence of myelofibrosis (MF) is 0.1-1.0 per 100,000 worldwide. Reported prevalence ranges 0.5 to 2.7 per 100,000 in Europe to 4 to 6 per 100,000 in the United States 4 . The median age of MF diagnosis is 69 years with < 15% of patients under 50 years old at the time of diagnosis 5 . The causes of MF are largely unknown.
# Signs and Symptoms
Patients with myelofibrosis (MF) can have significant debilitating symptoms and poor quality of life. Symptoms are caused by chronically elevated aberrant cytokine production, myeloproliferation, ineffective erythropoiesis and extramedullary hematopoiesis . Symptoms of chronic cytokine production include night sweats, muscle and bone pain, pruritus, fever and cachexia. Myeloproliferation leads to progressive cytopenias and results in associated symptoms. Consequently, anemia causes fatigue, weakness, and/or dyspnea; thrombocytopenia results in bruising and bleeding; leukopenia leads to increased susceptibility to infections. Extramedullary hematopoiesis (EMH) leads to hepatosplenomegaly. Splenomegaly causes early satiety and abdominal discomfort and leads to portal hypertension with risks of variceal bleeds and progressive liver dysfunction causing further coagulopathies. Non-hepatosplenic EMH may lead to paraspinal masses with risks of cord compression and pulmonary hypertension 3 .
Guideline Questions 1. What diagnostic and baseline investigations are recommended for adult patients with suspected or confirmed MF? 2. What are the recommended treatment options for MF?
# Search Strategy
This guideline was generated using systematic literature searches of PubMed and MEDLINE databases, ASCO abstracts and proceedings, and ASH abstracts and proceedings. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The guidelines were also adapted from the Canadian MPN Group recommendations.
# Target Population
Patients who are ≥18 years of age who are suspected of, or diagnosed with myelofibrosis.
# Summary of Recommendations
- The diagnosis of Myelofibrosis (MF) requires a bone marrow biopsy. 2. JAK2V617F mutation testing should be performed routinely in patients with MF. 3. If patients do not carry the JAK2V617F mutation, additional screening for driver mutations: CALR and MPL is required. Patients with no driver mutation are considered to be high risk "triple negative". Additional high-risk mutations can be attained via Next generation Sequencing (NGS). MF patients <75 years of age will have NGS testing performed. 4. If significant eosinophilia is present: screen for PDGFRA (FISH), PDGFRB and FGFR1 (conventional karyotype) rearrangements. 5. Prognostic scores should be calculated and documented which includes the IPSS used at time of diagnosis and the DIPSS and/or DIPSS-plus used during the remainder time of disease. If molecular information is available use MIPSS-70. 6. In low risk MF, watchful observation and symptom control is suggested. 7. For isolated anemia consider use of erythropoietin stimulation agents if epo level <125 u/l or if epo levels are elevated Danazol, IMIDS and/or steroids can be used in select patient populations. 8. In Intermediate or High-risk MF, treat symptomatic disease using JAK inhibitor first line therapy.
Ruxolitinib and Fedratinib are both available for use with different side effect profiles and dosing. Drug dose modifications are based on the degree of thrombocytopenia. Thiamine levels are required and supplementation to normal levels is necessary in order to use Fedratinib. Current data supports fedratinib's use post ruxolitinib failure. 9. Second line agents suggested are to use an alternative JAK inhibitor, or Hydroxyurea, Interferonalpha, IMIDs +/-steroids and clinical trials. 10. Allogeneic stem cell transplant (alloSCT) is the only curative treatment in MF. Fit patients with DIPSS Intermediate -2 or higher risk disease are eligible for consideration of allogeneic stem cell transplant. Patients who are transplant eligible should have NGS testing in order to assist with prognostication and alloSCT need (see below). Patients with estimated life survival 20 U PRBCs) or with higher liver iron content based on MRI studies with anticipated longer life survival, such as those going to alloSCT, should receive iron chelation. 13. Splenectomy and splenic radiation are offered in very select palliative cases particularly in the setting of refractory splenomegaly and/or thrombocytopenia. 14. Thromboembolic events should be managed according to accepted management guidelines.
Thromboprophylaxis should be used after surgery and in other high-risk situations.
# Discussion
# Diagnosis
Approximately 30% of patients with myelofibrosis (MF) are asymptomatic at time of diagnosis 9 . Diagnosis of PMF is based on revised 2016 WHO criteria ( The JAK2V617F mutation is an important driver mutation responsible for the pathogenesis of myeloproliferative disorders and is present in 50-60% of patients with PMF or post-ET MF and in 95% of those with post-PV MF . A JAK2V617F mutation screening should be performed routinely on all patients with suspected MF. Although higher JAK2V617F allele burdens are associated with higher transformation rates and higher allele burden correlates with poorer survival in MF, quantitative assays are not required in MF and do not change clinical management . Other driver mutations such as thrombopoetin receptor gene (MPL) have been documented in 3-8% of PMF and post ET MF patients, whereas Calreticulin gene (CALR), is present in approximately 50% of PMF and post ET MF patients without either JAK or MPL mutations . The presence of JAK2V617F, CALR, MPL, trisomy 9, or del13q supports the diagnosis of MF. CALR-mutated patients are less likely to be anemic and/or require transfusions and display less leukocytosis 3 .
Physical examination: Clinical features of MF may include cachexia and physical signs of anemia and thrombocytopenia. Ninety percent of patients with myelofibrosis have an enlarged spleen and hepatomegaly is present in 50% of patients 9 . Assess for clinical signs of portal hypertension.
# Laboratory investigations:
Baseline investigations include: complete blood count with differential (CBCD), peripheral smear, LDH, uric acid, liver panel including liver function (INR, PTT, Bilirubin, Albumin), ferritin and iron studies. Leukoerythroblastosis is present in most cases and with the presence of immature cells from the myeloid and erythroblastic lineages, dacrocytes (tear drop cells) and peripheral myeloid blasts. Additional baseline tests to consider are vitamin B12 level (often elevated in MPNs) and erythropoietin level (when considering treatment of anemic patients). HLA typing is suggested in young patients (≤ 75 years) who may be eligible for alloSCT. Hepatitis B/C serology and HIV testing are suggested for those patients anticipated to receive immunosuppressive therapy. Consider Quantiferon testing in patients with risk factors.
Bone marrow evaluation: Evaluation of bone marrow histopathology is critical for correct diagnosis of MF. The bone marrow aspirate is often difficult resulting in a "dry tap". The bone marrow biopsy of MF typically reveals megakaryocyte proliferation and atypia, usually with reticulin or collagen fibrosis 21 . A bone marrow (BM) biopsy report should include: age adjusted cellularity, presence of fibrosis (reticulin and collagen stains), evaluation of granulopoiesis with special reference to blast clusters, and characterization of erythropoiesis and megakaryocytes 22 . Overt bone marrow fibrosis might be absent in the setting of prefibrotic PMF. The possibility of prefibrotic primary myelofibrosis, as opposed to ET, should be considered in the presence of persistently increased serum LDH, anemia, leukoerythroblastosis, increased circulating CD34+ cell count, and splenomegaly. ET and prefibrotic PMF are clinically distinct with both overall and leukemia-free survival are significantly worse in prefibrotic PMF 23,24 .
Cytogenetics: Approximately one-third of patients with primary MF present with cytogenetic abnormalities. The most frequent are del(20q), del(13q), trisomy 8 and 9, and abnormalities of chromosome 1 including duplication 1q. Other less frequent lesions include -7 ⁄ del(7q), del(5q), del(12p), +21 and der(6)t(1;6)(q21;p21.3). A >80% 2-year mortality in PMF was predicted in the setting of monosomal karyotype, inv (3)/i(17q) abnormalities or with any 2 factors: circulating blast >9%, WBC >40 x 10 9 /L, or unfavorable karyotype 25 . Unfavorable karyotypes are incorporated into dynamic prognostic survival models (Table 3) and also result in a higher risk of leukemic transformation .
# Mutation testing:
Testing for the JAK2V617F mutation should be performed early during the diagnostic workup of suspected MPNs. JAK2V617F negative patients should be screened for mutually exclusive driver mutations CALR and/or MPL. CALR-mutated patients are less anemic and red cell transfusion dependent with less tendency to present with leukocytosis. CALR mutations are associated with younger age, higher platelet counts, lower DIPSS-plus score 3 . In the absence of all 3 driver mutations ("triple negative") disease, consideration of additional molecular mutations is suggested. BCR-ABL1 rearrangement testing should be considered if atypical features are present on the bone marrow biopsy with triple negative disease. PDGFRA and PDGFRB rearrangements should be performed in the setting of eosinophilia given that the presence of these rearrangements is highly sensitive to imatinib therapy.
Triple negative patients, who lack, JAK2, CALR, and MPL mutations have a poor outcome 28,29 . With access to next generation sequencing (NGS) additional mutations can be obtained. It has been found that mutations including: IDH, EZH2, SRSF2 and ASXL1 result in inferior survival 3, . In a study of 570 patients, longest survival was found in CALR +/ASXL-patients (median 10.4 yrs) compared to shortest survival among those with CALR-/ASXL+ status (2.3 years). CALR+/ASXL+ or CALR-ASXLwere considered intermediate with median survival of 5.8 years. The favorable prognostic impact of CALR is limited to type1 or type-1 like variants 28,34 .
# Prognosis
The clinical course of myelofibrosis (MF) is highly heterogeneous, and the disease can last from months to decades depending on risk status 9 . As the disease evolves, patients become symptomatic from their resultant cytopenias and increasing hepatosplenomegaly with constitutional symptoms.
Complications such as variceal bleeding can occur from resultant portal hypertension as well as having a higher risk of thrombosis. The 10-year survival of PMF patients is 81% lower than that of the general population 35 . Evolution of primary MF to acute myeloid leukemia (AML) occurs at a rate of 8% to 30% . Other causes of death include: MF progression (18%), thrombosis and cardiovascular complications (13%), infection (11%) or bleeding (5%), and portal hypertension (4%) 9 .
Risk stratification: Various prognostic models have been developed in MF. These models have been validated in only the PMF population but for practical purposes can be used in the setting of secondary MF. The International Prognostic Scoring System (IPSS) estimates prognostic risk at the time of diagnosis of primary myelofibrosis. It was developed by the IWG-MRT and includes 5 variables: age older than 65 years, the presence of constitutional symptoms, hemoglobin level 25 × 10 9 /L, and 1% or more blasts in the peripheral blood 9 . An IPSS calculator is available online. See Table 3 for IPSS score 9 .
The Dynamic IPSS (DIPSS) is used for re-evaluating survival predictions during the course of the disease and includes additional risk factors not present at diagnosis, such as the acquisition of anemia in particular 26,39 . Subsequently the DIPSS Plus further refines DIPSS by incorporating three additional factors: platelet count <100 x 10 9 /L, red cell transfusion status, and unfavorable karyotype (i.e. complex karyotype or sole or two abnormalities that include: +8, -7/7q-, i(17q), inv (3), -5/-5q-, 12p-, or 11q23 rearrangement with each variable being assigned one point 40 . A DIPSS 26,39 and DIPSS PLUS 40 calculator is available online. See Table 3 for these scores.
# Risk assessment tools under investigation:
Alternative approaches to MF prognostic risk has been based on specific gene mutations (i.e., ASXL1, EZH2, SRSF2, IDH1, IDH2, CALR, and MPL). Ongoing development of integrated systems for evaluating prognostic risk using molecular and cytogenetic markers in combination with clinical and hematologic findings have been proposed .
# Mutation-enhanced International Prognostic Scoring System (MIPSS):
The score was derived from a study of 986 PMF patients divided into learning (n=588) and validation (n=398) cohorts. In multivariable analysis, age >60 years, constitutional symptoms, hemoglobin <100g/L, platelets <200x10 9 /L, Triple negative, JAK2 or MPL mutation, ASXL1 and SRSF2 mutation were significant and these variables were subsequently assigned adverse points: 1.5, 0.5, 0.5, 1.0, 1.5, 0.5, 0.5 and 0.5, respectively. Based on this, four distinct risk groups were identified: low (score 0-0.5); intermediate-1 (score 1-1.5); intermediate-2 (score 2-3.5); and high (score 4 or greater). According to the MIPSS up to 67% of patients in the intermediate I category of the IPSS were upstaged to an intermediate II or high-risk MIPSS. The MIPSS also down staged 50% of IPSS high-risk patients. Median survival were 26.4 years, 9.7 years, 6.4 years, and 1.9 years for low, inter mediate-1, Intermediate-11, and high-risk disease, respectively 41 .
A recent prognostic tool was developed for transplant eligible patients with PMF that integrates clinical and mutation data with cytogenetics (MIPSS70-plus) or without cytogenetics (MIPSS70). Risk factors for OS included: hemoglobin 25 x 10 9 /L, platelets <100 x 10 9 /L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms and absence of CALR type -1 mutation, and presence of high molecular risk mutations (HMR) (ASXL1, EZH2, SRSF2, IDH1/2) and presence of 2 or more HMR specifically. Three risk categories were delineated for MIPSS70 (see Table 4) with 5-year OS: 95% in low risk (median OS 27.7 years), 70% for intermediate risk (7.1 years) and 29% in high risk 29% (median OS 2.3 years). The MIPSS70-plus model was divided into 4 categories with 5-year OS: 91% in low risk, 66% in intermediate risk, 42% in high risk, and 7% in very high risk. These models remained effective after inclusion of older patients 44 . Calculators are available: Recently, a personalized MPN prediction model was developed which incorporates genomic and clinical data in order to provide a more personalized risk stratification and prognosis. A total of 2035 patients (63 genomic and clinical variables) were included in the analysis and outcomes correlated with an independent external cohort. The calculator can be found at: and may assist physicians in providing a more personalized treatment approach for MF
# Genetics-based Prognostic Scoring System (GPSS):
An alternative genetics-based prognostic scoring system (GPSS) complements the MIPSS. In addition to high-risk mutations and age, the GPSS includes high-risk karyotypes: 5q-, +8, inv(3), i(17q), -7/7q-, 11q or 12p abnormalities, autosomal trisomies (except +9), monosomal and complex non-monosomal karyotypes. High risk GPSS was also associated with higher blast transformation rate (HR 7.4, 95% CI 2.1-26.3) 43 .
All of the above prognostic tools have been derived for primary myelofibrosis but often secondary myelofibrosis is categorized using the same tools. A post-PV and post-ET MF model has been developed: Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) (
# Treatment
The only curative treatment option for MF patients is allogeneic stem cell transplant (alloSCT). However, due to the associated morbidity and mortality, alloSCT is usually limited to fit patients with high risk features. Current conventional therapies are used for symptom control and target the treatment of the two most prominent symptoms of MF: splenomegaly and anemia 37 . Initiation of treatment is suggested for symptomatic anemia (Hgb persistently <90 g/L) or transfusion dependence (Hgb <80 g/L) and/or for symptomatic splenomegaly or splenomegaly resulting in secondary comorbidities/complications. Anemia: Prior to initiation of treatment, it is important to rule out secondary causes of anemia. Treatment of anemia is considered for a hemoglobin persistently below 100g/L and is suggested for symptomatic anemia or transfusion dependence. Therapeutic options include erythropoietic stimulating agents (ESAs), androgens and/or immunomodulators (IMiDS) either alone or in combination with low dose steroids 36,37 .
Erythropoietin: Erythropoietin (EPO) is a reasonable treatment option for selected MF patients with anemia and low EPO levels (<125 mU/mL) . Anemia responses are attained in 23-60% of patients with median duration of response of 12 months 46,47 weeks. If there is no response within 12 weeks, treatment should be discontinued 36 . Careful monitoring of spleen size is required as the use of EPO can result in progressive splenomegaly 37 .
Androgens: Nandrolone, Fluxymesterone, methandrostenolone and oxymetholone have been found to improve anemia in 30-60% of patients. Favorable responses are associated with female gender, prior splenectomy, normal karyotype 36 . Danazol (Cyclomen), is a semisynthestic attenuated androgen associated with less toxicity with a response rate of 40% 49 . Prior to the initiation of treatment, men must be screened for prostate cancer and all patients must have hepatic enzymes and function assessed with baseline ultrasound to rule out presence of hepatic tumors. Initial dosing of Danazol is 600 mg daily and should be maintained ≥ 6 months given most responses can only begin at 3-6 months of initiation. Once response is attained, consider dose reductions to maintain response, usually 200 mg/day is sufficient. Routine liver surveillance is required monthly and periodic hepatic ultrasounds are suggested with hepatic toxicity occurring in <20% of patients. Lastly, men require periodic prostate cancer screening and women should be counselled regarding hormonal side effects of treatment 36 .
Immunomodulators: Immunomodulators (IMiDs) include: thalidomide (100 -200 mg/day), lenalidomide (5-10 mg daily) and pomalidomide. IMiDs in combination with low dose steroids is suggested as an alternative to isolated anemia and/or thrombocytopenia treatment in low/int risk MF. Hematologic toxicity is a major side effect and precludes the use of IMiDS and often requires dose reduction and use of concomitant low dose steroids: prednisone (0.5 mg/kg daily for 3 months with taper) 36,37 . Lenalidomide results in 22% anemia response and 10-42% improvement of splenomegaly. Typical dosing of Lenalidomide is 5-10 mg daily for 3 weeks on a 4-week cycle .
Pomalidomide is a less toxic IMID however, phase 3 studies failed to should a significant improvement in comparison to placebo 53 . Prednisone can be used as single therapy at dosing of 30 mg daily with dose tapering within a few weeks to 15 -20mg daily 36 . agents can be used in combination in setting of severe anemia with or without transfusions.
# Splenomegaly & Constitutional Symptoms
Medical treatment is suggested for patients with symptomatic splenomegaly. Sustained responses are difficult to obtain particularly in the setting of massive splenomegaly. The discovery of the Janus kinase JAK2V617F mutation triggered the development of targeted therapy for myelofibrosis (MF), resulting in approval of the JAK1/2 inhibitor, ruxolitinib (Jakavi ® ).
# JAK Inhibitors:
Ruxolitinib: Ruxolitinib is an oral JAK1/JAK inhibitor that suppresses pro-inflammatory cytokines and growth factor receptors that use JAK1 and JAK2 for signaling and was first agent approved for treatment of MF 54 . Ruxolitinib is not selective for only JAK2 mutated disease and can be used in both JAK2 positive and JAK2 negative MF including secondary MF 55 . Regulatory approval in Canada was based on the results of two pivotal randomized phase III trials: Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT)-I and COMFORT II. Both trials included patients with Intermediate -2 or high-risk MF and compared ruxolitinib to placebo (COMFORT I) or to best available therapy (COMFORT II). In both COMFORT-I and -II, treatment with ruxolitinib led to significant reduction in spleen size, with primary end point of > 35% reduction in spleen size, by imaging techniques (MRI), at 24 and 48 weeks, respectively. Patients had significant improvement in MFrelated symptoms and quality of life. There was no significant difference in response among patients with or without the JAK2 V617F mutation or those with PMF compared to secondary MF 56,57 .
The final 5 year updates on the COMFORT trials have been published. Long-term comparisons in both trials is limited by crossover design with patients transitioned to comparator arms at either 6 months (COMFORT 1) or 12 months (COMFORT II). The rates of best response improve over time and median duration of spleen response is 3 years 58,59 . Long term findings from the COMFORT II trial showed that 28% of patients achieved a >35% reduction in spleen size at week 48 compared to no patients on BAT (P <0.001). Median survival was not reached in the ruxolitinib arm compared to 4.1 years in BAT arm with 33% reduced risk (crossover corrected HR 0.44) of death among patients on ruxolitinib compared to BAT 59 . Pooled data from both COMFORT studies (n=528) found a 30% risk reduction in death among patients with ruxolitinib compared to control arms with median survival of 5.3 years versus 3.8 years, respectively. Based on subgroup analysis, OS was improved with ruxolitinib regardless of age, sex, IPSS risk, spleen size, primary or secondary MF, anemia or thrombocytopenia and JAK mutational status 58 .
Overall, ruxolitinib is well tolerated, with the main toxicity being hematological. In COMFORT I, Grade 3-4 hematological effects occurring more frequently with ruxolitinib included anemia (45.2% vs. 19.2%), thrombocytopenia (12.9% vs. 1.3%), and neutropenia (7.1% vs. 2.0%). However, the platelet count and hemoglobin levels tend to stabilize and improve over time and do not affect response to ruxolitinib treatment 56 . Sudden withdrawal of ruxolitinib can lead to a shock-like syndrome due to reemergence of suppressed cytokines therefore, tapering of the drug is strongly suggested and current recommendations are to taper by 5 mg weekly 60 . Lastly, occasional reactivation of tuberculosis and opportunistic infections have been reported and linked to chronic suppression of T lymphocytes . Currently, no specific prophylaxis is provided for patients. Appropriate screening for TB is suggested in high risk populations.
The recommended starting dose of ruxolitinib is based on platelet count. For a platelet count >200 x 10 9 /L, the recommended starting dose is 20 mg BID and for a platelet count 100-200 x 10 9 /L, the recommended dose is 15 mg twice daily (BID). A dose of 15 mg BID may also be considered in transfusion independent patients, who may have difficulty tolerating a drop-in hemoglobin of 20 g/L.
Ruxolitinib can be used in moderate thrombocytopenia (50-100 x 10 9 /L) and it is feasible to start at lower dose such as 5 mg BID and escalate accordingly without causing severe thrombocytopenia 64 . Dose reduction should be considered for patients receiving ruxolitinib 15 or 20 mg BID if the platelet count declines below 100 x 10 9 /L. Complete blood and platelet counts must be performed before initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated, typically on a 4-week basis. Dose increases in increments of 5 mg BID can be considered on a monthly basis to a maximum dose of 25 mg BID in patients with inadequate response if no significant hematological toxicity occurs 37,65 . If no clinically meaningful response is achieved in 6 months, consider an alternative treatment. No specific criteria define ruxolitinib failure but if spleen response is less than 25% from baseline or constitutional symptoms persists it is suggested to consider alternative treatment 36 .
# Ruxolitinib failure:
There is currently no consensus on the definition of Ruxolitinib failure. The Canadian MPN Group recently published practical recommendations for management of patients on ruxolitinib with suboptimal or loss of response and/or intolerance. 102 Studies of second-line JAK inhibitor therapy in patients including fedratinib, momelotinib and pacratinib are briefly described below. Limited data exists for ruxolitinib usage second line. There are reports of the effectiveness of ruxolitinib rechallenge via a case series of 13 patients with MF who were retreated with ruxolitinib after loss of an initial response or inadequate response to a median initial ruxolitinib duration of 62 weeks. Among all 13 patients, ruxolitinib rechallenge was associated with a significant spleen size reduction in 9 patients and symptom improvement in 12 patients. Four patients received a second rechallenge and all 4 experienced some improvement in spleen length and constitutional symptoms. 103 high-risk primary MF, post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF, including patients who have been previously exposed to ruxolitinib. Recommended dose of fedratinib is 400 mg taken orally once daily for patients with a baseline platelet count of ≥50 x 10 9 /L Approval was on the basis of two JAKARTA trials. The path to approval included a period of FDA clinical hold (2013-2017). Recent approval includes a "black box warning" regarding the risk of serious and fatal encephalopathy, particularly, Wernicke encephalopathy (WE), which, ultimately was determined not to be resulting from fedratinib, following investigations during the clinical hold.
Fedratinib is selective for JAK2 relative to other kinases which could be advantageous because JAK1, JAK3, and TYK2, the other members of the Janus family of kinases, are critical for proper immune function. Therefore, activity against JAK1, JAK3, or TYK2, promotes immune suppression which may pose increased risk of infections. 104 The JAKARTA study was a phase 3 randomized MF study for intermediate 2 and high-risk disease including patients with platelets ≥50 x 10 9 /L included 3 equal arms (400 mg daily, 500 mg daily, or placebo for 24 weeks with crossover from placebo after that time. The primary end point was reduction in spleen volume (SVR) by at least 35%, with confirmation 4 weeks later by diagnostic imaging. The secondary end point was 50% reduction in total symptom burden by the Myelofibrosis Symptom Assessment Form (MFSAF). Between 2011 and 2012, prior to hold, 289 patients were enrolled (96 at 400 mg of fedratinib, 97 at 500 mg of fedratinib, and 96 placebo). The SVR (all confirmed 4 weeks later) observed at week 24 was 36% in the 400mg group, 40% in the 500mg group versus 1% in the placebo group. The MFSAF symptom response (durable until week 24) was 36% for 400 mg, 34% for 500 mg, and 7% for placebo. Anemia was the most common hematological toxicity (~45%) with an initial nadir, as seen with ruxolitinib, but usually followed by improvement. GI toxicities (~50%) of nausea and diarrhea were the most common nonhematological side effects requiring supportive management. 105 JAKARTA-2 72 was a single-arm, open-label, nonrandomized, phase 2, multicenter study conducted to evaluate the utility of fedratinib in intermediate-1, intermediate-2, or high-risk primary or secondary MF who had previously been treated with ruxolitinib, which was performed in parallel with the JAKARTA study and also included patients evaluated with platelet count of 50 x 10 9 /L or higher. Patients received initial oral fedratinib doses of 400 mg once daily in repeated 28-day treatment cycles. The primary endpoint was SVR of ≥ 35% reduction from baseline spleen volume at the end of cycle 6 (EOC6), and a key secondary endpoint was symptom response rate of ≥ 50% reduction in total symptom score (TSS) on MFSAF. This study was also halted early due to the clinical hold placed by the FDA concerning Wernicke's Encephalopathy (WE) and once resumed ruxolitinib failure was redefined. Patients initially were deemed resistant or intolerant to rollatini according to the individual investigator initially. Following removal of the clinical hold, a more stringent criteria for resistance/intolerance: relapse/refractory was defined for prior ruxolitinib therapy . In all, 97 patients were enrolled and treated in JAKARTA2 and comprised the intention-to-treat (ITT) population. For the entire intention-to-treat cohort, with a median age of 67 years, SVR of ≥35% after 6 cycles was met by 31% (95% confidence interval, 22, 41). Of the 79 patients (81% who met more stringent criteria for ruxolitinib resistance or intolerance) 30% (95% confidence interval, 21, 42) achieved at least 35% SVR following 6 cycles of treatment with no significant difference in responses between either category. TSS reduction of ≥50% were observed in 27% of both the intention-to-treat group and stringent criteria groups. Most common grade 3-4 hematological adverse events were anemia (46%) and thrombocytopenia (24%). Non-hematological adverse events were mainly GI in ~50% in both JAKARTA studies. /L. Practical issues for choosing first line JAKi might include their side effect profiles, thiamine requirements as well as dosing of therapy (once daily vs twice daily). Certainly, JAKARTA 2 72 provides data supporting fedratinib's effectiveness post ruxolitinib so it is reasonable to consider this as a second line option. Whether there is a benefit to the lack of JAK1 inhibition with fedratinib, or it has a wider kinome effects such as FLT3 and bromodomain targets remains uncertain. In terms of safely for transition from ruxolitinib to fedratinib, most patients can switch directly from one drug to another without "washing out" the first drug and ruxolitinib tapering is always advised. No tapering of fedratinib is required due to its long half-life (~41 hrs vs ~3 hrs for ruxolitinib).
Additional JAK inhibitors have been tested in MF and reviewed in detail elsewhere with most having been discontinued due to toxicity or poor response in comparison to ruxolitinib 71 . Momelotinib (MMB) is a JAK1/JAK inhibitor, which in murine models of anemia in chronic disease, inhibited bone morphogenic protein receptor kinase activin A receptor type I (ACVR1)-mediated hepcidin expression, which resulted in erythropoiesis. 109 In a phase I/II study of momelotinib in myelofibrosis (MF) the rates of spleen and anemia response, per International Working Group criteria, were 48% and 59%, respectively 110 SIMPLIFY-1 74 and SIMPLFY-2 75 phase III studies compared momelotinib(MMB) to ruxolitinib in MF without prior Jak inhibitor therapies and momelotinib vs BAT in MF with prior JAK inhibitor exposure, respectively. SIMPLIFY I (n=432) found MMB to be non-inferior to ruxolitinib with ≥35% spleen response of 26.5% vs. 29.0% (p=0.011) although it had a better anemia response at Week 24. Secondary endpoints of TSS reduction was seen in 28.4% and 42.2% of patients in MMB cohort and ruxolitinib cohort with no statistical difference (p = 0.98). The incidence of grade ≥3 AEs in MMB and ruxolitinib group were 35.5% and 43.5%, respectively. The most common hematological toxicities in both groups were thrombocytopenia and anemia, but the incidence of grade 3 or 4 anemia in ruxolitinib group was significantly higher than that in MMB (23.1% and 5.6%). A main side effect was neuropathy with 10% vs 5% peripheral neuropathy (grade 10%) grade 3 or 4 were thrombocytopenia and anemia. Overall in patients with platelet counts < 50 x 10 9 /L, there was no evidence of increasing thrombocytopenia in the pacritinib or BAT arms during treatment. However, there were concerns of high-grade cardiac and hemorrhagic events in the PERSIST studies which led to clinical hold. The follow-up PAC203 trial 112 a dose-finding study of pacritinib in patients with ruxolitinib failure, evaluated the efficacy of the 200 mg BID dose compared to lower pacritinib doses (100 mg QD and 100 mg BID). This incorporated more stringent eligibility/exclusion criteria, monitoring, and further dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Patients had strict ruxolitinib failure criteria (similar to JAKARTA-2. 72) The endpoints were ≥35% SVR and ≥50% reduction in TSS at week 24. Of 161 patients, 73% were intolerant of and 76% had ruxolitinib resistance with a total of 50% meeting criteria for both. Severe thrombocytopenia (platelet count <50 x 10 9 /L) was present in 44% of patients enrolled. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%). The TSS response rate was not statististically different between doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%). Overall the greatest SVR and TSS reduction were seen at 200 mg twice per day compared with lower doses. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile without an excess of hemorrhagic or cardiac events at 200 mg twice per day therefore this is recommended dose for a following phase three studies and use. 112 Several ongoing trials are investigating novel therapies that target different pathways used alone or in combination with ruxolitinib 77,78 .
Cytoreductive therapies: Hydroxyurea has been longstanding treatment prior to the development of JAK inhibitors and can be initiated at a dose of 500-1000 mg oral daily. The overall response is 40% with median duration of 13.2 months. Hydroxyurea does provide symptom control for constitutional symptoms and is suggested to be used second line to ruxolitinib. Alternatively, it can be used first line for low risk MF patients who would not be eligible for ruxolitinib. Other drugs such as busulfan are rarely used and its use is limited to elderly patients with shortened life survival due to concerns of leukemic potential 36 .
Interferon: Myelofibrosis can be very symptomatic resulting from elevated cytokines with a large inflammatory component that may benefit from immune modulation through interferon. Silver et al. performed a prospective single centre study on the use of recombinant interferon-α (rIFN-α) in "early" primary myelofibrosis in settings of grade 1 and 2 myelofibrosis with residual hematopoiesis. Seventeen patients received either rIFNα-2b 500,000 to 3 million units three times weekly or pegylated rIFN-α-2α 45 to 90µg weekly. Based on IWG prognostic and response criteria, 11 patients were low risk with 6 were intermediate-1 risk with complete remission (CR) and partial remission (PR) achieved in 2 and 7 patients, respectively. Overall, 58.8% patients derived clinical benefit with 23.5% achieving disease stability. The median time to any documented response was 1.0 years (0.4-7.4 years) with median duration of response of 2.0 years (0.1-14.0 years). Based on bone marrow followup in 15 patients, performed in a median of 3.2 years (0.9 -7.6 years) after therapy initiation, marrow morphology remained unchanged in 11 patients with 4 remissions achieved (2 CR and 2 PR). In the 4 with marrow improvement, sustained reduction in splenomegaly was also achieved. Quantitative JAK2 allele burden was assessed in 17 patients with 12 patients having mutated JAK status and 16 undergoing serial analysis whereby 14 had no molecular response and 2 had partial response. There was no correlation between molecular response and spleen response. Overall, rIFN-α was tolerated with 80 % of patients having some clinical benefit or stability in early phase PMF 79 . Overall, 13 small clinical studies have evaluated the use of interferon with PMF but unfortunately, are variable on disease definition and treatment response criteria. Overall response rates ranged from 0-79% with spleen reductions 0-26%. Three studies have included pegylated IFN-α2α or IFNα2b with overall response rates of 9-85% and spleen reductions of 0-76% with Silver et al. showing the most clinical benefit of 80% among patients, specifically among early PMF 79,80 . The largest study of 62 patients from French and Belgium centres retrospectively reviewed use of PEG-IFNα-2α therapy in myelofibrosis including 29 PMF, 19 PPV-MF, and 14 PET-MF of all risk categories. Treatment was initiated at median of 19.1 months from time of diagnosis with median age of 66 years at time of initiation of therapy. At mean follow up of 26 months, 64% of anemic patients achieved a complete response (time to achieve best response was 7.1 months) with 38.5% becoming transfusion independent. For patients in proliferative stages of their disease, complete resolution of leukocytosis and thrombocytosis occurred in 68.8% and 82.8% of patients, respectively. Eighty-two percent had resolution of constitutional symptoms and 46.5% had resolution of splenomegaly. Treatment was stopped in 45% patients after mean time of 11.7 months but was relatively well tolerated with majority of adverse events being grade 1-2 toxicities relating to cytopenias. Routine bone marrow assessments were not performed to assess morphological response. Spleen enlargement greater than 6 cm below costal margin was negatively associated with treatment response 81 . In a long-term follow up of these patients, at 58 months after PEG-IFN-α2α initiation and 69.6 months after MF diagnosis, 30 patients (48.4%) of patients were still alive and had treatment duration of 39 months. The median overall survival (OS) of the cohort was 7.4 years with leukemia free survival (LFS) not reached. Median OS was 30 months among patients treated with PEG-IFN-α2α for less than 2 years compared to 70 months if treated >2 years (p95% reduction however, no difference in OS or LFS was observed based on allele burden reduction. All seven patients that proceeded to alloSCT died within median time of 10 months associated with mainly graft versus host disease (GHVD) in 5/7 patients. Overall, PEG-IFN-α2α is a treatment option in MF and is currently being considered moreso, in low risk MF. Its impact on molecular allele burden does not clearly correlate with survival rates and also requires further understanding 82 .
Splenectomy: Traditionally, splenectomy has been used to manage burdensome symptoms associated with splenomegaly, but the procedure involves substantial risk with 31% and 9% morbidity and mortality, respectively 83 . The main complications are bleeding, infections, and thrombosis (primarily in the splanchnic veins) 84 . Subsequent extramedullary hematopoiesis resulting in massive hepatomegaly develops in 16-24% of patients and can result in liver failure 85 . Splenectomy may be considered in immune related hemolysis unresponsive to steroids or in refractory transfusiondependent anemia or those with refractory splenomegaly. Durable responses in transfusiondependent anemia occur in 23% of patients 84 .
Splenic irradiation: Splenic irradiation has been used in selected patients for palliative purposes when splenomegaly is resistant to medication and a splenectomy is contraindicated. The doses used range from 30-365 Gy in 5-10 fractions. The benefit is transient but the risk of severe and prolonged cytopenias occurs in 1/3 of patients and an increase in transfusion requirements occurs in 40% of cases 37,86 . 90 . These findings identify MF patients who may likely benefit from earlier alloSCT given their anticipated poorer response to medical treatment and expected shorter survival. We therefore recommend that MF patients who are ineligible for JAK inhibitor treatment or lack of response to JAK inhibitor therapy, display pretreatment transfusion dependence, have high risk DIPSS score, are "triple negative" or have the presence of ASXL1 or EZH2 be referred and considered early for alloSCT. In retrospective comparative analysis of patients treated with drugs or alloSCT, the latter was superior in DIPSS int-2 and high risk patients with expected median survival of 4.5 year and 2 years, respectively 88 . Recently, integrated clinical, genetic and molecular prognostic models with (MIPSS70-plus) or without (MIPSS-70) cytogenetics have been developed to better stratify transplant eligible patients who are ≤ 70 years old and are best suited for transplant 44 . Risk factors for OS included: hemoglobin 25 x 10 9 /L, platelets <100 x 10 9 /L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms and absence of CALR type -1 mutation, and presence of high molecular risk mutations (HMR) (ASXL1, EZH2, SRSF2, IDH1/2) and presence of 2 or more HMR specifically. Three risk categories were delineated for MIPSS70 (see Table 4) with a median OS of 2.3 years among high risk patients and a risk of death of 81% at 5 years without disease intervention, suggesting upfront use of alloSCT. Similarly, based on the MIPSS70-plus model with four categories (Table 4), the 5-year OS among patients with high risk and very high risk was 42% and 7%, respectively with median OS of 3.9 years and 1.7 years, respectively 44 . In both cases, alloSCT should be strongly considered in MIPSS-70 high risk disease and/or high or very high risk MIPSS70-Plus MF patients.
Recently, a personalized MPN prediction model was developed which incorporates genomic and clinical data in order to provide a more personalized risk stratification and prognosis. A total of 2035 patients (63 genomic and clinical variables) were included in the analysis and outcomes correlated with an independent external cohort. The calculator can be found at: and may assist physicians in providing a more personalized treatment approach for MF; in particular provide a better understanding for an optimal timeline for consideration of alloSCT 91 . Despite advances in our understanding of molecular markers, and the development of novel prognostic tools, the complete understanding of their relevance for alloSCT remains to be studied prospectively. There are no definite guidelines on integration of these newer scores in clinical practice. Ultimately, many factors need to be considered when proceeding to alloSCT including the Hematopoietic stem cell transplant comorbidity index (HCT-CI) and donor status 92 .
It has been demonstrated that pretreatment with JAK1/2 inhibitors has no adverse impact on the outcomes of subsequent alloSCT but rather improves clinical status and symptom burden, particularly reduction of splenomegaly pre-alloSCT. Furthermore, serious adverse events during drug discontinuation appear to be less frequent when JAK inhibitors are continued until close to the conditioning regimen. Patients undergoing alloSCT while responding to JAK inhibitors appear to have better outcomes compared to those with progressive disease 93,94 . It is important to consider timing of alloSCT and recognizing that 50% discontinue at 2-3 years and it is best to proceed with alloSCT before loss of ruxolitinib response 36 . We suggest ruxolitinib use pre-transplant and that it be discontinued at the start of conditioning for alloSCT.
Transplant: Recommendations 1. Allogeneic stem cell transplant (alloSCT) is the only curative treatment in MF and should be considered in fit patients with DIPSS Intermediate -2 or higher risk disease. Ultimately fit patients (<75yrs) with expected overall survival less than 5 years are suggested for referral to alloSCT. Younger patients with Intermediate -1 risk disease should be assessed for additional prognostic factors (see below) with consideration for alloSCT as future therapy. 2. Newer scores such as MIPSS70 and MIPSS70-Plus also identify patients with "high" or "very high" risk as being appropriate candidates for alloSCT. Personalized MPN genomic and clinical calculators are also available.
Additional factors for early alloSCT consideration include: ineligibility for JAK inhibitor treatment or lack of response to JAK inhibitor therapy, pretreatment transfusion dependence, or presence of HMR mutations.
# Emerging Treatments
Anemia is a significant problem among MF patients. A novel class of drugs termed activing receptor type II ligand traps consist of fusion proteins that sequester ligands belonging to the transforming growth factor B (TGFRB) superfamily and therefore inhibit their suppressive effects on terminal erythropoiesis 95 . Sotatercept is the first molecule in its class studied which has had response rates of 40% 78 . In a phase 2 trial in MF patients, 6 of 17 patients (35%) and 1 of 8 patients (12.5%) treated with sotatercept alone and combined with ruxolitinib, respectively, achieved erythroid response, with good tolerance. 113 Likewise, phase 2 study of MF patients (n=74) with anemia were randomized to luspatercept with or without ruxolitinib. Among those patients on ruxoilitinib and transfusion dependant (n=19) , 53% had a ≥ 50% reduction in RBC transfusion burden with 32% achieving transfusion independence ≥ 12 weeks, Among those on ruxolitinib with anemia that were nontransfusion dependant 57% achieved a mean increase of Hgb level of 15 g/L. 114
# Additional Concerns
Blast phase myelofibrosis: Blast phase MF (MPN-BP) is synonymous with acute myeloid leukemia (AML) and is defined by the presence of ≥20% blasts in the blood or bone marrow 96 . The risk of leukemic transformation depends on the MPN variant and is highest in PMF, with an incidence of 10-20% during the first decade 42 . The prognosis is poor with median survival of approximately 3 months which has not improved in 15 years 97,98 . In a recent retrospective study, intensive chemotherapy resulted in complete remission (CR) or CR with incomplete count recovery (CRi) rates of 35% and 24%, respectively. Treatment-specified 3-and 5-year survival rates were 32% and 10% for patients receiving alloSCT (n = 24), compared to 19% and 13% for patients achieving CR/CRi but were not transplanted (n = 24), and 1% vs 1% in the absence of both alloSCT and CR/CRi (n = 200) (p < 0.01). Less intensive strategies, such as Azacitidine fail to achieve CR rates however at a dose of 75 mg/m 2 x 7 days on 28-day cycle overall response rate (ORR) of 38% including in 4/7 cases of transformed MF resulted in median survival of 8 months 99 . AlloSCT remains the only curative option in transformed MF but can only be offered to a select few patients. Overall 3-year survival is dismal at 6-11% 98 . Refer to current AML guidelines for further treatment options.
# Appendix A: Assessment Tools
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) MPN-SAF TSS, also known as MPN10, includes 10 items: fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fever. The tool has been validated in a prospective study of over 1400 patients and results correlated with other measures of disease burden. It can be used to: quantitatively assess the burden of symptoms of patients with MPNs, track disease progression and response to treatment 100 . MPN Symptom Assessment Form Total Symptom Score: Reassess thiamine monthly for first 3 months
# Reassess thiamine every 3 months thereafter or as clinically indicated
Do not start fedratinib treatment unless thiamine levels are within normal range
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Hematology Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, hematologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020 and revised in 2021.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. | # Background
Myelofibrosis (MF) is a clonal myeloproliferative stem cell disorder characterized by reactive bone marrow fibrosis, extramedullary hematopoiesis, and abnormal cytokine expression leading to systemic symptoms. The purpose of this guideline is to provide a practical approach to diagnosis, investigation and management of myelofibrosis.
Primary myelofibrosis (PMF) is a "BCR-ABL1 negative MPN" categorized alongside polycythemia vera (PV) and essential thrombocytosis (ET) according to current 2016 World Health Organization (WHO) classification (Table 1) 1,2 . Myelofibrosis may arise de novo as primary myelofibrosis (PMF) or develop secondary to either PV or ET, post-PV and post-ET MF, respectively. Clinical manifestations of MF are heterogeneous including: cytopenias, hepatosplenomegaly, constitutional symptoms (night sweats, fevers, and weight loss), chronic fatigue and bone pain. Disease complications include: symptomatic portal hypertension, pulmonary hypertension, non-hepatosplenic extramedullary hematopoesis, bleeding and/or thrombosis and leukemic transformation 3 . Currently, the only curative treatment option is allogeneic stem cell transplant (alloSCT) which is an option in only a selection of patients. As a result, treatment options are to alleviate patient symptoms with novel therapy modalities being investigated.
# Epidemiology
The estimated incidence of myelofibrosis (MF) is 0.1-1.0 per 100,000 worldwide. Reported prevalence ranges 0.5 to 2.7 per 100,000 in Europe to 4 to 6 per 100,000 in the United States 4 . The median age of MF diagnosis is 69 years with < 15% of patients under 50 years old at the time of diagnosis 5 . The causes of MF are largely unknown.
# Signs and Symptoms
Patients with myelofibrosis (MF) can have significant debilitating symptoms and poor quality of life. Symptoms are caused by chronically elevated aberrant cytokine production, myeloproliferation, ineffective erythropoiesis and extramedullary hematopoiesis [6][7][8] . Symptoms of chronic cytokine production include night sweats, muscle and bone pain, pruritus, fever and cachexia. Myeloproliferation leads to progressive cytopenias and results in associated symptoms. Consequently, anemia causes fatigue, weakness, and/or dyspnea; thrombocytopenia results in bruising and bleeding; leukopenia leads to increased susceptibility to infections. Extramedullary hematopoiesis (EMH) leads to hepatosplenomegaly. Splenomegaly causes early satiety and abdominal discomfort and leads to portal hypertension with risks of variceal bleeds and progressive liver dysfunction causing further coagulopathies. Non-hepatosplenic EMH may lead to paraspinal masses with risks of cord compression and pulmonary hypertension 3 .
Guideline Questions 1. What diagnostic and baseline investigations are recommended for adult patients with suspected or confirmed MF? 2. What are the recommended treatment options for MF?
# Search Strategy
This guideline was generated using systematic literature searches of PubMed and MEDLINE databases, ASCO abstracts and proceedings, and ASH abstracts and proceedings. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The guidelines were also adapted from the Canadian MPN Group recommendations.
# Target Population
Patients who are ≥18 years of age who are suspected of, or diagnosed with myelofibrosis.
# Summary of Recommendations
1. The diagnosis of Myelofibrosis (MF) requires a bone marrow biopsy. 2. JAK2V617F mutation testing should be performed routinely in patients with MF. 3. If patients do not carry the JAK2V617F mutation, additional screening for driver mutations: CALR and MPL is required. Patients with no driver mutation are considered to be high risk "triple negative". Additional high-risk mutations can be attained via Next generation Sequencing (NGS). MF patients <75 years of age will have NGS testing performed. 4. If significant eosinophilia is present: screen for PDGFRA (FISH), PDGFRB and FGFR1 (conventional karyotype) rearrangements. 5. Prognostic scores should be calculated and documented which includes the IPSS used at time of diagnosis and the DIPSS and/or DIPSS-plus used during the remainder time of disease. If molecular information is available use MIPSS-70. 6. In low risk MF, watchful observation and symptom control is suggested. 7. For isolated anemia consider use of erythropoietin stimulation agents if epo level <125 u/l or if epo levels are elevated Danazol, IMIDS and/or steroids can be used in select patient populations. 8. In Intermediate or High-risk MF, treat symptomatic disease using JAK inhibitor first line therapy.
Ruxolitinib and Fedratinib are both available for use with different side effect profiles and dosing. Drug dose modifications are based on the degree of thrombocytopenia. Thiamine levels are required and supplementation to normal levels is necessary in order to use Fedratinib. Current data supports fedratinib's use post ruxolitinib failure. 9. Second line agents suggested are to use an alternative JAK inhibitor, or Hydroxyurea, Interferonalpha, IMIDs +/-steroids and clinical trials. 10. Allogeneic stem cell transplant (alloSCT) is the only curative treatment in MF. Fit patients with DIPSS Intermediate -2 or higher risk disease are eligible for consideration of allogeneic stem cell transplant. Patients who are transplant eligible should have NGS testing in order to assist with prognostication and alloSCT need (see below). Patients with estimated life survival <5 yrs. should be referred for alloSCT. 11. Other factors for early alloSCT consideration include: ineligibility for JAK inhibitor treatment or lack of response to JAK inhibitor therapy, pretreatment transfusion dependence, ASXL-1 or EZH2 mutated MF, and "Triple negative" MF. Newer prognostic models such as the MIPSS-70 and MIPSS-70 Plus suggest "high" and "very high" risk patients should undergo alloSCT. 12. Patients with transfusion dependency (given > 20 U PRBCs) or with higher liver iron content based on MRI studies with anticipated longer life survival, such as those going to alloSCT, should receive iron chelation. 13. Splenectomy and splenic radiation are offered in very select palliative cases particularly in the setting of refractory splenomegaly and/or thrombocytopenia. 14. Thromboembolic events should be managed according to accepted management guidelines.
Thromboprophylaxis should be used after surgery and in other high-risk situations.
# Discussion
# Diagnosis
Approximately 30% of patients with myelofibrosis (MF) are asymptomatic at time of diagnosis 9 . Diagnosis of PMF is based on revised 2016 WHO criteria ( The JAK2V617F mutation is an important driver mutation responsible for the pathogenesis of myeloproliferative disorders and is present in 50-60% of patients with PMF or post-ET MF and in 95% of those with post-PV MF [11][12][13] . A JAK2V617F mutation screening should be performed routinely on all patients with suspected MF. Although higher JAK2V617F allele burdens are associated with higher transformation rates and higher allele burden correlates with poorer survival in MF, quantitative assays are not required in MF and do not change clinical management [14][15][16][17] . Other driver mutations such as thrombopoetin receptor gene (MPL) have been documented in 3-8% of PMF and post ET MF patients, whereas Calreticulin gene (CALR), is present in approximately 50% of PMF and post ET MF patients without either JAK or MPL mutations [18][19][20] . The presence of JAK2V617F, CALR, MPL, trisomy 9, or del13q supports the diagnosis of MF. CALR-mutated patients are less likely to be anemic and/or require transfusions and display less leukocytosis 3 .
Physical examination: Clinical features of MF may include cachexia and physical signs of anemia and thrombocytopenia. Ninety percent of patients with myelofibrosis have an enlarged spleen and hepatomegaly is present in 50% of patients 9 . Assess for clinical signs of portal hypertension.
# Laboratory investigations:
Baseline investigations include: complete blood count with differential (CBCD), peripheral smear, LDH, uric acid, liver panel including liver function (INR, PTT, Bilirubin, Albumin), ferritin and iron studies. Leukoerythroblastosis is present in most cases and with the presence of immature cells from the myeloid and erythroblastic lineages, dacrocytes (tear drop cells) and peripheral myeloid blasts. Additional baseline tests to consider are vitamin B12 level (often elevated in MPNs) and erythropoietin level (when considering treatment of anemic patients). HLA typing is suggested in young patients (≤ 75 years) who may be eligible for alloSCT. Hepatitis B/C serology and HIV testing are suggested for those patients anticipated to receive immunosuppressive therapy. Consider Quantiferon testing in patients with risk factors.
Bone marrow evaluation: Evaluation of bone marrow histopathology is critical for correct diagnosis of MF. The bone marrow aspirate is often difficult resulting in a "dry tap". The bone marrow biopsy of MF typically reveals megakaryocyte proliferation and atypia, usually with reticulin or collagen fibrosis 21 . A bone marrow (BM) biopsy report should include: age adjusted cellularity, presence of fibrosis (reticulin and collagen stains), evaluation of granulopoiesis with special reference to blast clusters, and characterization of erythropoiesis and megakaryocytes 22 . Overt bone marrow fibrosis might be absent in the setting of prefibrotic PMF. The possibility of prefibrotic primary myelofibrosis, as opposed to ET, should be considered in the presence of persistently increased serum LDH, anemia, leukoerythroblastosis, increased circulating CD34+ cell count, and splenomegaly. ET and prefibrotic PMF are clinically distinct with both overall and leukemia-free survival are significantly worse in prefibrotic PMF 23,24 .
Cytogenetics: Approximately one-third of patients with primary MF present with cytogenetic abnormalities. The most frequent are del(20q), del(13q), trisomy 8 and 9, and abnormalities of chromosome 1 including duplication 1q. Other less frequent lesions include -7 ⁄ del(7q), del(5q), del(12p), +21 and der(6)t(1;6)(q21;p21.3). A >80% 2-year mortality in PMF was predicted in the setting of monosomal karyotype, inv (3)/i(17q) abnormalities or with any 2 factors: circulating blast >9%, WBC >40 x 10 9 /L, or unfavorable karyotype 25 . Unfavorable karyotypes are incorporated into dynamic prognostic survival models (Table 3) and also result in a higher risk of leukemic transformation [25][26][27] .
# Mutation testing:
Testing for the JAK2V617F mutation should be performed early during the diagnostic workup of suspected MPNs. JAK2V617F negative patients should be screened for mutually exclusive driver mutations CALR and/or MPL. CALR-mutated patients are less anemic and red cell transfusion dependent with less tendency to present with leukocytosis. CALR mutations are associated with younger age, higher platelet counts, lower DIPSS-plus score 3 . In the absence of all 3 driver mutations ("triple negative") disease, consideration of additional molecular mutations is suggested. BCR-ABL1 rearrangement testing should be considered if atypical features are present on the bone marrow biopsy with triple negative disease. PDGFRA and PDGFRB rearrangements should be performed in the setting of eosinophilia given that the presence of these rearrangements is highly sensitive to imatinib therapy.
Triple negative patients, who lack, JAK2, CALR, and MPL mutations have a poor outcome 28,29 . With access to next generation sequencing (NGS) additional mutations can be obtained. It has been found that mutations including: IDH, EZH2, SRSF2 and ASXL1 result in inferior survival 3,[30][31][32][33] . In a study of 570 patients, longest survival was found in CALR +/ASXL-patients (median 10.4 yrs) compared to shortest survival among those with CALR-/ASXL+ status (2.3 years). CALR+/ASXL+ or CALR-ASXLwere considered intermediate with median survival of 5.8 years. The favorable prognostic impact of CALR is limited to type1 or type-1 like variants 28,34 .
# Prognosis
The clinical course of myelofibrosis (MF) is highly heterogeneous, and the disease can last from months to decades depending on risk status 9 . As the disease evolves, patients become symptomatic from their resultant cytopenias and increasing hepatosplenomegaly with constitutional symptoms.
Complications such as variceal bleeding can occur from resultant portal hypertension as well as having a higher risk of thrombosis. The 10-year survival of PMF patients is 81% lower than that of the general population 35 . Evolution of primary MF to acute myeloid leukemia (AML) occurs at a rate of 8% to 30% [36][37][38] . Other causes of death include: MF progression (18%), thrombosis and cardiovascular complications (13%), infection (11%) or bleeding (5%), and portal hypertension (4%) 9 .
Risk stratification: Various prognostic models have been developed in MF. These models have been validated in only the PMF population but for practical purposes can be used in the setting of secondary MF. The International Prognostic Scoring System (IPSS) estimates prognostic risk at the time of diagnosis of primary myelofibrosis. It was developed by the IWG-MRT and includes 5 variables: age older than 65 years, the presence of constitutional symptoms, hemoglobin level < 100 g/L, leukocyte count > 25 × 10 9 /L, and 1% or more blasts in the peripheral blood 9 . An IPSS calculator is available online. See Table 3 for IPSS score 9 .
The Dynamic IPSS (DIPSS) is used for re-evaluating survival predictions during the course of the disease and includes additional risk factors not present at diagnosis, such as the acquisition of anemia in particular 26,39 . Subsequently the DIPSS Plus further refines DIPSS by incorporating three additional factors: platelet count <100 x 10 9 /L, red cell transfusion status, and unfavorable karyotype (i.e. complex karyotype or sole or two abnormalities that include: +8, -7/7q-, i(17q), inv (3), -5/-5q-, 12p-, or 11q23 rearrangement with each variable being assigned one point 40 . A DIPSS 26,39 and DIPSS PLUS 40 calculator is available online. See Table 3 for these scores.
# Risk assessment tools under investigation:
Alternative approaches to MF prognostic risk has been based on specific gene mutations (i.e., ASXL1, EZH2, SRSF2, IDH1, IDH2, CALR, and MPL). Ongoing development of integrated systems for evaluating prognostic risk using molecular and cytogenetic markers in combination with clinical and hematologic findings have been proposed [41][42][43] .
# Mutation-enhanced International Prognostic Scoring System (MIPSS):
The score was derived from a study of 986 PMF patients divided into learning (n=588) and validation (n=398) cohorts. In multivariable analysis, age >60 years, constitutional symptoms, hemoglobin <100g/L, platelets <200x10 9 /L, Triple negative, JAK2 or MPL mutation, ASXL1 and SRSF2 mutation were significant and these variables were subsequently assigned adverse points: 1.5, 0.5, 0.5, 1.0, 1.5, 0.5, 0.5 and 0.5, respectively. Based on this, four distinct risk groups were identified: low (score 0-0.5); intermediate-1 (score 1-1.5); intermediate-2 (score 2-3.5); and high (score 4 or greater). According to the MIPSS up to 67% of patients in the intermediate I category of the IPSS were upstaged to an intermediate II or high-risk MIPSS. The MIPSS also down staged 50% of IPSS high-risk patients. Median survival were 26.4 years, 9.7 years, 6.4 years, and 1.9 years for low, inter mediate-1, Intermediate-11, and high-risk disease, respectively 41 .
A recent prognostic tool was developed for transplant eligible patients with PMF that integrates clinical and mutation data with cytogenetics (MIPSS70-plus) or without cytogenetics (MIPSS70). Risk factors for OS included: hemoglobin <100 g/L, leukocytes >25 x 10 9 /L, platelets <100 x 10 9 /L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms and absence of CALR type -1 mutation, and presence of high molecular risk mutations (HMR) (ASXL1, EZH2, SRSF2, IDH1/2) and presence of 2 or more HMR specifically. Three risk categories were delineated for MIPSS70 (see Table 4) with 5-year OS: 95% in low risk (median OS 27.7 years), 70% for intermediate risk (7.1 years) and 29% in high risk 29% (median OS 2.3 years). The MIPSS70-plus model was divided into 4 categories with 5-year OS: 91% in low risk, 66% in intermediate risk, 42% in high risk, and 7% in very high risk. These models remained effective after inclusion of older patients 44 . Calculators are available: [Link] Recently, a personalized MPN prediction model was developed which incorporates genomic and clinical data in order to provide a more personalized risk stratification and prognosis. A total of 2035 patients (63 genomic and clinical variables) were included in the analysis and outcomes correlated with an independent external cohort. The calculator can be found at: [Link] and may assist physicians in providing a more personalized treatment approach for MF
# Genetics-based Prognostic Scoring System (GPSS):
An alternative genetics-based prognostic scoring system (GPSS) complements the MIPSS. In addition to high-risk mutations and age, the GPSS includes high-risk karyotypes: 5q-, +8, inv(3), i(17q), -7/7q-, 11q or 12p abnormalities, autosomal trisomies (except +9), monosomal and complex non-monosomal karyotypes. High risk GPSS was also associated with higher blast transformation rate (HR 7.4, 95% CI 2.1-26.3) 43 .
All of the above prognostic tools have been derived for primary myelofibrosis but often secondary myelofibrosis is categorized using the same tools. A post-PV and post-ET MF model has been developed: Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) (
# Treatment
The only curative treatment option for MF patients is allogeneic stem cell transplant (alloSCT). However, due to the associated morbidity and mortality, alloSCT is usually limited to fit patients with high risk features. Current conventional therapies are used for symptom control and target the treatment of the two most prominent symptoms of MF: splenomegaly and anemia 37 . Initiation of treatment is suggested for symptomatic anemia (Hgb persistently <90 g/L) or transfusion dependence (Hgb <80 g/L) and/or for symptomatic splenomegaly or splenomegaly resulting in secondary comorbidities/complications. Anemia: Prior to initiation of treatment, it is important to rule out secondary causes of anemia. Treatment of anemia is considered for a hemoglobin persistently below 100g/L and is suggested for symptomatic anemia or transfusion dependence. Therapeutic options include erythropoietic stimulating agents (ESAs), androgens and/or immunomodulators (IMiDS) either alone or in combination with low dose steroids 36,37 .
Erythropoietin: Erythropoietin (EPO) is a reasonable treatment option for selected MF patients with anemia and low EPO levels (<125 mU/mL) [46][47][48] . Anemia responses are attained in 23-60% of patients with median duration of response of 12 months 46,47 weeks. If there is no response within 12 weeks, treatment should be discontinued 36 . Careful monitoring of spleen size is required as the use of EPO can result in progressive splenomegaly 37 .
Androgens: Nandrolone, Fluxymesterone, methandrostenolone and oxymetholone have been found to improve anemia in 30-60% of patients. Favorable responses are associated with female gender, prior splenectomy, normal karyotype 36 . Danazol (Cyclomen), is a semisynthestic attenuated androgen associated with less toxicity with a response rate of 40% 49 . Prior to the initiation of treatment, men must be screened for prostate cancer and all patients must have hepatic enzymes and function assessed with baseline ultrasound to rule out presence of hepatic tumors. Initial dosing of Danazol is 600 mg daily and should be maintained ≥ 6 months given most responses can only begin at 3-6 months of initiation. Once response is attained, consider dose reductions to maintain response, usually 200 mg/day is sufficient. Routine liver surveillance is required monthly and periodic hepatic ultrasounds are suggested with hepatic toxicity occurring in <20% of patients. Lastly, men require periodic prostate cancer screening and women should be counselled regarding hormonal side effects of treatment 36 .
Immunomodulators: Immunomodulators (IMiDs) include: thalidomide (100 -200 mg/day), lenalidomide (5-10 mg daily) and pomalidomide. IMiDs in combination with low dose steroids is suggested as an alternative to isolated anemia and/or thrombocytopenia treatment in low/int risk MF. Hematologic toxicity is a major side effect and precludes the use of IMiDS and often requires dose reduction and use of concomitant low dose steroids: prednisone (0.5 mg/kg daily for 3 months with taper) 36,37 . Lenalidomide results in 22% anemia response and 10-42% improvement of splenomegaly. Typical dosing of Lenalidomide is 5-10 mg daily for 3 weeks on a 4-week cycle [50][51][52] .
Pomalidomide is a less toxic IMID however, phase 3 studies failed to should a significant improvement in comparison to placebo 53 . Prednisone can be used as single therapy at dosing of 30 mg daily with dose tapering within a few weeks to 15 -20mg daily 36 . agents can be used in combination in setting of severe anemia with or without transfusions.
# Splenomegaly & Constitutional Symptoms
Medical treatment is suggested for patients with symptomatic splenomegaly. Sustained responses are difficult to obtain particularly in the setting of massive splenomegaly. The discovery of the Janus kinase JAK2V617F mutation triggered the development of targeted therapy for myelofibrosis (MF), resulting in approval of the JAK1/2 inhibitor, ruxolitinib (Jakavi ® ).
# JAK Inhibitors:
Ruxolitinib: Ruxolitinib is an oral JAK1/JAK inhibitor that suppresses pro-inflammatory cytokines and growth factor receptors that use JAK1 and JAK2 for signaling and was first agent approved for treatment of MF 54 . Ruxolitinib is not selective for only JAK2 mutated disease and can be used in both JAK2 positive and JAK2 negative MF including secondary MF 55 . Regulatory approval in Canada was based on the results of two pivotal randomized phase III trials: Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT)-I and COMFORT II. Both trials included patients with Intermediate -2 or high-risk MF and compared ruxolitinib to placebo (COMFORT I) or to best available therapy (COMFORT II). In both COMFORT-I and -II, treatment with ruxolitinib led to significant reduction in spleen size, with primary end point of > 35% reduction in spleen size, by imaging techniques (MRI), at 24 and 48 weeks, respectively. Patients had significant improvement in MFrelated symptoms and quality of life. There was no significant difference in response among patients with or without the JAK2 V617F mutation or those with PMF compared to secondary MF 56,57 .
The final 5 year updates on the COMFORT trials have been published. Long-term comparisons in both trials is limited by crossover design with patients transitioned to comparator arms at either 6 months (COMFORT 1) or 12 months (COMFORT II). The rates of best response improve over time and median duration of spleen response is 3 years 58,59 . Long term findings from the COMFORT II trial showed that 28% of patients achieved a >35% reduction in spleen size at week 48 compared to no patients on BAT (P <0.001). Median survival was not reached in the ruxolitinib arm compared to 4.1 years in BAT arm with 33% reduced risk (crossover corrected HR 0.44) of death among patients on ruxolitinib compared to BAT 59 . Pooled data from both COMFORT studies (n=528) found a 30% risk reduction in death among patients with ruxolitinib compared to control arms with median survival of 5.3 years versus 3.8 years, respectively. Based on subgroup analysis, OS was improved with ruxolitinib regardless of age, sex, IPSS risk, spleen size, primary or secondary MF, anemia or thrombocytopenia and JAK mutational status 58 .
Overall, ruxolitinib is well tolerated, with the main toxicity being hematological. In COMFORT I, Grade 3-4 hematological effects occurring more frequently with ruxolitinib included anemia (45.2% vs. 19.2%), thrombocytopenia (12.9% vs. 1.3%), and neutropenia (7.1% vs. 2.0%). However, the platelet count and hemoglobin levels tend to stabilize and improve over time and do not affect response to ruxolitinib treatment 56 . Sudden withdrawal of ruxolitinib can lead to a shock-like syndrome due to reemergence of suppressed cytokines therefore, tapering of the drug is strongly suggested and current recommendations are to taper by 5 mg weekly 60 . Lastly, occasional reactivation of tuberculosis and opportunistic infections have been reported and linked to chronic suppression of T lymphocytes [61][62][63] . Currently, no specific prophylaxis is provided for patients. Appropriate screening for TB is suggested in high risk populations.
The recommended starting dose of ruxolitinib is based on platelet count. For a platelet count >200 x 10 9 /L, the recommended starting dose is 20 mg BID and for a platelet count 100-200 x 10 9 /L, the recommended dose is 15 mg twice daily (BID). A dose of 15 mg BID may also be considered in transfusion independent patients, who may have difficulty tolerating a drop-in hemoglobin of 20 g/L.
Ruxolitinib can be used in moderate thrombocytopenia (50-100 x 10 9 /L) and it is feasible to start at lower dose such as 5 mg BID and escalate accordingly without causing severe thrombocytopenia 64 . Dose reduction should be considered for patients receiving ruxolitinib 15 or 20 mg BID if the platelet count declines below 100 x 10 9 /L. Complete blood and platelet counts must be performed before initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated, typically on a 4-week basis. Dose increases in increments of 5 mg BID can be considered on a monthly basis to a maximum dose of 25 mg BID in patients with inadequate response if no significant hematological toxicity occurs 37,65 . If no clinically meaningful response is achieved in 6 months, consider an alternative treatment. No specific criteria define ruxolitinib failure but if spleen response is less than 25% from baseline or constitutional symptoms persists it is suggested to consider alternative treatment 36 .
# Ruxolitinib failure:
There is currently no consensus on the definition of Ruxolitinib failure. The Canadian MPN Group recently published practical recommendations for management of patients on ruxolitinib with suboptimal or loss of response and/or intolerance. 102 Studies of second-line JAK inhibitor therapy in patients including fedratinib, momelotinib and pacratinib are briefly described below. Limited data exists for ruxolitinib usage second line. There are reports of the effectiveness of ruxolitinib rechallenge via a case series of 13 patients with MF who were retreated with ruxolitinib after loss of an initial response or inadequate response to a median initial ruxolitinib duration of 62 weeks. Among all 13 patients, ruxolitinib rechallenge was associated with a significant spleen size reduction in 9 patients and symptom improvement in 12 patients. Four patients received a second rechallenge and all 4 experienced some improvement in spleen length and constitutional symptoms. 103 high-risk primary MF, post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF, including patients who have been previously exposed to ruxolitinib. Recommended dose of fedratinib is 400 mg taken orally once daily for patients with a baseline platelet count of ≥50 x 10 9 /L Approval was on the basis of two JAKARTA trials. The path to approval included a period of FDA clinical hold (2013-2017). Recent approval includes a "black box warning" regarding the risk of serious and fatal encephalopathy, particularly, Wernicke encephalopathy (WE), which, ultimately was determined not to be resulting from fedratinib, following investigations during the clinical hold.
Fedratinib is selective for JAK2 relative to other kinases which could be advantageous because JAK1, JAK3, and TYK2, the other members of the Janus family of kinases, are critical for proper immune function. Therefore, activity against JAK1, JAK3, or TYK2, promotes immune suppression which may pose increased risk of infections. 104 The JAKARTA study was a phase 3 randomized MF study for intermediate 2 and high-risk disease including patients with platelets ≥50 x 10 9 /L included 3 equal arms (400 mg daily, 500 mg daily, or placebo for 24 weeks with crossover from placebo after that time. The primary end point was reduction in spleen volume (SVR) by at least 35%, with confirmation 4 weeks later by diagnostic imaging. The secondary end point was 50% reduction in total symptom burden by the Myelofibrosis Symptom Assessment Form (MFSAF). Between 2011 and 2012, prior to hold, 289 patients were enrolled (96 at 400 mg of fedratinib, 97 at 500 mg of fedratinib, and 96 placebo). The SVR (all confirmed 4 weeks later) observed at week 24 was 36% in the 400mg group, 40% in the 500mg group versus 1% in the placebo group. The MFSAF symptom response (durable until week 24) was 36% for 400 mg, 34% for 500 mg, and 7% for placebo. Anemia was the most common hematological toxicity (~45%) with an initial nadir, as seen with ruxolitinib, but usually followed by improvement. GI toxicities (~50%) of nausea and diarrhea were the most common nonhematological side effects requiring supportive management. 105 JAKARTA-2 72 was a single-arm, open-label, nonrandomized, phase 2, multicenter study conducted to evaluate the utility of fedratinib in intermediate-1, intermediate-2, or high-risk primary or secondary MF who had previously been treated with ruxolitinib, which was performed in parallel with the JAKARTA study and also included patients evaluated with platelet count of 50 x 10 9 /L or higher. Patients received initial oral fedratinib doses of 400 mg once daily in repeated 28-day treatment cycles. The primary endpoint was SVR of ≥ 35% reduction from baseline spleen volume at the end of cycle 6 (EOC6), and a key secondary endpoint was symptom response rate of ≥ 50% reduction in total symptom score (TSS) on MFSAF. This study was also halted early due to the clinical hold placed by the FDA concerning Wernicke's Encephalopathy (WE) and once resumed ruxolitinib failure was redefined. Patients initially were deemed resistant or intolerant to rollatini according to the individual investigator initially. Following removal of the clinical hold, a more stringent criteria for resistance/intolerance: relapse/refractory was defined for prior ruxolitinib therapy . In all, 97 patients were enrolled and treated in JAKARTA2 and comprised the intention-to-treat (ITT) population. For the entire intention-to-treat cohort, with a median age of 67 years, SVR of ≥35% after 6 cycles was met by 31% (95% confidence interval, 22, 41). Of the 79 patients (81% who met more stringent criteria for ruxolitinib resistance or intolerance) 30% (95% confidence interval, 21, 42) achieved at least 35% SVR following 6 cycles of treatment with no significant difference in responses between either category. TSS reduction of ≥50% were observed in 27% of both the intention-to-treat group and stringent criteria groups. Most common grade 3-4 hematological adverse events were anemia (46%) and thrombocytopenia (24%). Non-hematological adverse events were mainly GI in ~50% in both JAKARTA studies. /L. Practical issues for choosing first line JAKi might include their side effect profiles, thiamine requirements as well as dosing of therapy (once daily vs twice daily). Certainly, JAKARTA 2 72 provides data supporting fedratinib's effectiveness post ruxolitinib so it is reasonable to consider this as a second line option. Whether there is a benefit to the lack of JAK1 inhibition with fedratinib, or it has a wider kinome effects such as FLT3 and bromodomain targets remains uncertain. In terms of safely for transition from ruxolitinib to fedratinib, most patients can switch directly from one drug to another without "washing out" the first drug and ruxolitinib tapering is always advised. No tapering of fedratinib is required due to its long half-life (~41 hrs vs ~3 hrs for ruxolitinib).
Additional JAK inhibitors have been tested in MF and reviewed in detail elsewhere with most having been discontinued due to toxicity or poor response in comparison to ruxolitinib 71 . Momelotinib (MMB) is a JAK1/JAK inhibitor, which in murine models of anemia in chronic disease, inhibited bone morphogenic protein receptor kinase activin A receptor type I (ACVR1)-mediated hepcidin expression, which resulted in erythropoiesis. 109 In a phase I/II study of momelotinib in myelofibrosis (MF) the rates of spleen and anemia response, per International Working Group criteria, were 48% and 59%, respectively 110 SIMPLIFY-1 74 and SIMPLFY-2 75 phase III studies compared momelotinib(MMB) to ruxolitinib in MF without prior Jak inhibitor therapies and momelotinib vs BAT in MF with prior JAK inhibitor exposure, respectively. SIMPLIFY I (n=432) found MMB to be non-inferior to ruxolitinib with ≥35% spleen response of 26.5% vs. 29.0% (p=0.011) although it had a better anemia response at Week 24. Secondary endpoints of TSS reduction was seen in 28.4% and 42.2% of patients in MMB cohort and ruxolitinib cohort with no statistical difference (p = 0.98). The incidence of grade ≥3 AEs in MMB and ruxolitinib group were 35.5% and 43.5%, respectively. The most common hematological toxicities in both groups were thrombocytopenia and anemia, but the incidence of grade 3 or 4 anemia in ruxolitinib group was significantly higher than that in MMB (23.1% and 5.6%). A main side effect was neuropathy with 10% vs 5% peripheral neuropathy (grade <3) experienced in each arm. Overall, in JAKi-naïve MF patients, MMB treatment was noninferior to ruxolitinib for spleen response and TSS reduction but with evidence supporting MMB providing better anemia response. 74 SIMPLIFY-II (N=156) 75 compared the efficacy and safety of MMB with BAT (which included ruxolitinib, chemotherapy, steroids, hydroxyurea, no treatment, or other standard interventions) in the treatment of MF patients who had previously been treated with ruxolitinib. To note, is that most patients (89%) in BAT group chose ruxolitinib as comparator. In this study, momelotonib was not superior to BAT (mainly ruxolitinib) with a SVR of 6.6% vs. 5.8% at week 24 (p=0.9). In secondary endpoint analyses, more patients in the momelotinib arm were transfusion independent at week 24 than patients in the BAT arm (43% vs. 21%, P = 0.0012), and 40% of momelotinib-treated patients required no transfusions over the treatment phase, compared with 27% of patients in the BAT group (P = 0.10). 75 Alternative JAK inhibitors have been studied for use in thrombocytopenia, such as Pacritinib, a JAK2/IRAK1 inhibitor. Pacritinib's selectivity results in minimal immune suppression. The phase III PERSIST-1 study enrolled patients with JAK inhibitor-naïve MF 111 . Phase 3 study (PERSIST-2) 76 (n=311) compared pacritinib 400 mg OD versus 200 mg BID to best available therapy (BAT), including ruxolitinib (n =44, 45% of BAT). Patients with intermediate-1, intermediate -2 and high risk DIPSS MF with platelets ≤ 100 x 10 9/ L and palpable splenomegaly were included and randomized in 1:1:1 fashion and included patients with prior JAK inhibitor therapy. Co-primary endpoints were ≥ 35% SVR and ≥ 50% TSS reduction at week 24. Pacritinib (arms combined) was more effective than BAT for SVR 18% vs 3% p=0.001 with no significant difference in TSS reduction (~25%) (p=0.08). The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. Pacritinib (arms combined) was more effective than BAT for ≥35% SVR (18% vs. 3% P = .001) but had a nonsignificant greater rate of 50% or more reduction in TSS (25% vs14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; ≥50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily dosing. Adverse events (>10%) grade 3 or 4 were thrombocytopenia and anemia. Overall in patients with platelet counts < 50 x 10 9 /L, there was no evidence of increasing thrombocytopenia in the pacritinib or BAT arms during treatment. However, there were concerns of high-grade cardiac and hemorrhagic events in the PERSIST studies which led to clinical hold. The follow-up PAC203 trial 112 a dose-finding study of pacritinib in patients with ruxolitinib failure, evaluated the efficacy of the 200 mg BID dose compared to lower pacritinib doses (100 mg QD and 100 mg BID). This incorporated more stringent eligibility/exclusion criteria, monitoring, and further dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Patients had strict ruxolitinib failure criteria (similar to JAKARTA-2. 72) The endpoints were ≥35% SVR and ≥50% reduction in TSS at week 24. Of 161 patients, 73% were intolerant of and 76% had ruxolitinib resistance with a total of 50% meeting criteria for both. Severe thrombocytopenia (platelet count <50 x 10 9 /L) was present in 44% of patients enrolled. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%). The TSS response rate was not statististically different between doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%). Overall the greatest SVR and TSS reduction were seen at 200 mg twice per day compared with lower doses. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile without an excess of hemorrhagic or cardiac events at 200 mg twice per day therefore this is recommended dose for a following phase three studies and use. 112 Several ongoing trials are investigating novel therapies that target different pathways used alone or in combination with ruxolitinib 77,78 .
Cytoreductive therapies: Hydroxyurea has been longstanding treatment prior to the development of JAK inhibitors and can be initiated at a dose of 500-1000 mg oral daily. The overall response is 40% with median duration of 13.2 months. Hydroxyurea does provide symptom control for constitutional symptoms and is suggested to be used second line to ruxolitinib. Alternatively, it can be used first line for low risk MF patients who would not be eligible for ruxolitinib. Other drugs such as busulfan are rarely used and its use is limited to elderly patients with shortened life survival due to concerns of leukemic potential 36 .
Interferon: Myelofibrosis can be very symptomatic resulting from elevated cytokines with a large inflammatory component that may benefit from immune modulation through interferon. Silver et al. performed a prospective single centre study on the use of recombinant interferon-α (rIFN-α) in "early" primary myelofibrosis in settings of grade 1 and 2 myelofibrosis with residual hematopoiesis. Seventeen patients received either rIFNα-2b 500,000 to 3 million units three times weekly or pegylated rIFN-α-2α 45 to 90µg weekly. Based on IWG prognostic and response criteria, 11 patients were low risk with 6 were intermediate-1 risk with complete remission (CR) and partial remission (PR) achieved in 2 and 7 patients, respectively. Overall, 58.8% patients derived clinical benefit with 23.5% achieving disease stability. The median time to any documented response was 1.0 years (0.4-7.4 years) with median duration of response of 2.0 years (0.1-14.0 years). Based on bone marrow followup in 15 patients, performed in a median of 3.2 years (0.9 -7.6 years) after therapy initiation, marrow morphology remained unchanged in 11 patients with 4 remissions achieved (2 CR and 2 PR). In the 4 with marrow improvement, sustained reduction in splenomegaly was also achieved. Quantitative JAK2 allele burden was assessed in 17 patients with 12 patients having mutated JAK status and 16 undergoing serial analysis whereby 14 had no molecular response and 2 had partial response. There was no correlation between molecular response and spleen response. Overall, rIFN-α was tolerated with 80 % of patients having some clinical benefit or stability in early phase PMF 79 . Overall, 13 small clinical studies have evaluated the use of interferon with PMF but unfortunately, are variable on disease definition and treatment response criteria. Overall response rates ranged from 0-79% with spleen reductions 0-26%. Three studies have included pegylated IFN-α2α or IFNα2b with overall response rates of 9-85% and spleen reductions of 0-76% with Silver et al. showing the most clinical benefit of 80% among patients, specifically among early PMF 79,80 . The largest study of 62 patients from French and Belgium centres retrospectively reviewed use of PEG-IFNα-2α therapy in myelofibrosis including 29 PMF, 19 PPV-MF, and 14 PET-MF of all risk categories. Treatment was initiated at median of 19.1 months from time of diagnosis with median age of 66 years at time of initiation of therapy. At mean follow up of 26 months, 64% of anemic patients achieved a complete response (time to achieve best response was 7.1 months) with 38.5% becoming transfusion independent. For patients in proliferative stages of their disease, complete resolution of leukocytosis and thrombocytosis occurred in 68.8% and 82.8% of patients, respectively. Eighty-two percent had resolution of constitutional symptoms and 46.5% had resolution of splenomegaly. Treatment was stopped in 45% patients after mean time of 11.7 months but was relatively well tolerated with majority of adverse events being grade 1-2 toxicities relating to cytopenias. Routine bone marrow assessments were not performed to assess morphological response. Spleen enlargement greater than 6 cm below costal margin was negatively associated with treatment response 81 . In a long-term follow up of these patients, at 58 months after PEG-IFN-α2α initiation and 69.6 months after MF diagnosis, 30 patients (48.4%) of patients were still alive and had treatment duration of 39 months. The median overall survival (OS) of the cohort was 7.4 years with leukemia free survival (LFS) not reached. Median OS was 30 months among patients treated with PEG-IFN-α2α for less than 2 years compared to 70 months if treated >2 years (p<0.0001). Overall survival was greater than expected based on reference cohorts according to DIPSS scores (6.9 years vs. 4 years Int-2 risk and 4.58 vs 1.5 years in high risk). The 5 -year actuarial survival rate was 69.4% among entire cohort, or 60% among Int-2 and high risk patients. Median mutant allele burden was studied in 31 JAK2 patients. A greater than 50% decrease in JAK2 allele burden was observed in 10/27 (37%) of patients, including 15% with >95% reduction however, no difference in OS or LFS was observed based on allele burden reduction. All seven patients that proceeded to alloSCT died within median time of 10 months associated with mainly graft versus host disease (GHVD) in 5/7 patients. Overall, PEG-IFN-α2α is a treatment option in MF and is currently being considered moreso, in low risk MF. Its impact on molecular allele burden does not clearly correlate with survival rates and also requires further understanding 82 .
Splenectomy: Traditionally, splenectomy has been used to manage burdensome symptoms associated with splenomegaly, but the procedure involves substantial risk with 31% and 9% morbidity and mortality, respectively 83 . The main complications are bleeding, infections, and thrombosis (primarily in the splanchnic veins) 84 . Subsequent extramedullary hematopoiesis resulting in massive hepatomegaly develops in 16-24% of patients and can result in liver failure 85 . Splenectomy may be considered in immune related hemolysis unresponsive to steroids or in refractory transfusiondependent anemia or those with refractory splenomegaly. Durable responses in transfusiondependent anemia occur in 23% of patients 84 .
Splenic irradiation: Splenic irradiation has been used in selected patients for palliative purposes when splenomegaly is resistant to medication and a splenectomy is contraindicated. The doses used range from 30-365 Gy in 5-10 fractions. The benefit is transient but the risk of severe and prolonged cytopenias occurs in 1/3 of patients and an increase in transfusion requirements occurs in 40% of cases 37,86 . 90 . These findings identify MF patients who may likely benefit from earlier alloSCT given their anticipated poorer response to medical treatment and expected shorter survival. We therefore recommend that MF patients who are ineligible for JAK inhibitor treatment or lack of response to JAK inhibitor therapy, display pretreatment transfusion dependence, have high risk DIPSS score, are "triple negative" or have the presence of ASXL1 or EZH2 be referred and considered early for alloSCT. In retrospective comparative analysis of patients treated with drugs or alloSCT, the latter was superior in DIPSS int-2 and high risk patients with expected median survival of 4.5 year and 2 years, respectively 88 . Recently, integrated clinical, genetic and molecular prognostic models with (MIPSS70-plus) or without (MIPSS-70) cytogenetics have been developed to better stratify transplant eligible patients who are ≤ 70 years old and are best suited for transplant 44 . Risk factors for OS included: hemoglobin <100 g/L, leukocytes >25 x 10 9 /L, platelets <100 x 10 9 /L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms and absence of CALR type -1 mutation, and presence of high molecular risk mutations (HMR) (ASXL1, EZH2, SRSF2, IDH1/2) and presence of 2 or more HMR specifically. Three risk categories were delineated for MIPSS70 (see Table 4) with a median OS of 2.3 years among high risk patients and a risk of death of 81% at 5 years without disease intervention, suggesting upfront use of alloSCT. Similarly, based on the MIPSS70-plus model with four categories (Table 4), the 5-year OS among patients with high risk and very high risk was 42% and 7%, respectively with median OS of 3.9 years and 1.7 years, respectively 44 . In both cases, alloSCT should be strongly considered in MIPSS-70 high risk disease and/or high or very high risk MIPSS70-Plus MF patients.
Recently, a personalized MPN prediction model was developed which incorporates genomic and clinical data in order to provide a more personalized risk stratification and prognosis. A total of 2035 patients (63 genomic and clinical variables) were included in the analysis and outcomes correlated with an independent external cohort. The calculator can be found at: [Link] and may assist physicians in providing a more personalized treatment approach for MF; in particular provide a better understanding for an optimal timeline for consideration of alloSCT 91 . Despite advances in our understanding of molecular markers, and the development of novel prognostic tools, the complete understanding of their relevance for alloSCT remains to be studied prospectively. There are no definite guidelines on integration of these newer scores in clinical practice. Ultimately, many factors need to be considered when proceeding to alloSCT including the Hematopoietic stem cell transplant comorbidity index (HCT-CI) and donor status 92 .
It has been demonstrated that pretreatment with JAK1/2 inhibitors has no adverse impact on the outcomes of subsequent alloSCT but rather improves clinical status and symptom burden, particularly reduction of splenomegaly pre-alloSCT. Furthermore, serious adverse events during drug discontinuation appear to be less frequent when JAK inhibitors are continued until close to the conditioning regimen. Patients undergoing alloSCT while responding to JAK inhibitors appear to have better outcomes compared to those with progressive disease 93,94 . It is important to consider timing of alloSCT and recognizing that 50% discontinue at 2-3 years and it is best to proceed with alloSCT before loss of ruxolitinib response 36 . We suggest ruxolitinib use pre-transplant and that it be discontinued at the start of conditioning for alloSCT.
Transplant: Recommendations 1. Allogeneic stem cell transplant (alloSCT) is the only curative treatment in MF and should be considered in fit patients with DIPSS Intermediate -2 or higher risk disease. Ultimately fit patients (<75yrs) with expected overall survival less than 5 years are suggested for referral to alloSCT. Younger patients with Intermediate -1 risk disease should be assessed for additional prognostic factors (see below) with consideration for alloSCT as future therapy. 2. Newer scores such as MIPSS70 and MIPSS70-Plus also identify patients with "high" or "very high" risk as being appropriate candidates for alloSCT. Personalized MPN genomic and clinical calculators are also available.
# 3.
Additional factors for early alloSCT consideration include: ineligibility for JAK inhibitor treatment or lack of response to JAK inhibitor therapy, pretreatment transfusion dependence, or presence of HMR mutations.
# Emerging Treatments
Anemia is a significant problem among MF patients. A novel class of drugs termed activing receptor type II ligand traps consist of fusion proteins that sequester ligands belonging to the transforming growth factor B (TGFRB) superfamily and therefore inhibit their suppressive effects on terminal erythropoiesis 95 . Sotatercept is the first molecule in its class studied which has had response rates of 40% 78 . In a phase 2 trial in MF patients, 6 of 17 patients (35%) and 1 of 8 patients (12.5%) treated with sotatercept alone and combined with ruxolitinib, respectively, achieved erythroid response, with good tolerance. 113 Likewise, phase 2 study of MF patients (n=74) with anemia were randomized to luspatercept with or without ruxolitinib. Among those patients on ruxoilitinib and transfusion dependant (n=19) , 53% had a ≥ 50% reduction in RBC transfusion burden with 32% achieving transfusion independence ≥ 12 weeks, Among those on ruxolitinib with anemia that were nontransfusion dependant 57% achieved a mean increase of Hgb level of 15 g/L. 114
# Additional Concerns
Blast phase myelofibrosis: Blast phase MF (MPN-BP) is synonymous with acute myeloid leukemia (AML) and is defined by the presence of ≥20% blasts in the blood or bone marrow 96 . The risk of leukemic transformation depends on the MPN variant and is highest in PMF, with an incidence of 10-20% during the first decade 42 . The prognosis is poor with median survival of approximately 3 months which has not improved in 15 years 97,98 . In a recent retrospective study, intensive chemotherapy resulted in complete remission (CR) or CR with incomplete count recovery (CRi) rates of 35% and 24%, respectively. Treatment-specified 3-and 5-year survival rates were 32% and 10% for patients receiving alloSCT (n = 24), compared to 19% and 13% for patients achieving CR/CRi but were not transplanted (n = 24), and 1% vs 1% in the absence of both alloSCT and CR/CRi (n = 200) (p < 0.01). Less intensive strategies, such as Azacitidine fail to achieve CR rates however at a dose of 75 mg/m 2 x 7 days on 28-day cycle overall response rate (ORR) of 38% including in 4/7 cases of transformed MF resulted in median survival of 8 months 99 . AlloSCT remains the only curative option in transformed MF but can only be offered to a select few patients. Overall 3-year survival is dismal at 6-11% 98 . Refer to current AML guidelines for further treatment options.
# Appendix A: Assessment Tools
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) MPN-SAF TSS, also known as MPN10, includes 10 items: fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fever. The tool has been validated in a prospective study of over 1400 patients and results correlated with other measures of disease burden. It can be used to: quantitatively assess the burden of symptoms of patients with MPNs, track disease progression and response to treatment 100 . MPN Symptom Assessment Form Total Symptom Score: Reassess thiamine monthly for first 3 months
# Reassess thiamine every 3 months thereafter or as clinically indicated
Do not start fedratinib treatment unless thiamine levels are within normal range
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Hematology Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, hematologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020 and revised in 2021.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. | None | None |
62a633c8503680a65f88407759b21629678e4000 | cma | None | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY# Introduction
The overall incidence of acute lymphoblastic leukemia (ALL) in Canada is 0.8 per 100,000 person years. ALL incidence follows an age-dependent biphasic distribution with a peak incidence at 1 to 4 years, and a second peak at approximately age 75 . The overall survival for adult ALL has improved significantly over the last 20 years due to advances in treatment and supportive care, but is still lagging behind pediatric ALL. The 5-year survival rate for adult ALL is now 50% or more in adults up to 50 to 60 years of age, and has also improved for older patients.
ALL is a disease that is characterized by genomic alterations that result in the abnormal differentiation and proliferation of lymphoid precursor cells. In adults, 85% of cases develop from precursors of the B-cell lineage, with the remainder having a T-cell phenotype . The identification of cytogenetic and molecular abnormalities in B-ALL provides important prognostic information and helps to guide treatment decisions. The most frequent abnormality in adult ALL is the BCR-ABL1 translocation t(9;22)(q34;q11) (Philadelphia chromosome ). Leukemias with this translocation, Ph-positive ALL, comprise about 25% of cases of adult ALL overall, but with an increasing incidence with age, reaching 40 to 50% of adult ALL cases above age 50 . ALLs bearing the BCR-ABL1 translocation have historically had a particularly poor prognosis. The development of tyrosine kinase inhibitor therapy for Ph-positive B-ALL has dramatically improved outcomes for these patients, however . Similarly, while the treatment of ALL relapse has historically been mostly unsuccessful, the advent of the targeted immunotherapies, inotuzumab ozogamicin and blinatumomab, as well as of chimeric antigen receptor (CAR)-T cell therapy, has also improved outcomes for B-ALL patients with relapsed/refractory disease .
Over the last decade, additional subtypes of Ph-negative B-ALL have been identified , many of which are associated with a distinct prognosis. Identifying sub-type specific therapy for such patients is an ongoing research effort. One subtype, Ph-like (BCR-ABL1-like) B-ALL was originally defined as having a gene expression profile identical to that of Ph-positive ALL, but lacking the t(9;22)(q34;q11). Ph-like B-ALL peaks in adolescents and young adults, with an incidence of approximately 28% in adults, and is associated with unfavourable outcomes and a higher risk of treatment failure . In addition, rearrangements of genes such as CRLF2 and CEBP family members into the immunoglobulin heavy chain variable gene (IGHV gene) locus are predominantly found in adult B-ALL, and confer a poor prognosis . Other B-ALL subtypes that confer a more favourable prognosis include the PAX5 D80R subtype, and DUX4-rearranged B-ALL .
Although most adults with B-ALL achieve complete morphological remission with intensive induction and consolidation therapy, 40 to 50% will ultimately relapse over time . A strong prognostic factor for relapse is the presence of post-treatment measurable (minimal) residual disease (MRD) . While the sensitivity of MRD detection depends on the assay used, a common operational cut-off for MRD positivity is 10 −4 (1 leukemic cell in 10,000 cells assayed). Patients who achieve MRD negativity after induction, or at a later time point, have improved relapse-free survival as well as improved overall survival. These outcomes are noted across all subgroups, including both Ph-positive and Ph-negative patients . Therefore, MRD levels not only inform decisions regarding the need for, and timing of, allogeneic hematopoietic stem cell transplantation (alloSCT), but also help guide modifications to ongoing management. In the case of alloSCT, not only do patients that are MRD-negative prior to alloSCT have better outcomes than do those with detectable MRD , but alloSCT also improves outcomes in patients that are persistently MRD positive. By extension, there is increasing evidence suggesting that patients with an optimal treatment response and MRD negativity may not need alloSCT . MRD positivity at defined timepoints may also be used to guide changes in ongoing leukemia management. For example, in Ph-positive ALL, MRD testing may indicate the need to change the TKI used, while in Ph-negative ALL, persistent MRD positivity may trigger the use of MRD-directed therapies such as blinatumomab. Based on the ability of MRD testing to predict treatment outcomes post chemotherapy, antibody/BiTE, and CAR-T therapies, thereby informing alloSCT decisions, it is likely that MRD levels will soon function as surrogate outcome indicators, at least in the context of a clinical trial.
To be optimally useful clinically, MRD assessment requires accurate, reproducible, and sensitive detection of very low levels of residual leukemia. This can be done using either flow cytometry, or molecular genetic methods. Flow cytometry for MRD analysis involves identifying and tracking aberrant leukemia-associated immunophenotypes (LAIP) found on leukemic cells . Molecular genetic methods include quantitative polymerase chain reaction (qPCR), droplet digital PCR (ddPCR), or next generation sequencing (NGS) to detect the presence of leukemia-specific gene fusions, such as BCR-ABL1, or clonal rearrangements in the immunoglobulin (Ig) and T-cell receptor (TCR) gene families .
The clinical value of MRD results depend on the accuracy and reliability of these assays. In contrast to the long-established standardized and centralized MRD approaches employed in other jurisdictions (especially in Europe) , MRD testing in adult ALL in Ontario is currently highly variable in terms of how and when it is performed, and this lack of consistency affects the quality of care that can be delivered to patients. There are currently no Canadian guidelines for laboratories doing MRD testing in ALL, although Cancer Care Ontario has recently published recommendations stating that MRD testing can be considered to help select between various treatment options for adults with ALL, in addition to its use as a prognostic test . An expert multidisciplinary working group was convened to discuss the status of MRD testing in Ontario, and to define recommendations for improving the delivery of MRD testing in adult B-ALL.
# Working Group and Methods
An expert multidisciplinary working group meeting was held in Toronto in November, 2019. Four Ontario institutions were represented, selected for their expertise in ALL treatment and diagnosis (including MRD testing). The corresponding Hematology, Hematopathology, and Laboratory Medicine physicians/PhDs divided into subgroups within the meeting to draft recommendations on when to perform MRD testing in Phpositive and Ph-negative B-ALL patients, and how to perform MRD testing with respect to methodology and standardization. Current evidence from the literature, as well as evidence gaps, were considered when drafting recommendations. Subgroups presented draft recommendations to the complete group and a set of consensus recommendations was created.
# Recommendations from the Working Group
# Ensuring Quality of MRD Testing
Recommendations:
MRD testing in Ontario should be centralized in an accredited laboratory. Until centralization is implemented, the standardization of testing approaches and the use of common quality metrics is mandatory among labs doing MRD testing.
Bone marrow specimens should be used for MRD testing.
The most sensitive methods of MRD detection should be chosen for routine clinical use. While both flow cytometric and molecular genetic approaches can deliver sensitivities of 10 −4 , this sensitivity is more consistently delivered by molecular analysis.
MRD results must be timely, accurate and reliable, to ensure the validity of MRDbased prognostic and therapeutic decisions. Regardless of the methodology used, a certain volume of testing is necessary to achieve the required level of expertise in MRD testing. For example, accurate flow cytometry assessment is highly dependent on the expertise of the interpreting Hematopathologist . In addition, assay sensitivity for a standardized reverse transcription real-time quantitative PCR (RT-qPCR) MRD assay for the BCR-ABL1 transcript in Ph-positive ALL is related to the laboratory's level of experience with the specific protocol . Given the relatively low incidence of adult ALL, performing MRD testing in experienced centralized laboratories will provide clinicians with the most consistent and reliable results. Shipping of samples to centralized laboratories is feasible, even for flow cytometry samples, which require the sample to arrive at the laboratory for testing within 48 h. This model of centralized testing is standard practice in European countries: a survey of MRD testing patterns in France, Germany, Italy, Spain and the UK found that the majority of clinicians in those countries used centralized laboratories for testing, consistent with national protocols that recommend MRD testing to inform treatment decisions .
To improve the quality of MRD testing in Ontario, the working group recommends that MRD testing should be centralized. Until this is achieved, the shared use of a single, standardized, internationally validated, method by laboratories performing MRD testing is essential. Standardization of approaches and of quality metrics is required to ensure that MRD tests done at different laboratories perform equally well, that results from different laboratories can be compared, and that results are reliably and consistently interpreted. In the absence of centralization, it is only with standardization of technique that the clinical relevance and potential actionability of MRD positivity/negativity can be interpreted in a consistent manner across the province.
All laboratories performing MRD testing must be able to reproducibly detect low levels of MRD at a threshold agreed upon for clinical relevance, and using an appropriately sensitive test. A common operational cut-off for MRD positivity is 10 −4 . This level of sensitivity is achieved routinely by molecular genetic approaches, but is not obtained routinely by flow cytometry, although some laboratories in Ontario using state-of-the-art flow cytometric techniques can achieve this, assuming that the patient sample submitted is adequate. In addition, whether MRD testing is centralized or not, EQA/proficiency testing (PT) is essential to ensure consistency in testing among laboratories. Accreditation for MRD assays in Ontario is not yet provided by IQMH, or included in the general ISO 15189 accreditation, which any laboratory performing MRD testing should have. Laboratories are also required to participate in proficiency testing initiatives for all MRD assays they perform, which could include PT programs from CAP, UKNEQAS, and EuroMRD. It is recommended that Ontario laboratories performing MRD analyses also participate in assay-specific, internationally defined quality control initiatives, and many consortia have established accreditation programs for laboratories participating in their studies.
Guidelines for data interpretation and reporting are critical to ensure accurate results across multiple laboratories. While the interpretation of flow cytometric data is the most difficult component to standardize , variability in interpretation of the same data set can also occur in molecular genetic MRD testing . The manner in which MRD is reported is also important, to ensure that clinicians have the information they need to guide decisionmaking. Both flow cytometry and molecular MRD reports should be concise to allow clinicians to draw clear conclusions. Reports should include information on the quality of the sample (when relevant), the reproducible sensitivity (lower level of quantitation) and level of detection, the MRD value, a description of the detected LAIP or molecular marker, and a conclusion, and should be in keeping with all other laboratory accreditation requirements for reporting. For molecular-based tests, MRD-positive results that are below the defined quantifiable range should also be clearly indicated if applicable. The molecular reports should also include the specific target(s) tested to ensure that the appropriate genomic analyte was ascertained for MRD analysis. A brief summary of the molecular method and its limitations should be described in the final report, as is required by Ontario laboratory accreditation requirements.
The working group recommends that bone marrow specimens be used for MRD testing. Bone marrow specimens are preferred, as studies have shown that blood and marrow results can be highly discordant, with MRD levels up to 10 3 times higher in the bone marrow than in the peripheral blood . In addition, it is bone marrow samples that have been used historically in studies of the prognostic and predictive value of MRD testing in B-ALL, and thus there is no real evidence base supporting the use of peripheral blood samples for this purpose 18,33]. Nevertheless, while studies in ALL have shown that the percentage of blasts is lower in peripheral blood than in bone marrow samples analayzed in parallel, it has been suggested that peripheral blood could be used for MRD analysis, assuming that the assay is suitably sensitive, and the total number of input cells is sufficient (i.e., ≥10 6 cells) . This approach is not standardized, however. When bone marrow is used, it is similarly important to ensure that the input cell number is optimal. For this reason, the first aspirated marrow specimen (the 'first pull'), with a volume of 1 to 2 mL is required for MRD testing, and this requirement is particularly important in the context of flow cytometry MRD, for which input cell number is key. For molecular MRD, genomic input minimums (rather than input cell numbers) ensure that appropriate sensitivity requirements can be achieved. For example, 1 µg of DNA corresponds to approximately 150,000 cells (assuming 6.5 pg DNA per cell) to achieve a sensitivity of 10 −5 for Ig/TCR rearrangement analysis . Similarly, an RNA input sufficient to produce 100,000 copies of ABL1 by RT-qPCR would result in a sensitivity of 10 −5 for BCR-ABL1 detection .
# MRD Testing in Ph-Negative ALL
Recommendations:
Adult Ph-negative ALL patients should receive MRD testing after induction chemotherapy, and at least one additional time point later in treatment, around 12-16 weeks.
Flow cytometry and analysis of Ig/TCR gene rearrangements are both acceptable approaches for MRD testing in adult Ph-negative ALL patients, provided that the laboratory can reliably meet the required sensitivity of at least 10 −4 . Standardized, accredited protocols with a validated quality assurance program must be used.
The importance of incorporating MRD assessment into routine care for Ph-negative ALL patients has been demonstrated in multiple studies. Patients with lower MRD levels after induction and consolidation chemotherapy had longer duration of remission, longer relapse-free survival, and longer overall survival . MRD levels may also be used as a stratification tool to inform treatment decisions: for example, alloSCT may be avoided, while maintaining favourable outcomes, for patients with good early MRD responses . MRD testing in first or second complete remission also informs the use of the targeted therapy blinatumomab, which is the first Health Canada-approved therapy for Ph-negative B-ALL patients with MRD greater than or equal to 0.1%. Further, patients with MRD reappearance have worse outcomes compared to those with MRD persistence, suggesting that ongoing monitoring of MRD levels is helpful for risk assessment . The optimal timing of MRD assessment in adults has been studied in detail . Based on these data, the working group recommends that all Ph-negative ALL patients should receive MRD testing after induction chemotherapy. At a minimum, one additional MRD test should be done around 12-16 weeks, after all drugs have been delivered at a maximal dose. There may be a need for further MRD tests in some patients depending on disease progression and characteristics. This approach aligns with current recommendations from the National Comprehensive Cancer Network in the U.S. and the European Society for Medical Oncology . It is important to remember that the predictive value of MRD testing depends both on the specific treatment regimen employed, and on the time points used for MRD testing. The optimal time points for testing related to the therapy regimens typically used in Canada are not yet clearly defined in a protocol-specific manner, but the 12-16 week rule can be applied widely.
Currently in Ontario, MRD testing in Ph-negative B-ALL patients is done using flow cytometry, although some laboratories are developing molecular genetic testing methods. The working group recognizes that flow cytometry and Ig/TCR gene rearrangement analysis are both widely accepted approaches for MRD testing in Ph-negative B-ALL patients, provided that the minimum sensitivity requirement of 10 −4 is met by a standardized protocol (Table 1). These approaches are not fully interchangeable, however, as they may provide complementary information in some clinical contexts, such as post-induction. Notably, while both methods can provide high sensitivity detection of MRD at a level of 10 −4 , this is more likely achievable on a routine basis using a molecular approach. In general, molecular methods also allow for greater interlaboratory comparability than do flow cytometry-based methods . Standardized protocols have been developed and used successfully in Europe for both technologies, however . Standardization of methodologies reduces inter-laboratory variability, minimizes the rates of false positive and false negative results, allows for the optimization of protocols, and creates consistency in interpretation and reporting of results. Application of standardized protocols to MRD testing in Ontario will improve the quality of testing and will provide clinicians with more reliable results to guide clinical decision making. Flow cytometry is currently the most widely used technique in North America for assessing MRD in Ph-negative B-ALL patients. Modern flow cytometry techniques using 6 or more fluorochromes are capable of detecting MRD with a sensitivity of approximately 10 −4 (assuming an adequate sample), and there is the potential for even greater sensitivity with more than 8 fluorochromes and a higher number of input cells, although such sensitivity is not achieved routinely . MRD assessment by flow cytometry is affordable and has a quick turnaround time. However, the interpretation of flow cytometry results for MRD assessment requires substantial expertise from the Hematopathologist . Currently, Ontario laboratories performing flow cytometry for MRD assessment in adult B-ALL are not all using standardized protocols. Several different consortia have published standardized methods with external quality assurance programs, including the EuroFlow Consortium, the AIEOP-BFM Consortium, the Children's Oncology Group and the NOPHO group . The working group recommends that MRD assessment by flow cytometry in Ontario should be centralized, and that the laboratory performing testing must use one of these standardized protocols. The laboratory should provide flow cytometry results in less than 48 h.
Although molecular methods for MRD assessment in Ph-negative B-ALL patients are widely used in Europe, these methods still require development in Canada. The use of real-time quantitative PCR (RQ-PCR) to identify and follow Ig/TCR rearrangements has been standardized by the EuroMRD consortium, and although this method is highly sensitive, it is labour intensive and requires a reference diagnostic sample to define patientspecific primers and to use as a quantification stardard . Recent progress has been made by the EuroMRD group to develop, validate, and standardize NGS assays to evaluate Ig/TCR rearrangements for MRD assessment in ALL . Although this method does not require the use of patient-specific probes, it does require a diagnostic sample to identify the leukemia-associated Ig/TCR rearrangement. Sensitivity of this method varies based on the amount of input DNA: a sensitivity of 10 −4 to 10 −5 can be reached with 500 ng to 1 µg of input DNA. In comparison with flow cytometry and RQ-PCR, NGS generally shows better sensitivity . However, the quantification of MRD levels by NGS can be challenging. Given the advantages of NGS compared to RQ-PCR for MRD detection, and its increased adoption and standardization in Europe, as Canadian laboratories develop molecular assays for MRD detection in Ph-negative ALL, the working group recommends that molecular MRD testing be performed in a central laboratory in Ontario. Ideally, an NGSbased assay should be used, with a standardized lab-developed and validated protocol such as the EuroClonality-NGS assay. However, a hybrid NGS/RQ-PCR approach may currently be more feasible, in which NGS is used to identify PCR MRD targets, which subsequently can be used to monitor MRD with the well-established patient-specific RQ-PCR method. In situations where no Ig/TCR rearrangement can be identified due to limitations of PCR reactivity, flow cytometry should be performed as an alternative. Turnaround time for molecular MRD testing results should ideally be within 10 calendar days, to ensure results are received in a clinically relevant time frame. However, recognizing that achievement of this goal will require additional resources and funding to be provided to laboratories, the maximum acceptable turnaround time in the current laboratory environment is 14 calendar days, with the optimal goal of returning results to the clinician within 10 calendar days. In contrast, the turnaround time for flow cytometric MRD assessment will be much shorter.
# MRD Testing in Ph-Positive ALL
Recommendations:
Adult Ph-positive ALL patients should receive MRD testing after induction chemotherapy, with ongoing monitoring thereafter.
At a minimum, MRD testing for Ph-positive ALL should be centralized in a laboratory using reverse transcription real-time quantitative PCR for both the p210 and p190 BCR-ABL1 transcripts, using standardized assays. MRD assessment using RQ-PCR/NGS assays evaluating Ig/TCR rearrangements should ideally also be used in parallel for Ph-positive patients, as this approach may provide additional, complementary clinical information.
Ph-positive ALL has an aggressive clinical course, with a high risk of relapse despite progress in treatments. As with Ph-negative ALL, MRD testing is useful for prognosis and management of patients with Ph-positive B-ALL. MRD negativity at three months after chemotherapy plus TKI therapy is associated with improved relapse-free and overall survival . In addition, the evaluation of MRD assists in making decisions regarding alloSCT, and in directing modifications to ongoing treatment. Growing lines of evidence indicate that patients with deep MRD responses to initial therapy may not require alloSCT, but rather can be treated with ongoing chemotherapy plus TKI, with good outcomes . In patients undergoing alloSCT, measurable MRD levels at the time of transplant are associated with a significantly higher risk of post-alloSCT relapse than observed in MRDnegative patients . Ongoing MRD testing also informs the need for ABL mutation analysis and potential mutation-guided changes in TKI therapy, such as switching from imatinib to dasatinib, or to ponatinib. Therefore, the working group recommends that all Ph-positive ALL patients should receive MRD testing after induction chemotherapy, and ongoing monitoring thereafter. This recommendation aligns with Cancer Care Ontario and international guidelines on MRD monitoring in Ph-positive disease. For example, ESMO and NCCN guidelines both mandate MRD assessment post-induction, and periodic monitoring thereafter, including post-SCT . Ideally, Ph-positive patients should have MRD assessment by flow cytometry after induction, and ongoing monitoring thereafter by molecular testing (Table 1).
The working group recommends that molecular MRD testing for Ph-positive ALL should be centralized in a laboratory using reverse transcription real-time quantitative PCR (RT-qPCR) for both the p210 and p190 BCR-ABL1 transcripts . If centralization is not feasible, then standardization of the RT-qPCR protocol between labs should be ensured, such as in the Europe Against Cancer Program . Turnaround time, as with MRD testing for Ph-negative ALL, should be no longer than 10 calendar days to allow for rapid treatment decisions. Although many laboratories in Canada routinely perform PCR assays for the p210 transcript in CML from peripheral blood, optimal MRD testing for Ph-positive patients in ALL requires the use of bone marrow samples. The advantages of RT-qPCR include high sensitivity of 10 −4 to 10 −5 , and a rapid turnaround time . Using the BCR-ABL1 fusion as a marker for MRD in Ph-positive B-ALL patients is more efficient and less labour-intensive than is RQ-PCR detection of Ig/TCR gene rearrangements, which requires patient-specific probes. Nevertheless, the RQ-PCR detection of rearrangements of Ig/TCR genes, highly standardized and widely used in Europe , is in development in Canada, and may be clinically useful in Ph-positive ALL as well (see below). Use of this method requires a diagnostic patient sample. Ig/TCR gene rearrangement monitoring and flow cytometry are also suitable for patients with variant BCR-ABL1 breakpoints, where MRD testing using p210 or p190 specific qPCR methods cannot be used.
Detection of MRD in Ph-positive patients using both Ig/TCR rearrangement and BCR-ABL1 fusion transcript detection should be considered, as it has been shown that discordance can occur between the two methods. A false positive (or negative) MRD result could influence important treatment decision-making, such as the decision to proceed to alloSCT. In both pediatric and adult studies, discordance has been reported in more than 20% of cases between positive MRD results from BCR-ABL1 RT-qPCR, and negative MRD results from Ig/TCR rearrangement RQ-PCR (the latter indicates the absence of a leukemic clone). In such 'MRD discordant' cases, BCR-ABL1 positivity was found to reside in non-ALL B-lymphocytes, T-cells, and/or myeloid cells, suggesting that a multipotent hematopoietic progenitor cell was the source of the translocation , resulting in a more CML-like clinical picture. In contrast, and consistent with this interpretation, in 'MRD concordant' cases, BCR-ABL1 positivity was found only in ALL B-cell precursors, suggesting that the source of the translocation was a later, more-restricted precursor cell. Using both assays to monitor MRD would ensure that BCR-ABL1 positivity not representing true residual disease does not lead to intensification of therapy that may not be necessary. Whether the requirements for alloSCT differ between MRD 'concordant' and 'discordant' adult ALL cases, as has been suggested in a pediatric series , remains unknown.
Going forward, as discussed above for Philadelphia-negative ALL, current methods for detection of Ig/TCR rearrangements, may soon be replaced by NGS-based methods, for which standardized protocols are already available. In addition, the current RT-qPCR approach to BCR-ABL1 transcript quantitation may become supplanted by more sensitive droplet digital PCR (ddPCR)-based approaches . The clinical utility of the latter approach remains undefined at present, however.
# Conclusions
Consistent, reproducible, and accurate MRD testing is required for optimal management of adult B-cell ALL. Technologies for MRD testing are evolving, with the development of standardized protocols for high sensitivity flow cytometry, for RT-qPCR (or ddPCR) analysis of the BCR-ABL1 transcript, and for PCR or NGS to evaluate Ig/TCR rearrangement. There are no published guidelines for Canadian laboratories regarding MRD testing in adult B-cell ALL, and as a result, testing methods and quality are highly variable. The Ontario expert working group recommends that MRD testing in Ontario should be centralized, as this allows for the necessary development of expertise in MRD testing and provides consistent, reliable results to clinicians. Standardized and accredited protocols for MRD testing must be used. Optimal care of adult B-cell ALL patients depends on accurate MRD testing, which would benefit from implementation of the recommendations described herein. | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY# Introduction
The overall incidence of acute lymphoblastic leukemia (ALL) in Canada is 0.8 per 100,000 person years. ALL incidence follows an age-dependent biphasic distribution with a peak incidence at 1 to 4 years, and a second peak at approximately age 75 [1,2]. The overall survival for adult ALL has improved significantly over the last 20 years due to advances in treatment and supportive care, but is still lagging behind pediatric ALL. The 5-year survival rate for adult ALL is now 50% or more in adults up to 50 to 60 years of age, and has also improved for older patients.
ALL is a disease that is characterized by genomic alterations that result in the abnormal differentiation and proliferation of lymphoid precursor cells. In adults, 85% of cases develop from precursors of the B-cell lineage, with the remainder having a T-cell phenotype [3]. The identification of cytogenetic and molecular abnormalities in B-ALL provides important prognostic information and helps to guide treatment decisions. The most frequent abnormality in adult ALL is the BCR-ABL1 translocation t(9;22)(q34;q11) (Philadelphia chromosome [Ph]). Leukemias with this translocation, Ph-positive ALL, comprise about 25% of cases of adult ALL overall, but with an increasing incidence with age, reaching 40 to 50% of adult ALL cases above age 50 [4][5][6]. ALLs bearing the BCR-ABL1 translocation have historically had a particularly poor prognosis. The development of tyrosine kinase inhibitor therapy for Ph-positive B-ALL has dramatically improved outcomes for these patients, however [7]. Similarly, while the treatment of ALL relapse has historically been mostly unsuccessful, the advent of the targeted immunotherapies, inotuzumab ozogamicin and blinatumomab, as well as of chimeric antigen receptor (CAR)-T cell therapy, has also improved outcomes for B-ALL patients with relapsed/refractory disease [8,9].
Over the last decade, additional subtypes of Ph-negative B-ALL have been identified [6], many of which are associated with a distinct prognosis. Identifying sub-type specific therapy for such patients is an ongoing research effort. One subtype, Ph-like (BCR-ABL1-like) B-ALL was originally defined as having a gene expression profile identical to that of Ph-positive ALL, but lacking the t(9;22)(q34;q11). Ph-like B-ALL peaks in adolescents and young adults, with an incidence of approximately 28% in adults, and is associated with unfavourable outcomes and a higher risk of treatment failure [10]. In addition, rearrangements of genes such as CRLF2 and CEBP family members into the immunoglobulin heavy chain variable gene (IGHV gene) locus are predominantly found in adult B-ALL, and confer a poor prognosis [11]. Other B-ALL subtypes that confer a more favourable prognosis include the PAX5 D80R subtype, and DUX4-rearranged B-ALL [6].
Although most adults with B-ALL achieve complete morphological remission with intensive induction and consolidation therapy, 40 to 50% will ultimately relapse over time [12,13]. A strong prognostic factor for relapse is the presence of post-treatment measurable (minimal) residual disease (MRD) [14,15]. While the sensitivity of MRD detection depends on the assay used, a common operational cut-off for MRD positivity is 10 −4 (1 leukemic cell in 10,000 cells assayed). Patients who achieve MRD negativity after induction, or at a later time point, have improved relapse-free survival as well as improved overall survival. These outcomes are noted across all subgroups, including both Ph-positive and Ph-negative patients [16]. Therefore, MRD levels not only inform decisions regarding the need for, and timing of, allogeneic hematopoietic stem cell transplantation (alloSCT), but also help guide modifications to ongoing management. In the case of alloSCT, not only do patients that are MRD-negative prior to alloSCT have better outcomes than do those with detectable MRD [17][18][19][20][21][22], but alloSCT also improves outcomes in patients that are persistently MRD positive. By extension, there is increasing evidence suggesting that patients with an optimal treatment response and MRD negativity may not need alloSCT [17,23,24]. MRD positivity at defined timepoints may also be used to guide changes in ongoing leukemia management. For example, in Ph-positive ALL, MRD testing may indicate the need to change the TKI used, while in Ph-negative ALL, persistent MRD positivity may trigger the use of MRD-directed therapies such as blinatumomab. Based on the ability of MRD testing to predict treatment outcomes post chemotherapy, antibody/BiTE, and CAR-T therapies, thereby informing alloSCT decisions, it is likely that MRD levels will soon function as surrogate outcome indicators, at least in the context of a clinical trial.
To be optimally useful clinically, MRD assessment requires accurate, reproducible, and sensitive detection of very low levels of residual leukemia. This can be done using either flow cytometry, or molecular genetic methods. Flow cytometry for MRD analysis involves identifying and tracking aberrant leukemia-associated immunophenotypes (LAIP) found on leukemic cells [25]. Molecular genetic methods include quantitative polymerase chain reaction (qPCR), droplet digital PCR (ddPCR), or next generation sequencing (NGS) to detect the presence of leukemia-specific gene fusions, such as BCR-ABL1, or clonal rearrangements in the immunoglobulin (Ig) and T-cell receptor (TCR) gene families [26].
The clinical value of MRD results depend on the accuracy and reliability of these assays. In contrast to the long-established standardized and centralized MRD approaches employed in other jurisdictions (especially in Europe) [27], MRD testing in adult ALL in Ontario is currently highly variable in terms of how and when it is performed, and this lack of consistency affects the quality of care that can be delivered to patients. There are currently no Canadian guidelines for laboratories doing MRD testing in ALL, although Cancer Care Ontario has recently published recommendations stating that MRD testing can be considered to help select between various treatment options for adults with ALL, in addition to its use as a prognostic test [28]. An expert multidisciplinary working group was convened to discuss the status of MRD testing in Ontario, and to define recommendations for improving the delivery of MRD testing in adult B-ALL.
# Working Group and Methods
An expert multidisciplinary working group meeting was held in Toronto in November, 2019. Four Ontario institutions were represented, selected for their expertise in ALL treatment and diagnosis (including MRD testing). The corresponding Hematology, Hematopathology, and Laboratory Medicine physicians/PhDs divided into subgroups within the meeting to draft recommendations on when to perform MRD testing in Phpositive and Ph-negative B-ALL patients, and how to perform MRD testing with respect to methodology and standardization. Current evidence from the literature, as well as evidence gaps, were considered when drafting recommendations. Subgroups presented draft recommendations to the complete group and a set of consensus recommendations was created.
# Recommendations from the Working Group
# Ensuring Quality of MRD Testing
Recommendations:
1.
MRD testing in Ontario should be centralized in an accredited laboratory. Until centralization is implemented, the standardization of testing approaches and the use of common quality metrics is mandatory among labs doing MRD testing.
# 2.
Bone marrow specimens should be used for MRD testing.
# 3.
The most sensitive methods of MRD detection should be chosen for routine clinical use. While both flow cytometric and molecular genetic approaches can deliver sensitivities of 10 −4 , this sensitivity is more consistently delivered by molecular analysis.
MRD results must be timely, accurate and reliable, to ensure the validity of MRDbased prognostic and therapeutic decisions. Regardless of the methodology used, a certain volume of testing is necessary to achieve the required level of expertise in MRD testing. For example, accurate flow cytometry assessment is highly dependent on the expertise of the interpreting Hematopathologist [26]. In addition, assay sensitivity for a standardized reverse transcription real-time quantitative PCR (RT-qPCR) MRD assay for the BCR-ABL1 transcript in Ph-positive ALL is related to the laboratory's level of experience with the specific protocol [29]. Given the relatively low incidence of adult ALL, performing MRD testing in experienced centralized laboratories will provide clinicians with the most consistent and reliable results. Shipping of samples to centralized laboratories is feasible, even for flow cytometry samples, which require the sample to arrive at the laboratory for testing within 48 h. This model of centralized testing is standard practice in European countries: a survey of MRD testing patterns in France, Germany, Italy, Spain and the UK found that the majority of clinicians in those countries used centralized laboratories for testing, consistent with national protocols that recommend MRD testing to inform treatment decisions [27].
To improve the quality of MRD testing in Ontario, the working group recommends that MRD testing should be centralized. Until this is achieved, the shared use of a single, standardized, internationally validated, method by laboratories performing MRD testing is essential. Standardization of approaches and of quality metrics is required to ensure that MRD tests done at different laboratories perform equally well, that results from different laboratories can be compared, and that results are reliably and consistently interpreted. In the absence of centralization, it is only with standardization of technique that the clinical relevance and potential actionability of MRD positivity/negativity can be interpreted in a consistent manner across the province.
All laboratories performing MRD testing must be able to reproducibly detect low levels of MRD at a threshold agreed upon for clinical relevance, and using an appropriately sensitive test. A common operational cut-off for MRD positivity is 10 −4 [30]. This level of sensitivity is achieved routinely by molecular genetic approaches, but is not obtained routinely by flow cytometry, although some laboratories in Ontario using state-of-the-art flow cytometric techniques can achieve this, assuming that the patient sample submitted is adequate. In addition, whether MRD testing is centralized or not, EQA/proficiency testing (PT) is essential to ensure consistency in testing among laboratories. Accreditation for MRD assays in Ontario is not yet provided by IQMH, or included in the general ISO 15189 accreditation, which any laboratory performing MRD testing should have. Laboratories are also required to participate in proficiency testing initiatives for all MRD assays they perform, which could include PT programs from CAP, UKNEQAS, and EuroMRD. It is recommended that Ontario laboratories performing MRD analyses also participate in assay-specific, internationally defined quality control initiatives, and many consortia have established accreditation programs for laboratories participating in their studies.
Guidelines for data interpretation and reporting are critical to ensure accurate results across multiple laboratories. While the interpretation of flow cytometric data is the most difficult component to standardize [31], variability in interpretation of the same data set can also occur in molecular genetic MRD testing [29]. The manner in which MRD is reported is also important, to ensure that clinicians have the information they need to guide decisionmaking. Both flow cytometry and molecular MRD reports should be concise to allow clinicians to draw clear conclusions. Reports should include information on the quality of the sample (when relevant), the reproducible sensitivity (lower level of quantitation) and level of detection, the MRD value, a description of the detected LAIP or molecular marker, and a conclusion, and should be in keeping with all other laboratory accreditation requirements for reporting. For molecular-based tests, MRD-positive results that are below the defined quantifiable range should also be clearly indicated if applicable. The molecular reports should also include the specific target(s) tested to ensure that the appropriate genomic analyte was ascertained for MRD analysis. A brief summary of the molecular method and its limitations should be described in the final report, as is required by Ontario laboratory accreditation requirements.
The working group recommends that bone marrow specimens be used for MRD testing. Bone marrow specimens are preferred, as studies have shown that blood and marrow results can be highly discordant, with MRD levels up to 10 3 times higher in the bone marrow than in the peripheral blood [32]. In addition, it is bone marrow samples that have been used historically in studies of the prognostic and predictive value of MRD testing in B-ALL, and thus there is no real evidence base supporting the use of peripheral blood samples for this purpose [14][15][16]18,33]. Nevertheless, while studies in ALL have shown that the percentage of blasts is lower in peripheral blood than in bone marrow samples analayzed in parallel, it has been suggested that peripheral blood could be used for MRD analysis, assuming that the assay is suitably sensitive, and the total number of input cells is sufficient (i.e., ≥10 6 cells) [32,34]. This approach is not standardized, however. When bone marrow is used, it is similarly important to ensure that the input cell number is optimal. For this reason, the first aspirated marrow specimen (the 'first pull'), with a volume of 1 to 2 mL is required for MRD testing, and this requirement is particularly important in the context of flow cytometry MRD, for which input cell number is key. For molecular MRD, genomic input minimums (rather than input cell numbers) ensure that appropriate sensitivity requirements can be achieved. For example, 1 µg of DNA corresponds to approximately 150,000 cells (assuming 6.5 pg DNA per cell) to achieve a sensitivity of 10 −5 for Ig/TCR rearrangement analysis [35]. Similarly, an RNA input sufficient to produce 100,000 copies of ABL1 by RT-qPCR would result in a sensitivity of 10 −5 for BCR-ABL1 detection [36].
# MRD Testing in Ph-Negative ALL
Recommendations:
1.
Adult Ph-negative ALL patients should receive MRD testing after induction chemotherapy, and at least one additional time point later in treatment, around 12-16 weeks.
# 2.
Flow cytometry and analysis of Ig/TCR gene rearrangements are both acceptable approaches for MRD testing in adult Ph-negative ALL patients, provided that the laboratory can reliably meet the required sensitivity of at least 10 −4 . Standardized, accredited protocols with a validated quality assurance program must be used.
The importance of incorporating MRD assessment into routine care for Ph-negative ALL patients has been demonstrated in multiple studies. Patients with lower MRD levels after induction and consolidation chemotherapy had longer duration of remission, longer relapse-free survival, and longer overall survival [37]. MRD levels may also be used as a stratification tool to inform treatment decisions: for example, alloSCT may be avoided, while maintaining favourable outcomes, for patients with good early MRD responses [17,18]. MRD testing in first or second complete remission also informs the use of the targeted therapy blinatumomab, which is the first Health Canada-approved therapy for Ph-negative B-ALL patients with MRD greater than or equal to 0.1%. Further, patients with MRD reappearance have worse outcomes compared to those with MRD persistence, suggesting that ongoing monitoring of MRD levels is helpful for risk assessment [37]. The optimal timing of MRD assessment in adults has been studied in detail [38]. Based on these data, the working group recommends that all Ph-negative ALL patients should receive MRD testing after induction chemotherapy. At a minimum, one additional MRD test should be done around 12-16 weeks, after all drugs have been delivered at a maximal dose. There may be a need for further MRD tests in some patients depending on disease progression and characteristics. This approach aligns with current recommendations from the National Comprehensive Cancer Network in the U.S. and the European Society for Medical Oncology [39,40]. It is important to remember that the predictive value of MRD testing depends both on the specific treatment regimen employed, and on the time points used for MRD testing. The optimal time points for testing related to the therapy regimens typically used in Canada are not yet clearly defined in a protocol-specific manner, but the 12-16 week rule can be applied widely.
Currently in Ontario, MRD testing in Ph-negative B-ALL patients is done using flow cytometry, although some laboratories are developing molecular genetic testing methods. The working group recognizes that flow cytometry and Ig/TCR gene rearrangement analysis are both widely accepted approaches for MRD testing in Ph-negative B-ALL patients, provided that the minimum sensitivity requirement of 10 −4 is met by a standardized protocol (Table 1). These approaches are not fully interchangeable, however, as they may provide complementary information in some clinical contexts, such as post-induction. Notably, while both methods can provide high sensitivity detection of MRD at a level of 10 −4 , this is more likely achievable on a routine basis using a molecular approach. In general, molecular methods also allow for greater interlaboratory comparability than do flow cytometry-based methods [41]. Standardized protocols have been developed and used successfully in Europe for both technologies, however [42,43]. Standardization of methodologies reduces inter-laboratory variability, minimizes the rates of false positive and false negative results, allows for the optimization of protocols, and creates consistency in interpretation and reporting of results. Application of standardized protocols to MRD testing in Ontario will improve the quality of testing and will provide clinicians with more reliable results to guide clinical decision making. Flow cytometry is currently the most widely used technique in North America for assessing MRD in Ph-negative B-ALL patients. Modern flow cytometry techniques using 6 or more fluorochromes are capable of detecting MRD with a sensitivity of approximately 10 −4 (assuming an adequate sample), and there is the potential for even greater sensitivity with more than 8 fluorochromes and a higher number of input cells, although such sensitivity is not achieved routinely [26]. MRD assessment by flow cytometry is affordable and has a quick turnaround time. However, the interpretation of flow cytometry results for MRD assessment requires substantial expertise from the Hematopathologist [26]. Currently, Ontario laboratories performing flow cytometry for MRD assessment in adult B-ALL are not all using standardized protocols. Several different consortia have published standardized methods with external quality assurance programs, including the EuroFlow Consortium, the AIEOP-BFM Consortium, the Children's Oncology Group and the NOPHO group [31,[43][44][45]. The working group recommends that MRD assessment by flow cytometry in Ontario should be centralized, and that the laboratory performing testing must use one of these standardized protocols. The laboratory should provide flow cytometry results in less than 48 h.
Although molecular methods for MRD assessment in Ph-negative B-ALL patients are widely used in Europe, these methods still require development in Canada. The use of real-time quantitative PCR (RQ-PCR) to identify and follow Ig/TCR rearrangements has been standardized by the EuroMRD consortium, and although this method is highly sensitive, it is labour intensive and requires a reference diagnostic sample to define patientspecific primers and to use as a quantification stardard [32]. Recent progress has been made by the EuroMRD group to develop, validate, and standardize NGS assays to evaluate Ig/TCR rearrangements for MRD assessment in ALL [42]. Although this method does not require the use of patient-specific probes, it does require a diagnostic sample to identify the leukemia-associated Ig/TCR rearrangement. Sensitivity of this method varies based on the amount of input DNA: a sensitivity of 10 −4 to 10 −5 can be reached with 500 ng to 1 µg of input DNA. In comparison with flow cytometry and RQ-PCR, NGS generally shows better sensitivity [26]. However, the quantification of MRD levels by NGS can be challenging. Given the advantages of NGS compared to RQ-PCR for MRD detection, and its increased adoption and standardization in Europe, as Canadian laboratories develop molecular assays for MRD detection in Ph-negative ALL, the working group recommends that molecular MRD testing be performed in a central laboratory in Ontario. Ideally, an NGSbased assay should be used, with a standardized lab-developed and validated protocol such as the EuroClonality-NGS assay. However, a hybrid NGS/RQ-PCR approach may currently be more feasible, in which NGS is used to identify PCR MRD targets, which subsequently can be used to monitor MRD with the well-established patient-specific RQ-PCR method. In situations where no Ig/TCR rearrangement can be identified due to limitations of PCR reactivity, flow cytometry should be performed as an alternative. Turnaround time for molecular MRD testing results should ideally be within 10 calendar days, to ensure results are received in a clinically relevant time frame. However, recognizing that achievement of this goal will require additional resources and funding to be provided to laboratories, the maximum acceptable turnaround time in the current laboratory environment is 14 calendar days, with the optimal goal of returning results to the clinician within 10 calendar days. In contrast, the turnaround time for flow cytometric MRD assessment will be much shorter.
# MRD Testing in Ph-Positive ALL
Recommendations:
1.
Adult Ph-positive ALL patients should receive MRD testing after induction chemotherapy, with ongoing monitoring thereafter.
# 2.
At a minimum, MRD testing for Ph-positive ALL should be centralized in a laboratory using reverse transcription real-time quantitative PCR for both the p210 and p190 BCR-ABL1 transcripts, using standardized assays. MRD assessment using RQ-PCR/NGS assays evaluating Ig/TCR rearrangements should ideally also be used in parallel for Ph-positive patients, as this approach may provide additional, complementary clinical information.
Ph-positive ALL has an aggressive clinical course, with a high risk of relapse despite progress in treatments. As with Ph-negative ALL, MRD testing is useful for prognosis and management of patients with Ph-positive B-ALL. MRD negativity at three months after chemotherapy plus TKI therapy is associated with improved relapse-free and overall survival [46,47]. In addition, the evaluation of MRD assists in making decisions regarding alloSCT, and in directing modifications to ongoing treatment. Growing lines of evidence indicate that patients with deep MRD responses to initial therapy may not require alloSCT, but rather can be treated with ongoing chemotherapy plus TKI, with good outcomes [48]. In patients undergoing alloSCT, measurable MRD levels at the time of transplant are associated with a significantly higher risk of post-alloSCT relapse than observed in MRDnegative patients [19,49,50]. Ongoing MRD testing also informs the need for ABL mutation analysis and potential mutation-guided changes in TKI therapy, such as switching from imatinib to dasatinib, or to ponatinib. Therefore, the working group recommends that all Ph-positive ALL patients should receive MRD testing after induction chemotherapy, and ongoing monitoring thereafter. This recommendation aligns with Cancer Care Ontario and international guidelines on MRD monitoring in Ph-positive disease. For example, ESMO and NCCN guidelines both mandate MRD assessment post-induction, and periodic monitoring thereafter, including post-SCT [39,40]. Ideally, Ph-positive patients should have MRD assessment by flow cytometry after induction, and ongoing monitoring thereafter by molecular testing (Table 1).
The working group recommends that molecular MRD testing for Ph-positive ALL should be centralized in a laboratory using reverse transcription real-time quantitative PCR (RT-qPCR) for both the p210 and p190 BCR-ABL1 transcripts [29,51]. If centralization is not feasible, then standardization of the RT-qPCR protocol between labs should be ensured, such as in the Europe Against Cancer Program [52]. Turnaround time, as with MRD testing for Ph-negative ALL, should be no longer than 10 calendar days to allow for rapid treatment decisions. Although many laboratories in Canada routinely perform PCR assays for the p210 transcript in CML from peripheral blood, optimal MRD testing for Ph-positive patients in ALL requires the use of bone marrow samples. The advantages of RT-qPCR include high sensitivity of 10 −4 to 10 −5 , and a rapid turnaround time [29,53]. Using the BCR-ABL1 fusion as a marker for MRD in Ph-positive B-ALL patients is more efficient and less labour-intensive than is RQ-PCR detection of Ig/TCR gene rearrangements, which requires patient-specific probes. Nevertheless, the RQ-PCR detection of rearrangements of Ig/TCR genes, highly standardized and widely used in Europe [54], is in development in Canada, and may be clinically useful in Ph-positive ALL as well (see below). Use of this method requires a diagnostic patient sample. Ig/TCR gene rearrangement monitoring and flow cytometry are also suitable for patients with variant BCR-ABL1 breakpoints, where MRD testing using p210 or p190 specific qPCR methods cannot be used.
Detection of MRD in Ph-positive patients using both Ig/TCR rearrangement and BCR-ABL1 fusion transcript detection should be considered, as it has been shown that discordance can occur between the two methods. A false positive (or negative) MRD result could influence important treatment decision-making, such as the decision to proceed to alloSCT. In both pediatric and adult studies, discordance has been reported in more than 20% of cases between positive MRD results from BCR-ABL1 RT-qPCR, and negative MRD results from Ig/TCR rearrangement RQ-PCR (the latter indicates the absence of a leukemic clone). In such 'MRD discordant' cases, BCR-ABL1 positivity was found to reside in non-ALL B-lymphocytes, T-cells, and/or myeloid cells, suggesting that a multipotent hematopoietic progenitor cell was the source of the translocation [55,56], resulting in a more CML-like clinical picture. In contrast, and consistent with this interpretation, in 'MRD concordant' cases, BCR-ABL1 positivity was found only in ALL B-cell precursors, suggesting that the source of the translocation was a later, more-restricted precursor cell. Using both assays to monitor MRD would ensure that BCR-ABL1 positivity not representing true residual disease does not lead to intensification of therapy that may not be necessary. Whether the requirements for alloSCT differ between MRD 'concordant' and 'discordant' adult ALL cases, as has been suggested in a pediatric series [57], remains unknown.
Going forward, as discussed above for Philadelphia-negative ALL, current methods for detection of Ig/TCR rearrangements, may soon be replaced by NGS-based methods, for which standardized protocols are already available. In addition, the current RT-qPCR approach to BCR-ABL1 transcript quantitation may become supplanted by more sensitive droplet digital PCR (ddPCR)-based approaches [58,59]. The clinical utility of the latter approach remains undefined at present, however.
# Conclusions
Consistent, reproducible, and accurate MRD testing is required for optimal management of adult B-cell ALL. Technologies for MRD testing are evolving, with the development of standardized protocols for high sensitivity flow cytometry, for RT-qPCR (or ddPCR) analysis of the BCR-ABL1 transcript, and for PCR or NGS to evaluate Ig/TCR rearrangement. There are no published guidelines for Canadian laboratories regarding MRD testing in adult B-cell ALL, and as a result, testing methods and quality are highly variable. The Ontario expert working group recommends that MRD testing in Ontario should be centralized, as this allows for the necessary development of expertise in MRD testing and provides consistent, reliable results to clinicians. Standardized and accredited protocols for MRD testing must be used. Optimal care of adult B-cell ALL patients depends on accurate MRD testing, which would benefit from implementation of the recommendations described herein.
# Acknowledgments:
The authors would like to thank Amgen Canada for supporting the working group meeting and Precision Rx-Dx for assistance with the working group. The authors would like to acknowledge Philippa Bridge-Cook, the Precision RxDx for assistance with medical writing.
# Conflicts of Interest:
A.T. reports advisory board honoraria from Astellas Pharma, Jazz Pharmaceuticals, and Amgen. B.L. reports personal fees from Pfizer, Amgen, Jazz Pharmaceuticals, Novartis, Bristol Myers Squibb, and Paladin, outside the submitted work. P.J.B.S. reports personal fees from Amgen, during the conduct of the study. T.L.S. reports personal fees from Amgen, during the conduct of the study. J.F. reports honoraria from Amgen, Pfizer and Jazz Pharmaceuticals. A.C.S. reports personal fees from AbbVie, Agios, Amgen, BMS, Jazz, Novartis, Phebra, Pfizer, and Teva, unrelated to the current work. J.F., B.S., C.C., and E.M. have nothing to disclose.
#
Funding: Funding for the working group meeting and medical writing assistance was provided by Amgen Canada, in accordance with GPP3 guidelines (http://www.ismpp.org/gpp3, accessed on 7 January 2021).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
# Data Availability Statement:
No new data were created or analyzed in this study. Data sharing is not applicable to this article. | None | None |
a5fbf1e961ee053512d5aed60a028e3131924f00 | cma | None | This document provides guidance for COVID-19 immunization in patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). PNH is a rare, acquired disorder of complement mediated red cell hemolysis associated with a very high chance of thrombosis and, sometimes, neutropenia from associated bone marrow failure. Although data is very limited 1,2 on the impact of COVID-19 on PNH, rare thrombotic complications have been described 3 suggesting that there may be additional chance of severe complications from COVID-19 if PNH patients contract the virus. In addition, other viral infections are well recognized triggers for episodes of hemolysis in PNH which can have life-threatening consequences. aHUS is a rare kidney disease related to microangiopathy. Although no data has been published on the susceptibility to and impact of COVID-19 on people with aHUS, there are numerous reports of aHUS being triggered in genetically susceptible patients by viral infections including influenza. 4 Also, COVID-19 is more likely to be severe in patients with kidney diseases and renal involvement is a cardinal feature of aHUS. Crises in aHUS patients can be life-threatening with acute kidney injury and both thrombotic and hemorrhagic complications.#
Is COVID-19 immunization recommended for people with PNH and aHUS? COVID-19 vaccines should be encouraged for patients with PNH and aHUS and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
- PNH and aHUS are both thromboinflammatory disorders and this pathophysiology overlaps with the cytokine storm environment which characterizes severe COVID-19. 5 This shared pathophysiology does raise concerns that patients with PNH and aHUS will be more at risk of severe COVID-19 regardless of treatment status for PNH and aHUS. - PNH and aHUS are both treated with drugs targeting the complement cascade, like eculizumab. While eculizumab may not have a direct negative effect on COVID-19, 6 severe complications of the underlying PNH or aHUS condition in patients receiving eculizumab have been reported when they contracted COVID-19. 2,7 Also, eculizumab mediated complement blockade leads to an increased risk of some infections and, in particular, Neisseria infections, leading to mandatory meningococcal immunization for treated patients. 8 COVID-19 Vaccines for People with Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome Updated: April 18, 2023 2
- Agreement among professional societies recommending that aHUS and PNH patients receive COVID-19 immunizations. While data specific to the safety and efficacy of the COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna), and VAXZEVRIA (AstraZeneca) vaccines for people with PNH and aHUS is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 13 The authors of this guidance agree that the benefits of vaccineinduced immunity against COVID-19 for this population outweigh any theoretical risks of immunization.
Is COVID-19 immunization efficacious and safe for people with PNH and aHUS?
As both PNH and aHUS are considered to be severe underlying medical diseases, they would have been excluded from the COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna) and VAXZEVRIA (AstraZeneca) vaccine clinical trials. Therefore, it is unknown if the currently available COVID-19 vaccines are as efficacious for patients with PNH and aHUS as they were found to be for the trial population.
Vaccine efficacy may theoretically be reduced in patients with PNH who have been treated with anti-thymocyte globulin for aplastic anemia in the six months prior to receiving the vaccine. 6 It is expected that this consideration may apply to only a very small number of patients in the province, and the patient's hematologist should inform the patient taking this treatment that the vaccine may not provide optimum protection.
Otherwise, there is nothing from a disease perspective pertinent to PNH and aHUS to suggest that the vaccines would be less efficacious or safe for people with PNH and aHUS than they are for the general population. The mRNA vaccines (COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna) are not live vaccines, and the VAXZEVRIA (AstraZeneca) vaccine is a replication-defective adenovirus vaccine. Thus, they do not pose a risk to PNH and aHUS patients. The benefits of immunization are expected to be similar to that of the general population.
Are there any specific contraindications or exceptions for patients with PNH and aHUS?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 14 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if COVID-19 Vaccines for People with Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome Updated: April 18, 2023
informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. Other than allergy and the safety and efficacy considerations described above, and the medication timing considerations described below, and there are no specific contraindications or exceptions for people with PNH and aHUS.
Are there specific recommendations or considerations for safe and/or most effective administration?
Patients who are on eculizumab should time their vaccination so it occurs as close as possible to their dose (within days before or days after their dose) due to the theoretical possibility that this may reduce their chance of having exacerbation of their disease related to vaccine administration. Typical eculizumab dosing intervals are biweekly.
Some patients with these disorders may be thrombocytopenic or on anticoagulation medication. Guidance developed for the general population who may be on anticoagulants (e.g., prolonged pressure at the site, etc.) can also be applied to those members of this population as they are at increased bleeding risk. | This document provides guidance for COVID-19 immunization in patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). PNH is a rare, acquired disorder of complement mediated red cell hemolysis associated with a very high chance of thrombosis and, sometimes, neutropenia from associated bone marrow failure. Although data is very limited 1,2 on the impact of COVID-19 on PNH, rare thrombotic complications have been described 3 suggesting that there may be additional chance of severe complications from COVID-19 if PNH patients contract the virus. In addition, other viral infections are well recognized triggers for episodes of hemolysis in PNH which can have life-threatening consequences. aHUS is a rare kidney disease related to microangiopathy. Although no data has been published on the susceptibility to and impact of COVID-19 on people with aHUS, there are numerous reports of aHUS being triggered in genetically susceptible patients by viral infections including influenza. 4 Also, COVID-19 is more likely to be severe in patients with kidney diseases and renal involvement is a cardinal feature of aHUS. Crises in aHUS patients can be life-threatening with acute kidney injury and both thrombotic and hemorrhagic complications.#
Is COVID-19 immunization recommended for people with PNH and aHUS? COVID-19 vaccines should be encouraged for patients with PNH and aHUS and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
• PNH and aHUS are both thromboinflammatory disorders and this pathophysiology overlaps with the cytokine storm environment which characterizes severe COVID-19. 5 This shared pathophysiology does raise concerns that patients with PNH and aHUS will be more at risk of severe COVID-19 regardless of treatment status for PNH and aHUS. • PNH and aHUS are both treated with drugs targeting the complement cascade, like eculizumab. While eculizumab may not have a direct negative effect on COVID-19, 6 severe complications of the underlying PNH or aHUS condition in patients receiving eculizumab have been reported when they contracted COVID-19. 2,7 Also, eculizumab mediated complement blockade leads to an increased risk of some infections and, in particular, Neisseria infections, leading to mandatory meningococcal immunization for treated patients. 8 COVID-19 Vaccines for People with Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome Updated: April 18, 2023 2
• Agreement among professional societies recommending that aHUS and PNH patients receive COVID-19 immunizations. [9][10][11][12] While data specific to the safety and efficacy of the COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna), and VAXZEVRIA (AstraZeneca) vaccines for people with PNH and aHUS is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 13 The authors of this guidance agree that the benefits of vaccineinduced immunity against COVID-19 for this population outweigh any theoretical risks of immunization.
Is COVID-19 immunization efficacious and safe for people with PNH and aHUS?
As both PNH and aHUS are considered to be severe underlying medical diseases, they would have been excluded from the COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna) and VAXZEVRIA (AstraZeneca) vaccine clinical trials. Therefore, it is unknown if the currently available COVID-19 vaccines are as efficacious for patients with PNH and aHUS as they were found to be for the trial population.
Vaccine efficacy may theoretically be reduced in patients with PNH who have been treated with anti-thymocyte globulin for aplastic anemia in the six months prior to receiving the vaccine. 6 It is expected that this consideration may apply to only a very small number of patients in the province, and the patient's hematologist should inform the patient taking this treatment that the vaccine may not provide optimum protection.
Otherwise, there is nothing from a disease perspective pertinent to PNH and aHUS to suggest that the vaccines would be less efficacious or safe for people with PNH and aHUS than they are for the general population. The mRNA vaccines (COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna) are not live vaccines, and the VAXZEVRIA (AstraZeneca) vaccine is a replication-defective adenovirus vaccine. Thus, they do not pose a risk to PNH and aHUS patients. The benefits of immunization are expected to be similar to that of the general population.
Are there any specific contraindications or exceptions for patients with PNH and aHUS?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 14 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if COVID-19 Vaccines for People with Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome Updated: April 18, 2023
3
informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. [15][16][17][18] Other than allergy and the safety and efficacy considerations described above, and the medication timing considerations described below, and there are no specific contraindications or exceptions for people with PNH and aHUS.
Are there specific recommendations or considerations for safe and/or most effective administration?
Patients who are on eculizumab should time their vaccination so it occurs as close as possible to their dose (within days before or days after their dose) due to the theoretical possibility that this may reduce their chance of having exacerbation of their disease related to vaccine administration. Typical eculizumab dosing intervals are biweekly.
Some patients with these disorders may be thrombocytopenic or on anticoagulation medication. Guidance developed for the general population who may be on anticoagulants (e.g., prolonged pressure at the site, etc.) can also be applied to those members of this population as they are at increased bleeding risk. | None | None |
099faf65a13a8b1454be7efcae1ebec92f102fdf | cma | None | # Background
Acute Lymphoblastic Leukemia (ALL) is a highly aggressive hematological -malignancy resulting from the proliferation and expansion of lymphoid blasts in the blood, bone marrow and other organs. 1 ALL occurs with a bimodal distribution with an early peak in children 4 -5 years old followed by a second peak at ~ 50 years of age 2 with the worldwide incidence being ~ 1 -4.75/100,000 individuals with a male:female prevalence of roughly 13:1. 1 It is the most common childhood acute leukemia accounting for ~ 80% of the pediatric leukemias but contributing to only 20% of adult leukemias. Although significant progress has been made in treating adult ALL the overall survival amongst adults 18 to 60 years old is only 35% in contrast to childhood ALL in which overall survival at five years is more than 80%. 1 Over the past two decades the treatment of adult ALL has changed significantly with the introduction of pediatric protocols for the treatment of adolescents and young adults, the addition of tyrosine kinase (TKI) inhibitors for the treatment of Philadelphia positive/BCR-ABL positive ALL, a reevaluation of the role of allogeneic stem cell transplantation for standard risk ALL patients, the incorporation of minimal residual disease into risk assessments and most recently the introduction of novel agents such blinatumomab, inotuzumab and chimeric antigen receptor -T cell therapy for relapsed/refractory ALL.
Guideline Questions
# Search Strategy
The PubMed database was searched for relevant studies, guidelines and consensus documents published using the search term 'Acute Lymphoblastic Leukemia'. Clinical trials, clinical practice guidelines, systematic reviews and meta analyses written in English were included.
# Target Population
The following recommendations apply to adult cancer patients with suspicion or diagnosis of ALL. 2. Pre-treatment risk stratification should be ascertained for all patients using age and cytogenetics/FISH and/or molecular studies.
# Summary of Recommendations
Post-treatment risk stratification should include the outcomes of minimal residual disease assessment using either flow cytometry or PCR (see below)
Principles of Treatment Initiation 1. Induction therapy should only be administered in a leukemia centre with physician and nursing expertise in the management of acute leukemias.
- Induction therapy should not be initiated until the BCR-ABL status is known. If the patient is symptomatic, a steroid pre-phase should be indicated.
Initiation of induction therapy should be accompanied by tumour lysis syndrome (TLS) prophylaxis, including hydration, urate lowering agents and close monitoring of TLS chemistries.
Treatment of Ph/BCR-ABL negative ALL 1. Eligible adults under age 60 should be treated with a pediatric-based protocol. a. In Alberta the current standard regimen is the modified Dana Farber Cancer Institute (DFCI) protocol. b. Patients with co-morbidities, or those unable to tolerate the full DFCI protocol, may be treated with a less intensive regimen, such as the modified DFCI protocol for patients age 60 or over. 2. Fit adults age 60-75 should be treated with curative intent.
a. The Princess Margaret Hospital modified DFCI protocol for adults above age 60 has produced favourable results in this population compared to other regimens and may be used.
Other curative-intent regimens are also acceptable. 3. Patients over age 75, or those under age 75 with major co-morbidities precluding intensive chemotherapy, should be considered for palliative chemotherapy with corticosteroids and vincristine +/-low-dose asparaginase, followed by low-dose maintenance chemotherapy if CR is achieved.
Treatment of Ph/BCR-ABL positive ALL 1. Ph/BCR-ABL positive patients who are fit for chemotherapy should be treated with a BCR-ABL tyrosine kinase inhibitor (TKI) combined with induction and post-remission therapy. a. A less intensive induction regimen with corticosteroids, vincristine and TKI (e.g. Chalandon protocol) is preferred for initial induction, as it produces higher CR rates due to lower induction mortality. In younger, fit patients, this should be followed by intensification (e.g. HyperCVAD Part B + TKI, as per the Chalandon protocol).
b. Patients achieving a hematologic CR should be continued on post-remission chemotherapy + TKI. This may consist of the modified Princess Margaret Hospital DFCI CNS, intensification and maintenance phases, or HyperCVAD + TKI. Asparaginase should not be used due to increased toxicity when used concurrently with TKI. c. Imatinib (600 -800mg per day), is currently the standard first line TKI drug. i. Patients with intolerance to, or not achieving an adequate response to, imatinib should be switched to a second generation TKI such as dasatinib ii. Ponatinib should be used in patients with a T315I mutation iii. For patients with CNS disease at diagnosis, dasatinib should be used upfront due to its superior CNS penetration. d. Patients with Ph/BCR-ABL positive ALL who are elderly, or otherwise unfit for intensive chemotherapy or transplant, should be treated with the Chalandon induction protocol cycle A, or corticosteroids + TKI, followed by low-dose maintenance chemotherapy + TKI. e. TKIs should be continued indefinitely in patients who are not transplanted. f. Patients not transplanted should be closely monitored for disease progression with serial PCR testing every 3 months. Reappearance of PCR positivity, if confirmed, should prompt a change in TKI and referral for allogeneic HSCT, if a potential candidate. g. Patients with persistence of, or reappearance of BCR-ABL transcripts by PCR, should have mutational testing, specifically to look for the presence of a T315I mutation.
# Role of MRD (minimal or measurable residual disease) assessments
- Ph/BCR-ABL negative patients should have MRD assessments following induction chemotherapy, or by week 16, by flow cytometry or molecular techniques.
a. MRD positive B-ALL patients, defined as > 0.1% of mononuclear cells by flow (>10 -3 ), should receive immuno-therapy using 1-2 cycles of blinatumomab with an intent to achieve MRD negativity. b. MRD positive T-ALL patients should receive intensified chemotherapy with an intent to achieve MRD negativity.
c. MRD positive patients post-intensive induction or at week 16, defined as > 0.1% of mononuclear cells by flow, should be considered for allogeneic HSCT in CR1, as these patients are at higher risk of relapse.
- Ph/BCR-ABL positive patients should have MRD assessments following induction chemotherapy, or by week 16, by quantitative PCR.
a. Patients who are MRD positive by PCR at the end of a two-cycle induction using the Chalandon protocol, or by week 16 using other protocols, should be switched to a second generation TKI such as dasatinib. If already on a 2 nd generation TKI, the patient should be switched to ponatinib. The TKI should be combined with either chemotherapy or blinatumomab. b. MRD positive patients at these timepoints should be referred for allogeneic HSCT in CR1, as per below.
Role of allogeneic stem cell transplantation 1. Allogeneic HSCT should not be routinely performed in patients with Ph/BCR-ABL negative ALL in CR-1. However, patients with the following high-risk features should be considered for HSCT: i. t(4;11) with MLL (KMT2A) rearrangement ii. Early T-cell precursor (ETP) ALL iii. Lack of attainment of hematologic CR with first induction iv. MRD positivity at end of induction or by week 16, as per above. v. Inability to deliver sufficient asparaginase dosing during intensification therapy a. There is no clear evidence that other cytogenetic abnormalities, or specific cell surface markers, constitute high risk features when using a pediatric-based regimen b. It is also not clear whether patients with a high-risk feature at baseline who achieve MRD negativity after induction therapy require a transplant. 2. Fit BCR-ABL positive patients up to age 70 may be considered for allogeneic HSCT in CR-1.
a. Patients with BCR-ABL positivity by PCR, either post-induction or by week 16 (depending on the regimen), should be referred for allogeneic HSCT, as per 6.1.3. If an HLA matched related or unrelated donor is unavailable, a haploidentical transplant should be considered. b. Patients achieving early MRD negativity by PCR, either post-induction or by week 16 (depending on the regimen), may be continued on post-induction chemotherapy together with TKI without a transplant. Transplant is also an option in these patients. c. Reappearance of PCR positivity with monitoring, if confirmed, should prompt a referral for allogeneic HSCT, if a potential candidate, as per above.
# CNS prophylaxis 1.
Intrathecal chemotherapy: All patients should receive intrathecal chemotherapy prophylaxis, starting with the initiation of induction therapy, and continuing through maintenance therapy, for 11-12 total doses. a. If the initial CSF is positive, intrathecal chemotherapy should be administered twice weekly until CSF clearance is confirmed on at least 3 occasions.
Cranial Radiation: Cranial radiation may be omitted from CNS prophylaxis, unless there is evidence of fixed CNS disease.
# Relapsed
# CAR T-Cell Therapy:
- Indicated for fit B-ALL patients relapsing after allogeneic HSCT, refractory to 2 induction regimens, or relapsed and not considered suitable candidates for HSCT.
Patients should be referred for apheresis prior to administering salvage immunosuppressive chemotherapy such as corticosteroids or cyclophosphamide, to avoid interfering with the quality of the product.
Patients should in most cases receive bridging/cytoreductive therapy following apheresis, to prevent clinical deterioration due to disease progression and to achieve cytoreduction prior to CAR T infusion. This may consist of either chemotherapy or antibody-based therapy.
# Discussion and Recommendations
Pathogenesis ALL is thought to arise from interactions between exogenous or endogenous exposures, genetic susceptibility, and chance. Infection was the first suggested causal exposure for childhood acute lymphoblastic leukemia. After the Hiroshima and Nagasaki atomic detonations, ionizing radiation quickly became established as an exposure leading to childhood ALL. 3 Chromosomal translocations occurring in utero during fetal hematopoiesis have been suggested as the primary cause for pediatric ALL while postnatal genetic events are considered secondary contributors. 4,5 Many of these chromosomal rearrangements disrupt genes that regulate normal haematopoiesis and lymphoid development (e.g. RUNX1, ETV6), activate oncogenes (eg, MYC), or constitutively activate tyrosine kinases (e.g. ABL1). Patients with trisomy 21, Klinefelter's syndrome and inherited diseases with excessive chromosomal fragility such as Fanconi's anemia, Bloom's syndrome and ataxiatelangiectasia have a higher risk of developing ALL. 6 However, in the majority of ALL patients no gross chromosomal alteration is noted suggesting that additional submicroscopic genetic alterations likely contribute to leukaemogenesis. 5 Genome-wide association studies of childhood 5 have noted common allelic variants in IKZF1, ARID5B, CEBPE, and CDKN2A which have been significantly and consistently associated with childhood ALL. 5 Others have investigated the associations of genetic polymorphisms in folate pathway and DNA repair genes with susceptibility to ALL. 7 Although several genetic alterations have well established roles in leukemogenesis (e.g. activating mutations in NOTCH1) the roles of many others remains elusive.
# Clinical Manifestations, Diagnosis, and Work-up
Clinical manifestations of ALL are highly variable. At presentation patients may have a multitude of constitutional symptoms, easy bruising, bleeding, dyspnea, dizziness, and infections due to anemia, thrombocytopenia and neutropenia. Extremity and joint pain may be the only presenting symptoms in some patients. 8 Lymphadenopathy, splenomegaly and/or hepatomegaly are seen on physical examination in approximately 20% of patients. 8 Abdominal masses from gastrointestinal involvement or chin numbness from cranial nerve involvement may be seen but are more suggestive of mature B-ALL. Less than 10% of patients have symptomatic central nervous system (CNS) involvement. Tlineage ALL with a mediastinal mass can cause stridor and wheezing, pericardial effusions, and superior vena cava syndrome. Testicular involvement is rare in adults. 9 The diagnosis of ALL begins with an evaluation of the peripheral blood film which may identify the presence of blasts. Patients presenting with only a mediastinal mass or lymphadenopathy require a tissue biopsy. All patients should have a bone marrow examination. As per the 2008 and 2016 WHO classifications, in contrast to myeloid malignancies, there is no agreed-upon lower limit for the percentage of blasts required to establish a diagnosis of lymphoblastic leukemias. 10 Despite this, some guidelines suggest that the diagnosis of ALL requires demonstration of > 20% blasts in the bone marrow aspirate/biopsymaterial. 8 By convention the term lymphoma is used when the process is confined to a mass lesion with no or minimal evidence of peripheral blood and bone marrow involvement. Based on morphologic, genetic and immunophenotypic features, lymphoblastic lymphoma is indistinguishable from ALL, and is in fact not distinguished in the WHO 2016 classification.
The assessment of immunophenotype by flow cytometry is essential to establishing the diagnosis. 9 The initial immunophenotyping panel should be comprehensive enough to establish a leukemia associated phenotype (LAP) to allow for use in minimal disease monitoring (MRD). Cytogenetic examination with examination of metaphases and/or fluorescence in situ hybridization (FISH) is crucial (eg, for BCR-ABL and MLL-AF4) particularly in cases in which cytogenetics are unavailable or have failed. Screening by polymerase chain reaction (PCR) for the BCR-ABL transcripts is also essential as it significantly impacts treatment. Determination of the BCR-ABL breakpoint is also required for subsequent molecular monitoring. Some labs also evaluate blast cells with molecular methods for the detection of patient-specific immunoglobulin and T-cell receptor (Ig/TCR) rearrangements 9 ; however, this is not routinely performed within Alberta. If bone marrow transplant is a consideration, tissue typing of both the patient and siblings should also be performed at diagnosis. If there are no HLA-matched siblings, consideration should be given to prompt initiation of an unrelated donor search.
# Recommendations:
The initial work-up of patients with ALL should include a thorough history and physical examination as well as baseline laboratory investigations including complete blood count, chemistry with extended electrolytes, tests of renal and liver function including amylase and lipase, a disseminated intravascular coagulation panel, and a tumour lysis panel. Cardiac imaging e.g. echocardiogram, multigated acquisition (MUGA) scan or cardiac MRI should be undertaken for all patients due to the use of anthracyclines.
Bone marrow studies or peripheral blood studies incorporating, as noted above, immunophenotyping, cytogenetics, and molecular studies should be completed. Ideally results of BCR-ABL testing should be available prior to the initiation of induction therapy, and should be available within 5 days. Lastly, patients eligible for allogeneic stem cell transplantation, and their siblings should have human leukocyte antigen (HLA) typing performed.
# Classification and Prognostication
# Classification of ALL:
The WHO 2016 classification is largely based on recurrent cytogenetic abnormalities, but also includes molecular markers such at KMT2A and BCR-ABL (Table 1). There is also a new provisional entity encompassing the BCR-ABL-like genotype (described later), which is not to this point readily diagnosed using routine testing. B-lymphoblastic leukemia/lymphoma NOS encompasses all subtypes not otherwise defined by one of the recognized abnormalities.
It is notable that this classification does not primarily distinguish between different immunophenotypic features, apart from the provisional T cell entities. It also does not distinguish between Tlymphoblastic lymphoma and T-ALL, acknowledging the widely held view that these are different clinical presentations of the same disease, and should be managed similarly. On the other hand, early T-cell precursor (ETP) lymphoblastic leukemia has been identified as a distinct subtype with unque biologic and clinical characteristics.
# Prognostic Factors in ALL:
Prognostic models for ALL have been refined continuously with improvements in therapy rendering some prognostic variables invalid. 9 The following represent clinical, cytogenetic and important molecular risk factors. It is important to note that many of these factors were defined using adultbased protocols and more studies are needed to evaluate their significance with pediatric based protocols.
# Clinical Prognostic Factors:
# Age, Gender and Ethnicity
Age is an important prognostic factor in ALL. In children age (infant or ≥10 years old) is an unfavourable risk group especially those younger than 6 months old. 5,17 Regardless of the treatment protocol utilized older adults are regarded as a prognostically unfavorable group. One study noted that the outcomes of patients aged over 55 had a probability of survival of 20% at 3 years while others have noted that patients over the age of 35 have poorer outcomes. Recent data suggest that adolescents and young adults benefit with improved overall survival if treated according to pediatric protocols. 1 Several studies have suggested that the influence of age may relate to the increased prevalence of poor-risk features while others have suggested that it is independent of cytogenetic and molecular aberrations. 16,17 The ability to tolerate chemotherapy likely plays an important role. 13,18,19 Together with age, male gender and race (Hispanic or of African descent) have been considered negative prognostic factors in pediatric ALL Inaba, 2013 #20. Racial differences in prognosis have been linked to socioeconomic factors but also to differences in genomic variations. For example, germline single nucleotide polymorphisms of PDE4B and ARID5B are associated with Native American genetic ancestry and somatic CRLF2 were over-represented in children with a Hispanic background.
# White Blood Cell Count
In children, a presenting leucocyte count (≥50 × 10⁹/L) has been associated with a worse prognosis. 17 In many, but not all adult studies of ALL, high-risk ALL has been defined as WBC ≥ 30 x 10 9 /L for Bcell ALL and ≥100x10 9 /L for T-cell ALL. 1,11, Although most early studies identifying this factor used adult-based protocols, subgroup analyses in larger studies show that these continue to be important prognostic factors with pediatric-inspired regimens Brandwein, 2011 #51;Boissel, 2003 #357. In their study of the DFCI protocol in adults a high WBC (>30 x 10 9 /L for Pre-B ALL or >100 x 10 9 /L for T-ALL) was associated with inferior RFS and OS. 20 However, subsequent studies incorporating early MRD detection into multivariate models have demonstrated that baseline WBC was no longer an independent predictor of relapse (see section on MRD). 21
# Immunophenotype
The SEER database demonstrated a better prognosis with B cell as compared with T cell immunophenotype in patients < age 20 years; while in patients ≥ 20 years of age, T cell immunophenotype was more favorable. 22 This was confirmed in a metanalysis by Kako 23 Amongst adults T-cell ALL accounts for 14-22% of adult ALL 24 and is thought to be of favourable prognosis. In both the LALA 87 and the UKALL/EGOG 2993 trial, T-ALL was associated with male gender, age <35 -39 years old, CNS involvement and a high WBC count. The LALA-87 investigators also noted a higher incidence of a mediastinal mass and anemia. 15,24 In this study for patients age <40 treated with chemotherapy alone 3 year DFS was superior in the group with a T-cell phenotype relative to a B-ALL phenotype (59% vs. 20%). No difference in DFS was seen in patients with B-or T-ALL patients treated with allo-or auto -HSCT. 24 Similarly, Both Rowe et al. and Larson et al. noted that improved OS in patients with T-cell antigen expression relative to B-lineage antigens. 13,18 Kantarjian et al. using Hyper-CVAD noted similar results. 12 Using the pediatric Dana Farber Cancer Institute (DFCI) protocol a trend toward improved clinical outcomes was observed in adolescents 25 and adults 20,26 with T-ALL. The GRAALL study group 94 noted that when using a pediatric protocol at 42 months, EFS was estimated to be 62% (95% CI, 50% to 72%) in T-ALL patients and 52% (95% CI, 42% to 59%) in BCP-ALL patients (p=0.09). Within the T-cell ALL subset the prognosis is worse for pro-, pre-and mature-T subtypes (CD1a-, CD3-/CD3+) compared with the CD1a+ cortical/thymic phenotype. The early T-cell precursor ALL which retains stem cell-like features is associated with a dismal prognosis with conventional chemotherapy 27 in both adult and pediatric T-ALL. 28 As noted above, several studies have suggested that patients with B-cell phenotype fare worse than those with T-ALL. Patients with a CD10-negative pro-B phenotype are considered as high-risk particularly when associated with t(4;11)/abn q23. 1,26 The pre-B subtype expressing cytoplasmic heavy chains has a bad outlook when harboring MLL rearrangements. The CD20 antigen is expressed in nearly half of B-cell ALL and its impact on clinical outcomes is controversial. Maury et al. when using the pediatric GRAALL 2003 protocol in adults aged 15-60 years old with Ph-negative ALL noted that CD 20 expression did not influence achievement of complete remission but was associated with a higher cumulative incidence of relapse (CIR) and lower EFS at 42 months (42% vs. 29%) in patients with a WBC ≥ 30 ×10 9 /L (P=0.006). Thomas et al. also noted an inferior survival in CD20 positive patients using the adult-based hyper-CVAD protocol. 29 In contrast, a retrospective analysis by the Princess Margaret Hospital groups in adult patients, most of whom had received a pediatricbased regimen, did not find any association between CD20 expression and outcome 30 and in-fact there appeared to be a trend towards a favourable EFS in those showing CD20 positivity.
# Cytogenetic Studies
Karyotype is an important prognostic factor with a number of cytogenetic abnormalities being associated with altered prognosis in ALL (Table 2). The frequency of cytogenetic aberrations varies between adult and childhood ALL and may partially explain the differences in clinical outcomes between patient populations. 8 Whether cytogenetic abnormalities remains important with the use of pediatric protocols in adult patients remains unclear; some studies suggest that most abnormalities are not independent predictors of outcome in adults treated with such protocols, with the exception of KMT2A-associated abnormalities. 20,21,26 The Philadelphia chromosome, characterized by the t(9;22) translocation resulting in production of a BCR-ABL1 fusion gene and protein, is the most common cytogenetic and molecular abnormality in adult ALL. The frequency is age-dependent, being present in approximately 8-10% of adolescents, 15-30% of younger and middle aged adults, and 40-50% of elderly ALL patients. 9 Over two-thirds have the p190 gene, with the remaining harbouring the p190 gene.
Until recently the BCR-ABL1 fusion gene marked the most unfavourable subgroup of adult ALL. With chemotherapy alone the CR rate was 75%-80%, median DFS about 10 months and 5-year survival below 10-20%. 26,31,32 Most studies demonstrated superior outcomes with allogeneic HSCT compared to chemotherapy alone. 26,31,32 Combinations of tyrosine kinase inhibitors (TKIs) with chemotherapy have produced superior outcomes to chemotherapy alone, as will be discussed later.
The t(4;11) is present in up to 60 % of infants younger than 12 months but is uncommon in adult patients, constituting 5-10% of cases. When rearranged, the MLL (now called KMT2A) gene has been found to be associated with inferior RFS and OS in adult patients when using a pediatric protocol. 20 The t(1;19) is uncommon in adults; its prognostic significance is unclear, with conflicting data. Garg et al. noted that adults treated with Hyper CVAD had a significantly better CRD and OS compared with all other patients. 33 However, Foa et al. found that this abnormality is frequently associated with early treatment failure, and recommended that these patients should be considered for intensified treatment strategies. 34 The t(12;21) abnormality leading to ETV6-RUNX1 fusion is detectable in about 25 % of children and 3 % of adults with B-ALL. Patients generally have a favorable prognosis. 35,36 Hyperdiploidy (>50 chromosomes) is seen in approximately 25% -30% of paediatric cases and 7% of adults and represents the most common chromosomal abnormality in children. It is associated with a favourable prognosis regardless of age and leukocyte count at presentation. 37,38 Its characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21, with individual trisomies or tetrasomies being seen in over 75% of cases. The individual structural abnormalities do not appear to influence outcome in patients with hyperdiploidy except for the t(9;22), which is associated with a poor prognosis. 39 The favourable prognosis may reflect an increased propensity of these cells to undergo apoptosis. 17 In contrast, 5 % to 6 % of ALL patients, independent of age, have the loss of various chromosomes, resulting in a hypodiploid clone with fewer than 44 -46 chromosomes. These patients generally have a poor prognosis, especially those with near-haploid and low-hypodiploid clones. 17,36,40 Recent data suggest that complex karyotypes (≥ five chromosomal abnormalities) occur more frequently with increasing age and may be associated with inferior survival. 15,26,41 Intrachromosomal amplification of chromosome 21 (iAMP21) occurs at an incidence up to 2 % in older children with B-cell precursor ALL Harrison, 2005 #1056 and is defined by at least three copies of the RUNX1 gene (Children's Oncology Group, COG, definition for iAMP21). iAMP21 has been shown to be linked to a dismal outcome when patients are treated with standard therapy, because it is associated with an increased risk of both early and late relapses. 36, It is rare in adults.
Many of these prognostic factors may be regimen dependent. Many older studies used adult-based protocol. In contrast, using pediatric based regimens, most of these cytogenetic abnormalities have not been found to be of prognostic importance in adults, with the notable exception of t(4;11).
# Molecular Studies
Molecular genetics has identified several gene mutations, translocations and amplifications that may have prognostic significance in ALL. IKZF1 encodes IKAROS which has been established as one of the most clinically relevant tumor suppressors in ALL. It is a DNA-binding zinc finger transcription factor that regulates the development and function of the immune system and acts as a master regulator of normal hematopoietic differentiation and proliferation, particularly in lymphoid lineage. 48 Deletion of a single IKZF1 allele or mutations of a single copy of IKZF1 were first detected in 15 % of pediatric B-cell ALL and in more than 80 % of Ph+ ALL cases, either de novo Ph+ ALL or chronic myeloid leukemia at progression to lymphoid blast crisis suggesting a critical role in the pathogenesis of Ph+ ALL. The incidence in adults is about 50% in B-cell ALL and about 65% when BCR-ABL positive. Recent data further suggest that together with Ph+ve ALL, mutations in IKZF1 are also a hallmark of 'BCR-ABL1-like ALL. 5 Alteration of the IKAROS gene is associated with increased risk of treatment failure and relapse in both BCR-ABL1-positive and BCR-ABL1-negative disease independent of commonly used risk stratification features such as age, sex, white cell count, and levels of minimal residual disease (MRD). 21,52 PAX5 encodes a transcription factor known as B-cell specific activator protein, that plays a key role in B-cell commitment by activating essential components of the B-cell receptor signaling and repressing the transcription of genes necessary for T-lymphopoiesis. 53 Monoallelic deletion of PAX5 have been observed in about 30 % of children and adults 54,55 and have been demonstrated to not influence treatment outcome. 36,55,56 The CDKN2A/B locus encodes for the INK4-class cyclin dependent kinase inhibitors p15INK4B, p16INK4A and for p14ARF. CDKN2A and CDKN2B deletions have been identified in 29 % and 25 % of BCR-ABL1-positive ALL patients, respectively. 57 The association with prognosis is still controversial. 36,57,58 Four independent groups in late 2009 and early 2010 identified that up to 50 % of BCR-ABL1-like ALL cases have dysregulated expression of CRLF2, the gene encoding the cytokine receptor-like 2 factor. 56, Overall aberrant expression of CRLF2 was found in 12. Mutations of NOTCH1, a transmembrane receptor-encoding gene that regulates normal T-cell development, have been detected in in about 60% of T-ALL. 63 Early studies in paediatric T-ALL showed that NOTCH1 mutations may be associated with a favourable prognosis. 21, Similarly, in adult T-ALL patients, studies have demonstrated a better prognosis for patients with NOTCH1 and/or FBXW7 mutations, 67,69 but this could not be validated in a series of 88 patients treated in the MRC UKALLXII/ECOGE2993 protocol 70 or by the Zhu et al who in fact noted that Chinese adult TALL patients with mutated NOTCH1 had poorer survival compared with those with wild-type NOTCH1. 71 Overall these studies seem to suggest that NOTCH activation is associated with improved early therapeutic response. However, this early benefit translates into improved overall survival only in some series, probably due to differences in therapy. 63 Gene Expression Profiling:
# BCR-ABL like ALL
Mullighan and colleagues identified some patients with Ph-negative ALL which had a gene expression profile almost identical to Ph+ ALL and which were termed Ph-like ALL. 54,56,72 This genesignature has been noted in approximately 15% of pediatric cases, but the frequency is as high as 33% in adults with B-ALL. 73 Genetic alterations of activating kinases or cytokine receptor signaling, incuding ABL, JAK2, CSF1 and EPOR, are commonly observed in addition to overexpression of cytokine receptor-like factor 2 (CRLF2) and frequent deletions of IKZF1. 54,56,72,74 Some studies have found higher levels of MRD after induction therapy, 74,75 increased relapse rates and inferior overall survival. 8 However, reliable testing for this genotype is not routinely available in most laboratories, including in Alberta.
# Early T-cell precursor acute lymphoblastic leukaemia (ETP -ALL)
ETP -ALL accounts for 12% of paediatric T-ALL. It is an aggressive leukaemia characterised by an immature immunophenotype with lack of CD1a and CD8 expression, weak CD5 expression 76 and aberrant expression of myeloid and stem cell markers (CD117, CD34, HLA-DR, CD13, CD33, CD11b, or CD65) on at least 25% of lymphoblasts. 8 The long-term response to therapy is one of the worst among recognized high-risk forms of childhood ALL. 27 In one study, the 10 year OS was 19% compared with 84% in the non-ETP ALL. 27 Similarly inferior outcomes have been reported in adults with ETP-ALL. 77,78 The mutational spectrum in ETP-ALL is similar to myeloid tumours with a high frequency of activating mutations in the cytokine receptor and RAS signaling pathways including NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3, and BRAF, raising the possibility that addition of myeloid-directed therapies might improve the outcome of ETP ALL. 79 Given the poor outcomes with conventional ALL regimens, most ETP-ALL patients are referred for allogeneic HSCT in CR1, where there are data suggesting a survival benefit. 78
Other Factors:
# Pharmacogenetics and pharmacogenomics
Genome-wide analyses have identified specific gene signatures which may be prognostically relevant when associated with drug resistance e.g. polymorphism of genes metabolizing thiopurines, methotrexate, and cytarabine all of which have been associated with variable treatment response and are a mechanisms of drug resistance. 1 Rocha et al noted that the glutathioneS-transferasel1(GSTM1) non-null genotype was associated with a higher risk of recurrence, which was increased further by the thymidylate synthetase (TYMS) 3/3 genotype. Others have observed that hyperdiploid cells accumulate more methotrexate polyglutamates as they possess extra copies of the gene encoding reduced folate carrier, an active transporter of methotrexate. Hareedy et al found significant associations between variants in genes coding for enzymes and transporters related to the 6mercaptopurine pathway and clinical outcomes as well as hematological toxicity (neutropenia, agranulocytosis and leukopenia) in pediatric patients with acute lymphoblastic leukemia. 80 The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. Gregers et al. noted statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL. 81
# iAMP of chromosome 21
Poor prognosis 2% of older children with B-ALL.
# Hyperdiploidy
Favourable prognosis 25-30% of cases; nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21; The favourable prognosis may reflect an increased propensity of these cells to undergo apoptosis.
# Hypodiploidy
Poor prognosis 5-6% of ALL patients; near haploid and lowhypodiploid have the worst prognosis.
# Complex Karyotype
Poor prognosis More than 5 chromosomal abnormalities.
# Molecular Genetics IKZF1 mutations
Poor prognosis Most commonly present in BCR-ABL + ALL or BCR-ABL like ALL.
# Abnormality Clinical Impact Notes PAX5
No effect on treatment outcomes 30% of adults and paediatric patients.
# CDKN2A/B
# Pre-Treatment Risk Stratification
Over the past twenty years there has been continued debate regarding the risk stratification of patients with ALL with different groups using the above clinical, immunophenotype, cytogenetics and molecular tests to variably group patients into those that are standard risk, high risk or very high risk of having a leukemia relapse. As discussed, many of these discrepancies may be related to the type of treatment reigmens used (adult vs pediatric-based), and whether MRD analysis is taken into consideration in risk stratification.
Recent studies have found that, using pediatric-based protocols, most cytogenetic abnormalities are not independent predictors except for certain abnormalities, such as KMT2A-based abnormalities, t(9;22) and possibly hypodiploidy. 21,45 Given the poor prognosis of patients with Ph+ve ALL, the initial risk stratification for all patients should be based on the presence or absence of t(9;22)/BCR-ABL1. Amongst Ph-ve patients the NCCN considers those with hypodiploidy ( 30 for B-cell ALL and >100 for T-cell ALL were important risk factors, 20 MRD has since been demonstrated to be a more important predictor on multivariate analysis (discussed below). However, age remains an important predictor of outcome in nearly all studies, with patients > age 30-35 having worse outcomes than so-called AYA (adolescent and young adult) patients. 20 Recent evidence suggests that molecular profiling, and specifically the detection of a Ph-like genetic signature as discussed, may be the most important pre-treatment predictor of outcome in adults and children with BCR-ABL negative B-ALL. However, detection is time consuming and labour intensive, and is not routinely available at most centres, including in Alberta.
# Recommendations:
All patients should be classified as having B-cell or T-cell ALL based upon immunophenotyping results. Although some of the above noted prognostic factors are beyond the scope of routine clinical laboratories, all patients, should undergo cytogenetic evaluation and, if unsuccessful, FISH for the determination of the most clinically significant abnormalities, in particular BCR-ABL and MLL gene rearrangements. There is no convincing evidence that other cytogenetic abnormalities or cell surface markers add to risk-stratification when using paediatric or paediatric inspired protocols. Given the increasing recognization of minimal residual assessments, all patients should have immunophneotyping performed. This can be used to guide post-induction treatment.
# Post-Treatment Risk Stratification
# Role of MRD Assessments in the Management of Patients with ALL:
Measurable (or minimal) residual disease (MRD) refers to the detection of small amounts of residual disease, undetectable by morphology. Techniques for MRD detection include multiparameter flow cytometry (MPFC) or molecular techniques. For BCR-ABL+ ALL, molecular detection is readily performed by qRT-PCR for BCR-ABL1, and is regarded as the gold standard for MRD detection. For BCR-ABL negative ALL, many European studies have used immunoglobulin gene rearrangements for MRD detection; however, this technique is labour intensive and requires detection of the specific rearrangement for each patient. Consequently, MPFC is widely used for MRD detection due to its ease, and has a sensitivity of 10 -3 -10 -4 ; it is the technique used in Alberta.
Based on the paediatric literature, a number of studies over the past 15 years have explored the role of MRD in adults with ALL. Most of these have suggested that MRD may be the single most important factor predicting clinical outcomes. 9 A number of investigators have described differences in patterns and dynamics of clearance of MRD between adult and childhood ALL as well as between B-and T-cell ALL. Foroni et al. noted that MRD decreased faster in children than in adults particularly in the first 6 months of CR 96 while Parekh et al. noted that MRD clearance was slower with T-ALL. 97 Bruggemann and colleagues measured MRD at 9 different time points ranging from 11 days post-induction up to to 52 weeks post induction. 98 Only a minority of patients had undetectable MRD at day +11 while at 6 weeks approximately 50% had undetectable MRD.
Several groups have explored the prognostic value of MRD in adult ALL patients. Bruggman and colleagues noted that a combination of MRD measurements at day 11, day 24 and 16 weeks could classify patients into those with a low likelihood of ALL relapse (MRD -ve at day 11 and day 24), high likelihood of relapse (MRD + at week 16) or intermediate risk of relapse (all others). 98 Similar findings were noted by Bassan and colleagues who measured MRD at week 10 and week 22 post induction chemotherapy. 46 Regardless of whether they were SR, HR or VHR by traditional criteria, patients who were MRD negative had significantly better DFS relative to those that were MRD positive.
Whether treatment intensification can negate the negative effects of residual disease has also been investigated by several investigators. Bassan and colleagues assessed MRD at week, week 16 and week 22. 46 Patients that were MRD negative or with unknown MRD status but standard risk by traditional criteria received maintenance treatment only while patients that were MRD positive or with unknown MRD but high risk or very high risk by traditional criteria received an allogeneic SCT or autologous blood stem cell harvest/reinfusion with subsequent maintenance therapy. MRD positive patients receiving either SCT or intensive chemotherapy had improvements in DFS with no significant difference between those that received SCT and intensive chemotherapy. Moreover, patients who became MRD negative had improved DFS relative to those who remained MRD positive. Similar results were noted by Gokbuget et al. where 5 year CCR improved for MRD positive patients undergoing an allo SCT. 99 Ribera and colleagues noted that allo SCT in MRD -ve patients was unnecessary and counterproductive as it led to worse DFS and overall survival both in the whole series and an intention to-treat-analysis. 100 Beldjord et al. assessed 423 adult patients with Ph-negative ALL treated with a pediatric protocol. 21 MRD1 was evaluated at 6 weeks after induction initiation and MRD2 after the first consolidation phase i.e. 12 weeks after induction initiation. A study by the GRAALL group, using a pediatric inspired protocol for adults with B-ALL, evaluated the role of allogeneic HSCT according to MRD response with induction therapy. 47 Patient who were MRD positive, defined as a level > 10 -3 following induction therapy, had a significantly higher relapse rate and inferior OS as compared to those who achieved a level 10 -3 who underwent subsequent HSCT in CR1 had a significantly superior RFS and OS as compared to those who were not transplanted. In contrast, those with MRD levels < 10 -3 following induction did not benefit from HSCT. These effects were seen for both B-ALL and T-ALL.
The Edmonton group subsequently analyzed outcomes following DFCI induction therapy. Between 2013-2019 patients with BCR-ABL negative ALL underwent induction therapy with this protocol, and MRD postinduction was assessed by multiparameter flow cytometry, with a sensitivity of 0.1%. Of 46 patients who achieve CR, 26 (57%) were MRD negative and 43% were MRD positive. The cumulative incidence of relapse was 45% in patients who were MRD positive at a level of >0.1%, as compared with 12% in MRD negative patients (p=0.05) (unpublished data). These results essentially mirror those reported by the GRAALL group as described above.
These data further support the conclusion that patients who fail to achieve a 3 log reduction in MRD levels with intensive induction therapy represent a high-risk group for relapse, and that these patients should be considered for HSCT in CR1. In contrast, those who achieve who achieve a >3 log reduction with induction can be successfully managed by chemotherapy alone with a low relapse risk and favourable prognosis. A subsequent German study (Herold et al, 2017) found a strong association between MRD positivity and a Ph-like genotype; Ph like B-ALL patients only achieved a 33% MRD negativity rate, as comparted with 79% for Ph negative and non-Ph-like B-ALL patients (p=0.02) Therefore, MRD may represent a surrogate marker for a more resistant disease biology which is more destined to relapse with conventional chemotherapy.
# Treatment of MRD positive B-ALL:
Blinatumomab is a bispecific tumour-engaging (BiTE) antibody with an anti-CD19 domain that binds to B-cells, including B-ALL cells, and an anti-CD3 domain that engages T lymphocytes to lyse the B cells. A large European study 101 was recently published, evaluating the role of blinatumomab in 116 B-ALL patients in hematologic CR with MRD positivity, defined as a level > 0.1% by qRT-PCR.
Patients were permitted to received up to 4 treatment cycles, and could undergo allogeneic HSCT at any time after the first cycle. Overall, 78% of patients achieved an MRD negative state, with a sensitivity of 10 -4 , after one blinatumomab treatment cycle. Two additional patients achieved this after 2 cycles. Of patient in first CR, 83% achieved MRD negativity. The treatment was well-tolerated.
The median OS of the patients who achieved MRD negativity was 38.9 months, vs. 12.5 months in those who did not achieve MRD negativity (p=0.002); corresponding RFS were 23.6 vs. 5.7 months, respectively (p=0.002). With a median follow-up of 24 months, 49% of patient who underwent subsequent HSCT remained in continuous CR, as compared with 25% who did not undergo HSCT. By comparison, in Edmonton BCR-ABL negative B-ALL patients who were MRD positive at a level > 0.1% by flow cytometry after DFCI induction therapy were treated with intensified chemotherapy, using cycles 1A and 1B of Hyper-CVAD, between 2013-2018. Of 13 patients, only 5 (38%) were able to achieve MRD negativity; treatment was associated with considerable toxicity, including severe myelosuppression and mucositis.
These data indicate that (1) blinatumomab is able to induce a high rate of MRD negativity, usually after one cycle, with good tolerance, (2) patients who achieve MRD negativity have superior outcomes compared with those who do not, (3) patients who subsequently undergo allogeneic HSCT have favourable outcomes as compared with those who do not, and (4) intensified chemotherapy is less effective at inducing MRD negativity but is associated with considerably more toxicity. The use of blinatumomab for MRD positive B-ALL has now been widely incorporated into standard ALL protocols in Europe and North America.
# Recommendations:
Taken together, these data indicate that MRD assessment provides critical prognostic information in adults with ALL. There is convincing evidence in pediatric and adult ALL that a high level of MRD at the end of induction therapy is associated with a higher relapse rate. Furthermore, the persistence of MRD during consolidation and maintenance therapy, or its the re-emergence, all seem to herald relapse. In contrast, negative MRD results are associated with a favorable prognosis. It is therefore recommended that all patients have MRD ascertained at the end of intensive induction therapy, or early during intensification. Patients with persistent MRD at a level > 0.1% should receive further treatment with an intent to achieve MRD negativity; for B-ALL the treatment of choice is blinatumomab, while for T-ALL intensified chemotherapy would be appropriate. Furthermore, these patients should be referred for allogeneic HSCT if suitable candidates, optimally after achieving MRD negativity. In contrast, patient achieving MRD negativity do not appear to benefit from transplant, provided they can successfully complete the subsequent treatment protocol.
# Treatment Approaches in ALL
In general, the treatment of ALL is complex consisting of several different chemotherapy cycles and, for some patients, stem-cell transplantation. 1 A number of different approaches have been used as discussed below.
# Adult Multidrug Regimens:
Starting in the 1960s, researchers at St. Jude Children's Research Hospital designed combination therapies of available anti-leukemia drugs that were delivered in a sequence of extended courses of therapy. 9 Since then several multidrug combinations have been developed centered on a vincristine, prednisone, and anthracycline combination, with or without asparaginase and cyclophosphamide. This concept was modified in children to the Berlin-Frankfurt Munster (BFM) ALL model and later, by Hoelzer et al., to adult ALL. 11,102 Studies using this approach are presented in Table 5. Despite variations in chemotherapy regimens, variable use of allogeneic SCT or auto SCT the 5 year overall survivals ranged from 35 -60% in various subgroups with induction mortality ranging of 5-10%.
The second treatment model pioneered at the M.D. Anderson Cancer Center consists of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and cytarabine (Hyper-CVAD). The regimen consists of a total of eight courses: four courses of hyper-CVAD (courses 1, 3, 5, and 7) alternate with four courses of MTX and HIDAC (courses 2, 4, 6, and 8). 103,104 In the original report the mortality was 6% and the overall CR rate was 91%. The estimated median survival time was 35 months with a 5-year estimated survival of 39%. Younger age was associated with better survival (age 60 estimated 5-year survival rate of 25%). In an updated report of patients aged 15 -92 years old, the CR rate for patients age ≤30 years was 99% and for patients age ≥60 years 80%, mostly because of a higher induction mortality. Kantarjian, 2004 #710. The addition of rituximab was associated with CCR and OS rates of 60% and 58%, respectively. Treatment with Rituximab-hyper-CVAD was associated with improvement in 3-year CRD rates compared with hyper-CVAD (78% vs. 53%). In patients age < 60 improvements in 3-year OS (75% v47%; P 0=.003) rates favoring rituximab were observed. 105 The Pediatric Approach: A third approach was the adoption of pediatric protocols or "pediatric inspired"regimens particularly for adolescents and young adults variably defined as patients 15 to 35-45 years old. 1, 106 These regimens have common features, including significantly increasing the non-myelosuppressive agents such as vincristine and steroids, using much higher cumulative doses of asparaginase for prolonged asparagine depletion, and administering very early and extended intrathecal methotrexate together with high-dose systemic methotrexate. Several studies from Europe and the USA reported that pediatric inspired approaches are feasible in adolescents and adults (Table 6 and 7). These studies have shown that prolonged administration of non-myelosupressive agents such as asparaginase, vinca alkaloids and steroids is feasible and tolerated in a substantial portion of adults. Based on these studies, pediatric based regimens have now been widely accepted as the standard of care for younger adults with ALL.
# CNS Prophylaxis and Treatment:
Because of the high risk (up to 50%) of CNS relapse, CNS prophylaxis is an essential part of any treatment regimen for ALL. Standard approaches include the use of repeated (11)(12) doses of intrathecal (IT) chemotherapy. This has been demonstrated in many studies to reduce the risk of CNS relapse to 10% or less. Although many protocols use triple intrathecal chemotherapy with methotrexate, cytarabine and corticosteroids, a recent pediatric randomized study did not show any difference in CNS relapse rates between this approach and single-agent methotrexate. 112 A baseline LP is required to rule out CSF disease at diagnosis. If positive, the usual approach is to administer intrathecal chemotherapy twice weekly until the CSF has been adequately cleared (as evidenced by 3 consecutive negative results). Although the standard cerebrospinal fluid (CSF) diagnostic approach consists of morphologic analysis of a cytospin preparation, studies have shown that flow cytometry of CSF provides greater sensitivity, 113 and may thus be a more reliable indicator of blast clearance.
Most older treatment protocols incorporated prophylactic cranial radiation; however, this adds significant short-term and potential long-term toxicities. Recent pediatric studies have demonstrated that routine cranial radiation can be safely deleted without adversely impacting CNS relapse rates; 114 this is particularly the case if high-dose intravenous methotrexate, which has good CNS penetration, is used. However, if evidence of fixed leptomeningeal disease is present based on the presence of focal neurologic symptoms and corresponding MRI findings, CNS radiotherapy is indicated as intrathecal chemotherapy alone is usually insufficient.
# Provincial Recommendations for Treatment of ALL
# Adolescents and Young Adults (AYA):
Adolescents and young adults have been variably defined as those aged 15 -35 (40) years old. A multitude of accumulating evidence suggests that this group of patients is best treated with a pediatric or a pediatric inspired protocol. Ram et al. conducted a systematic review of 11 studies that compared adult and pediatric protocols. 115 Overall, all-cause mortality, relapse rates and non-relapse mortality were lower in the pediatric groups whereas CR rates and EFS were higher in the pediatric groups. It is important to note that in many of these studies the median age ranged from 12.9 -31 with only two studies including patients over age 55. The native E. coli asparaginase used in the DFCI 91-01 protocols is no longer available in Canada, and has been replaced by pegylated asparaginase (Pegaspargase). This should be given no more frequently than once every 3 weeks in adults due to its long half-life (see Appendix C and D).
# Patients Aged 35(40)-60:
The use of pediatric protocols for the treatment of adolescents has inspired some groups to explore the use of pediatric protocols in older adults however the data are not clear whether this represents a significant difference relative to adult protocols. When using the paediatric GRAALL-2003 protocol improvemnets in EFS and OS were noted at 42 months but only for patients <age 45. 94 Similarly, Storring and colleagues, when using a modified DFCI paediatric regimen 20
# Recommendations for Patients Aged 35(40)-60:
These data suggest that although results in patients 30-60 years old may be inferior to those in adolescents and young adults a use of a pediatric protocol may benefit these patients with 3-5 year OS improving from an historic 35-40% to 50-70%. The lower OS observed in some studies may be related to the preferential use of allo-SCT in this cohort of patients. Nonetheless, we recommend that patients in this age range continue to be treated with the DFCI protocol (Appendix A-C). However, given the increased toxicities seen in middle-aged adults, some patients, particularly those age 50-60, may require changing to a less toxic regimen such as the modified DFCI protocol for older patients (see below).
# Patients Aged >60:
The outcome of patients above age 60 treated with standard ALL chemotherapy has been generally poor. Larson et al. using the CALGB 8811 protocol noted a 3 year OS of only 17% with a median survival of only 1 month. 82 Brandwein et al. noted similar results when using a multitude of different adult based chemotherapy regimens. 116 In their study the 3 year OS was only 18.4%. Using the HyperCVAD protocol Kantarjian et al. noted a 5 year OS of 17%. 12 Thus, it appears that the majority of older patients with ALL will succumb to their disease although some older patients may remain long-term survivors.
Whether a paediatric inspired regimen might benefit this older subset of patients was investigated by Martell et al. who evaluated the outcomes of 51 patients treated with a modified DFCI paediatric regimen at the PMH (Appendix B). 109 Modifications from the full-dose DFCI 91-01 protocol during induction included the substitution of dexamethasone for two 4-d pulses instead of daily prednisone, reduction of the methotrexate dose from 4 g/m2 to 40 mg/m2, reduction in the asparaginase dose from 25 000 to 12 000 iu/m 2 and removal of one vincristine dose. In the CNS prophylaxis phase cranial radiation was removed. In the intensification phase seven cycles were given instead of 10, the dexamethasone dose was reduced to 6 mg PO BID and the asparaginase reduced to 6000 iu/m 2 from 12500 iu/m 2 . In the maintenance phase parenteral methotrexate was switched to oral, and the dexamethasone dose was again reduced from 6 mg/m 2 BID to 6 mg PO BID. For patients who developed progressive grade ≥2 neuropathy, intravenous vinblastine 10 mg was substituted for vincristine. Median age was 65 (60 -79), 12 patients were over the age of 70, 35 patients were BCR-ABL negative and 16 were BCR -ABL positive. CR rate was 75% for the entire cohort with 20% induction mortality. Interestingly CR rate was 81% in BCR -ABL positive patients and 71% in BCR -ABL1 negative patients. The estimated 5-year OS was 40.5% for the BCR-ABL1 negative patients, and 47.3% for the BCR-ABL1+ patients but there was no significant difference in OS between these two groups. The estimated 5-year OS for BCR-ABL1 negative patients presenting with low WBC (defined as <30 x 10 9 /L for B-ALL or <100 x 10 9 /L for T-ALL) was 44.3% respectively.
# Recommendations for Patients Aged >60:
Given that some medically fit patients above age 60 may be cured of ALL we recommend that eligible patients over age 60 be treated with curative intent therapy. Although, there are no randomized studies, based upon data from the PMH group, the modified DFCI provided superior results relative to historical controls. We therefore recommend that the modified DFCI protocol be used for older ALL patients (Appendix C). A more recent report from the Spanish PETHEMA group also showed reasonably good activity with their protocols, although relapse rates remained high. 117 Patients over age 75, or those age 60-75 with major co-morbidities precluding intensive chemotherapy, should be considered for palliative chemotherapy with corticosteroids and vincristine +/-low-dose asparaginase. Such patients should continue to receive central nervous system prophylaxis and may benefit from incorporation of a CNS phase. Patients not tolerating DFCI-type intensification, or judged to be unfit for such treatment, may be moved directly to the DFCI maintenance phase.
# Philadelphia Chromosome or BCR-ABL Positive ALL:
Tyrosine kinase inhibitors (TKI's) have become the standard of care for Ph+/BCR-ABL+ ALL and have led to improvements in the outcomes for all age groups. 1 The earliest TKI used in ALL was imatinib. Although, different chemotherapy regimens and schedules of imatinib have been assessed, all showed improvements in overall survival and reduction in the relapse rate. In the first large study done by the French GRAAPH-2003 group, the combination of imatinib with induction and postremission therapy 121 led to higher estimated OS (65% vs. 39%), lower CIR (30% vs. 49%) and improved DFS (51% vs. 31%) at 18 months in comparison to historical controls treated with the LALA-94 protocol. An Italian study also reported 5-year OS of 38% and DFS of 39% with imatinib combined with chemotherapy and again these results were significantly superior to a historical cohort receiving chemotherapy alone. 122 In the large UKALL/ECOG2993 trial investigators reported an improved post-induction CR rate with imatinib, improved 4 year OS, EFS and a considerable reduction in relapse risk in the imatinib cohort. 123 Lastly, The M.D. Anderson group also combined imatinib with their standard hyper-CVAD protocol and reported CR rates of 93% as well as results that were substantially superior to their retrospective results with chemotherapy. 124 Second and third generation TKI's have also been assessed in Ph+ ALL. Kim et al evaluated the outcomes of Nilotinib with multiagent chemotherapy for adult patients with newly diagnosed Ph+ve ALL. After achieving CR, subjects received either 5 courses of consolidation, followed by 2year maintenance with nilotinib, or allo-HCT. Amongst the 90 evaluable subjects the CR rate was 91%, the 2-year RFS was 72% and the 2-year OS was 72%. Unlike nilotinib, dasatinib has the ability to peneterate the CNS. Single agent dasatinib is associated with short-term cytogenetic remission and median relapse free survivals of only 3.3 months. Studies of dasatinib in combination with chemotherapy, however, have been associated with excellent response rates approaching 100% with minimal toxicity. 72,125 Ponatinib was evaluated in Ph+/BCR-Abl+ by Jabbour and colleagues for patients up to age 60 with previously untreated Ph +ve ALL. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously each subsequent cycle of hyper-CVAD. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The 2-year EFS rate was 81% (95% CI for the 37 patients enrolled in the study. 128 Several investigators have combined TKI's with paediatric based regimens used for the treatment of adult patients. Thyagu et al. evaluated the outcomes of 32 ALL patients age 18-60 with Philadelphia positive ALL treated between 2001 and December 2008 with imatinib. Ninety-four percent of patients (94%) achieved a CR and, of the 28 patients proceeding to intensification therapy, 16 received a HSCT. The 3-year OS was 56% in the transplanted group vs. 50% in the non-transplanted group. 129 They also noted increased rates of peripheral neuropathy, ileus, myopathies, deconditioning, infections and abnormal liver enzymes in a high proportion of patients. Therefore, a number of modifications were made to the original DFCI protocol. 129 Using an unmodified DFCI protocol, Deangelo et al. reported similar results amongst 18 Ph +ve patients treated with imatinib, 11 of whom went on to transplant. The 4 year DFS was 54% and 4 year OS was 53%. 95 Martell et al. also treated 16 BCR-ABL positive patients aged 62 -75 with a modified DFCI protocol together with imatinib. The CR rate was 81% with an induction mortality of 19% and the estimated 5-year OS was 47.3% for the BCR-ABL1+ patients. 109 Monotherapy with TKI has been explored in several studies particularly in elderly patients, who had an extremely poor outcome with chemotherapy alone. Ottmann et al evaluated imatinib monotherapy in 27 patients older than 55 years of age, and observed CR in 26 patients and a partial remission in the remaining patient. 130 Vignetti et al. treated patients aged 61 to 83 years with Ph-+ ALL with a 45day induction of imatinib 800 mg daily plus prednisone (40 mg/m 2 daily). Post-remission therapy was not specified. All 29 assessable patients (100%) experienced a CR. At 12 months, the OS and DFS probabilities were 74% and 48%, respectively. 131 The French GRAALL group conducted a large randomised controlled trial comparing a reduced intensity induction with imatinib, vincristine and dexamethasone (Arm A) to standard imatinib/hyper-CVAD A part (Arm B) in 268 adults with Ph+ve ALL up to age 60; both arms then received a second cycle with Hyper-CVAD B part. 132 The CR rate was higher in arm A than in arm B (98% vs 91%), mainly related to a lower induction death rate in Arm A, whereas the MMolR rate was similar in both arms (66% vs 64%). The OS was superior in the patients that subsequently proceeded to allogeneic HSCT; however, on subgroup analysis, patients who had achieved MRD negativity (defined as a >4 log reduction in BCR-ABL transcripts by PCR) by the end of the second induction cycle had a similar RFS with or without allogeneic HSCT. In contract patients who were MRD positive at that timepoint had a significantly better RFS with allogeneic HSCT, compared to those who were not transplanted. Therefore, MRD assessment with this regimen could be used to help identify a high-risk cohort for whom HSCT was beneficial.
Foa et al. evaluated a similar regimen consisting of dasatinib (70 mg twice daily for 84 days) together with prednisone 60 mg/m 2 daily for 32 days plus two doses of intrathecal methotrexate in untreated patients with Ph +ve ALL. 125 Post remission therapy was not defined with two patients receiving no further therapy, 19 continuing on TKI only (16 dasatinib, 2 imatinib and 1 imatinib-dasatinib), 10 receiving intensive chemotherapy with TKI, 4 having an auograft and 18 receiving an allogeneic HSCT. Overall, 53 patients aged 24 -76 were treated. A CR rate of 100% was seen with 92.5% by day 22 and no deaths occurred during induction. Of the patients that had MRD measured by PCR 10 achieved levels lower than 10 -3 and 8 had a complete molecular remission. Twenty-three patients relapsed after completing induction with 12/17 relapsing patients showing a T315I mutation. This trial demonstrated impressive remission rates for dasatinib and steroids only but at the same time underscored the importance of adding intensive chemotherapy and/or HSCT to maintain durable remissions.
More recent studies suggest that the treatment landscape is changing. The MD Anderson group evaluated the use of ponatinib + Hyper-CVAD chemotherapy in fit patients with BCR-ABL+ ALL. 133 The 3-year EFS of 69% and OS of 84%, without transplant, were significantly superior to a historical group that had received dasatinib + Hyper-CVAD. These results suggest that using ponatinib with intensive chemotherapy upfront may potentially circumvent the need for transplant in CR1 for most patients. More recently the Italian GIMEMA group reported on a chemo-free regimen using dasatinib + blinatumomab. 134 The CR rate was 98%, with 70-80% eventually achieving a complete molecular response; at a median follow-up of 18 months, the OS was 95% and DFS 88%. The MD Anderson group is currently using a combination of ponatinib + blinatumomab for 4 cycles, followed by ponatinib maintenance therapy, as their standard frontline regimen; the CR rate was 100% and 86% achieved a complete molecular response 154 . While very promising, follow-up is brief, and these treatments are not currently approved as upfront therapy for BCR-ABL+ ALL.
# Recommendations Philadelphia Chromosome or BCR-ABL Positive ALL:
All patients with Ph+/BCR-ABL+ve ALL should receive a TKI combined with chemotherapy. No randomized studies are available comparing different TKI's in adults; therefore, a firm recommendation regarding the choice of TKI upfront cannot be made. Currently, only imatinib (600-800 mg daily) is approved as first line therapy. Patients intolerant to imatinib should be switched to another TKI such as dasatinib; dasatinib may also be preferred for patients with CNS disease due to its excellent CNS penetration. Patients with documented T315I BCR-ABL mutations, or those refractory to or progressing on, a 2 nd generation TKI, should be treated with ponatinib.
Fit BCR-ABL+ve ALL patients should be treated with a TKI combined with induction and postremission chemotherapy. Given recent studies showing higher remission rates and decreased mortality using corticosteroids, TKI + vincristine during induction, this combination is recommenedd as initial induction therapy (see Appendix F); however, such patients require additional intensive chemotherapy +/-HSCT to maintain a durable remission.
Given data suggesting increased toxicity of asparaginase and vincristine with TKI, asparaginase should be deleted, and vinblastine substituted for vincristine, in the post-remission phases.
Patients above age 65, particularly, those with major co-morbidities, poor performance status or ineligible for SCT should be treated with steroid and TKI +/-vincristine or vinblastine. Post induction therapy should be individualized based upon patient tolerance. Patients not transplanted should continue TKI indefinitely.
BCR-ABL monitoring by quantitative RT-PCR should be performed in all patients, post-induction and then every 3 months. Patients with inadequate response or loss of response should be switched to a second or third generation TKI as indicated and, depending on circumstances, may require switching from chemotherapy to blinatumomab.
# Role of Allogeneic Stem Cell Transplantation
# Ph-/BCR-ABL-ALL:
In the largest adult ALL trial to date (MRC-ECOG UKALLXII/E2993) patients in first complete remission 35, WBC >30,000/ mL for B-lineage or WBC >100,000/mL for T-ALL, Philadelphia chromosome positivity, t(4;11), t(8;14), complex karyotype, low hypodiploidy or triploidy. All other patients were considered standard risk. In a donor versus no-donor analysis, patients with a sibling donor had improved OS than those with no donor (53% vs. 45%). In the standard risk group, the OS at 5 years was 62% for patients with a donor compared to 52% for patients with no donor (P=.02). In contrast, for high-risk patients OS was 41% for those with a donor vs. 35% for those without a donor (p=0.2) likely due to the high non-relapse mortality. The 10 year relapse rate was substantially lower in patients with a donor (24% for standard risk and 37% for high-risk) versus those without a donor (49% standard risk and 37% high-risk). 19 The Spanish PETHEMA group reported similar findings in their cohort of high-risk patients defined as those with age 30-50 years old, WBC count >25,000/ mL, Ph +ve, t(4;11)/other 11q23 rearrangements, or t(1;19). 87 In contrast, two French studies both reported that there was an advantage for high-risk patients having a donor. 86,135 A meta-analysis of 7 studies that included 1274 patients also noted improvements in overall survival for patients with donors relative to those in the no-donor groups undergoing allogeneic stem-cell transplantation. When only high-risk patients were analyzed, the survival advantage was greater. 136 More recently, Gupta et al. conducted a meta-analysis using individual patient data from a total of 20 trials that included a donor no-donor comparison. Overall survival at 5 years was significantly better in the donor arm (49.9% vs 42.7%, p=.003). However, because TRM was much higher in those age >35 both in the donor and no-donor arms there was no difference in OS in this age group. Interestingly, unlike in previous studies and using standardized definitions of high/standard risk, there was no evidence that survival differed by risk category. It was therefore concluded that patients age35.
Despite the above data, it remains unclear whether adult patients treated with paediatric protocols would gain a benefit from SCT. In their study of a 156 BCR-ABL -ve patients treated with the DFCI protocol the 5 year OS amongst patients receiving an allogeneic SCT was 44% while for those not undergoing a SCT the survival was 74% with the difference possibly related to transplant related mortality. Seftel and colleagues compared 422 Ph-ve ALL patients aged 18-50 years with 108 patients receiving DFCI chemotherapy 155 . Expectedly, treatment related mortality was higher in those receiving a SCT (37% vs. 6%). At 4 years, the incidence of relapse was similar for those receiving SCT and chemotherapy (24% vs. 23%), however, both DFS and OS were improved for those receiving chemotherapy alone (40% vs. 71% for DFS and 45% vs. 73% for OS). Dhedin and colleagues further assessed the the role of allogeneic stem cell transplantation in Ph-ve ALL adult patients with at least 1 conventional high-risk factor treated with the paediatric inspired GRAALL 2003 and 2005 protocols. 47 In all, 522 patients age 15 to 55 years old were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission while 240 (46%) did not. As with previous studies, the lower CIR observed in the SCT was counterbalanced by a higher NRM. When analyzing SCT in CR1 as a time-dependent event RFS and OS were not significantly improved in the SCT cohort. No significant effect of SCT on RFS was noted in patients younger or older than age 45 or on any prespecified baseline risk factor. RFS and OS were significantly longer, however, in patients who presented with morphologic poor early BM blast clearance or in late CR patients. Furthermore, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) >10 -3 but not in good MRD responders.
For pediatric-based protocols, asparaginase is a critical agent in achieving the high cure rates reported. There is evidence in both pediatric and adult studies with the DFCI protocol that the inability to deliver the intended asparabinase dosing during intensification (defined as >80%) is associated with a higher relapse rate. 20,137 Therefore, the inability to deliver effective asparaginase dosing (e.g. due to pancreatitis) places the patients in a higher risk category and warrants consideration of allogeneic HSCT.
# Recommendations for Ph-/BCR-ABL-ALL:
These data suggest that patients with Ph-/BCR-ABL -ve ALL treated with a paediatric protocol who attain an MRD negative complete remission are at low risk of subsequent relapse and will not benefit from an allogeneic SCT. It is therefore recommended that such patients not proceed with allogeneic SCT, unless they are unable to complete the protocol. Given that patients with MLL (KMT2A) rearrangements remain a high-risk group with pediatric based regimens, SCT may be a reasonable recommendation for younger ALL patients with this abnormality. Failure to achieve a complete hematologic remission after the first induction cycle is also generally considered a high risk features; transplantation is also recommended for these patients. Although high presenting WBC has been identified in the past as a high-risk feature, its prognostic value is superceded by MRD based on data from GRAALL. Failure to deliver effective asparaginase dosing during intensification should also warrant consideration of allogeneic SCT.
Patients who are MRD +ve at >10 -3 (or >0.1%) after induction therapy, or >10 -4 (<0.01%) at 16-18 weeks, are at higher risk of relapse and may benefit from transplant. Such patients should be considered for allogeneic HSCT, optimally after receiving further cytoreduction to attain an MRD negative state prior to transplant.
# Role of SCT in Patients with Ph/BCR-ABL Positive ALL:
The UKALLXII/ECOG 2993 study evaluated the outcome of allo-SCT in Ph+/BCR-ABL+ patients younger than 55 years of age achieving complete remission with an adult ALL protocol. Of the 267 patients, 76 (28%) proceeded to alloHSCT in first CR (45 with cells from a sibling and 31 with cells from a MUD) whereas 86 received chemotherapy alone. The median EFS for all 267 Ph+ patients was 9 months and the median OS was 13 months. At 10 years, OS was 39% for sib alloHSCT, 31% for MUD alloHSCT, and 13% for chemotherapy. Comparing the outcome after any alloHSCT with the outcome after chemotherapy alone, OS, EFS, and RFS were all significantly superior for patients receiving any alloHSCT over those receiving chemotherapy alone. Whereas the leading cause of death in chemotherapy treated patients was relapse, the leading cause of death after transplantation was TRM, which was 27% after sib HSCT and 39% after MUD HSCT. 31 Limited information is available comparing adult Ph+ patients receiving a paediatric protocol with those undergoing an allo SCT. Thyagu et al. treated 32 patients with Ph+ ALL with DFCI protocol together with imatinib. Of the 28 patients proceeding to intensification therapy, 16 underwent an allo-SCT. The 3 year OS was 56% in the transplanted group and 50% in the non-transplanted group. 129 Recent studies in the pediatric setting noted that children receiving intensive multidrug chemotherapy with imatinib had a survival higher than 80% compared to 35% in historical controls, and even better than related or unrelated HSCT (>60%). In the recent US Children's' Oncology Group study, the outcomes at 3 years were not significantly different for those treated with chemotherapy plus imatinib compared with those assigned to alloHSCT. 138 However, limited patient numbers precluded rigorous subgroup analysis.
Recent studies in adults are also demonstrating the impact of molecular status on relapse risk in Ph+ ALL. The MD Anderson Cancer Center 139 found that molecular positivity at a variety of time points was associated with a significantly higher cumulative incidence of relapse. The French GRAAPH study 132 found that the benefit of alloHCT in CR1 was restricted to patients who were molecularly positive post-induction chemotherapy. On subgroup analysis, patients who had achieved MRD negativity (defined as a >4 log reduction in BCR-ABL transcripts by PCR) by the end of the second induction cycle had a similar RFS with or withour allogeneic HSCT. In contract patients who were MRD positive at that timepoint had a significantly better RFS with allogeneic HSCT, compared to those who were not transplanted. Therefore, MRD assessment with this regimen could be used to help identify a high risk cohort for which HSCT was clearly indicated.
In contrast, a study using nilotinib plus chemotherapy 140 found that overall survival was superior in patients undergoing HSCT regardless of MRD status; however, 60% of patients achieving molecular negativity remained free of relapse at 30 months without a transplant. Taken together, these data suggest that some patients who achieve MRD negativity early on may remain relapse-free with continuing chemotherapy + TKI, potentially sparing them the toxicity associated with transplant.
# Recommendations for the Role of SCT in Patients with Ph/BCR-ABL Positive ALL:
Although allogeneic HSCT remains the standard post-remission approach for many patients with BCR-ABL positive ALL, patients who achieve early MRD negativity by PCR (e.g. after induction with the Chalandon protocol) may be continued on post-induction chemotherapy + TKI without a transplant; these patients should continue with indefinite TKI and regular PCR monitoring. However, all patients with persistent molecular positivity should be referred for allogeneic HSCT if otherwise eligible. Consideration should be given to switching to a more potent TKI such as dasatinib or ponatinib in these MRD+ patients prior to transplant. Furthermore, patients with subsequent recurrence of MRD detectable disease by PCR should also be referred for transplant.
# Role of Cranial Radiation
CNS involvement at the time of presentation is uncommon in adults with ALL being reported in 5% to 7% of patients. 141 Before the use of central nervous system (CNS) prophylaxis, the CNS was the most frequently reported site of initial recurrence in children with ALL, accounting for up to 75% of cases. 141 Similarly, amongst adults with ALL, CNS recurrence occurs in approximately 30% of those in a hematological remission. 1 Aur et al. published the results of St. Jude Total Study V in 1971 demonstrating that 2,400 cGy cranial radiation and five doses of intrathecal methotrexate greatly diminished CNS relapse resulting in the first cures of childhood ALL. 142 Subsequently, widespread incorporation of CNS prophylaxis led to the largest single "step up" in 10-year survival from approximately 20% to 60% among those diagnosed from 1970 to 1972 versus 1972 to 1975. 142 Given the significant risk of CNS relapse current adult and pediatric protocols incorporate CNS prophylaxis with both systemic and intrathecal chemotherapy and/or radiation.
Cranial irradiation is an effective form of CNS-directed treatment, but its effectiveness is offset by substantial rates of secondary neoplasms, endocrinopathies, growth impairment, neurocognitive dysfunction, and neurotoxic effects. Amongst the pediatric population, Pui et al. found that prior cranial radiation was associated with a 20.9% cumulative risk of second neoplasms at 20 years in addition to a higher mortality and a greater likelihood of being unemployed when compared to an age matched general population. 142 Subsequently, multiple trials compared CNS prophylaxis using intrathecal chemotherapy and/or intravenous methotrexate with cranial radiation. These trials demonstrated the efficacy of IT/IV therapy without cranial radiation leading to use of cranial irradiation for patients at especially high risk of CNS relapse and elimination of cranial radiation for infants or very young children, irrespective of their presenting features Jeha, 2009 #199. More recently, in the St Jude Total XV and Dutch Childhood Oncology Group acute lymphoblastic leukaemia-9 protocols cranial irradiation is replaced by triple intrathecal chemotherapy with methotrexate, hydrocortisone, and cytarabine for all newly diagnosed patients. The 5 year cumulative risk of isolated CNS relapse was 27% with the St Jude and 26% with the Dutch Childhood Oncology Group protocol similar to the relapse rates observed with prophylactic cranial irradiation (15-45%). In the largest study to date Vora and colleagues 143 obtained data on 16623 patients aged 1 to 18 years old treated between 1996 and 2007 by 10 cooperative groups. In their analysis cranial radiation was associated with a reduced risk of relapse but only in patients with overt CNS disease at time of presentation. In other patients there was no difference in CNS relapse between those that received and did not receive cranial radiation. These data suggest that, in the context of a pediatric protocol prophylactic cranial irradiation can be safely omitted in patients in the context of effective intrathecal and systemic chemotherapy.
# Recommendations for the Role of Cranial Radiation:
Given the above data we recommend that cranial irradiation not be used for CNS prophylaxis in patients receiving a pediatric protocol such as the DFCI if intrathecal or systemic chemotherapy is used, unless there is evidence of fixed intracranial disease at presentation on MRI.
# Supportive Care
Supportive care remains an important aspect of the care of the ALL patient throughtout all phases of treatment. All patients should be transfused packed red blood cells as per institutional guidelines and particularly for symptomatic anemia. Similarly, platelets should be transfused to maintain platelet counts > 10 x 10 9 /L. All patients receive prophylaxis, and if indicated, treatment for tumour lysis syndrome with allopurinol and/or rasburicase during induction therapy. Disseminated intravascular coagulation should be treated aggressively with clotting factor replacement. Patients with signs and symptomns of febrile neutropenia should be managed with broad spectrum antibiotics and intensive care support as necessary. As corticosteroids may mask fevers in such patients, broad spectrum antibiotics should be instituted for clinical suspicion of sepsis (e.g. unexplained hypotension) even in the absence of fever. Antifungal prophylaxis against Candida is recommended during induction due to the risk of Candida septicemia.
Clinicians should be continuously aware of both the short-and long-term consequences of potential toxicities associated with specific agents used in ALL and use prevention, treatment or dose adjustment as necessary:
# Treatment of Relapsed ALL
Adult ALL patients experiencing hematologic relapse have a poor prognosis with conventional chemotherapy salvage regimens. CR2 rates have been in the 30-50% range. Second remissions are invariably brief unless followed by allogeneic HSCT, and OS is in the 10-20% range. 147,148 Recent studies have demonstrated the superiority of antibody-based therapies for relapsed patients with B-ALL. Blinatumomab, a BiTE antibody construct described earlier (see MRD Section) ,was evaluated in the Phase III randomized TOWER trial 156 . Adult B-ALL patients with relapsed (CR1 CR2) or refractory disease were randomized to receive either blinatumomab for 2 cycles, followed by up to 3 consolidation cycles, or conventional salvage chemotherapy. The CR rate was higher with blinatumomab (44% vs. 25%, p=0.001), and OS was significantly longer in the blinatumomab arm (7.7 months vs. 4 months, p=0.01). Responses in the blinatumomab arm were influenced by tumour burden: The CR rate was 65% in those with 50% BM blasts; nevertheless, CR rates were higher in both subgroups as compared with the chemotherapy arm. Although this study only included patients with BCR-ABL negative ALL, a subsequent study demonstrated a 36% CR rate in patients with relapsed/refractory BCR-ABL+ B-ALL, all of whom had failed second or later generation TKI's. 149 Inotuzumab ozogamicin is an anti-CD22 antibody conjugated to the toxin calicheamycin. The immunoconjugate is internalized into CD22+ B-cells, followed by release of the calicheamicin, which induces DNA strand breaks. The INO-VATE trial was a Phase III randomized study in patients with relapsed/refractory CD22+ B-ALL. 150 Patients were randomized to receive inotuzumab or conventional salvage chemotherapy. The CR rate was significantly higher in the inotuzumab arm (81% vs. 29%, p50% BM blasts). Notably, this study included patients with BCR-ABL+ ALL, where a 79% CR rate was reported.
In addition to being more effective, both antibody drugs were well tolerated. The major toxicities of blinatumomab included cytokine release syndrome and neurologic toxicity, both of which were usually grade 1-2 and treated successfully with corticosteroids. The major toxicities of inotuzumab were nausea, febrile neutropenia and veno-occlusive disease (VOD/SOS) of the liver. The latter was a particular issue in patients who received >3 cycles and in those who subsequently proceeded to allogeneic HSCT using a duel alkyator conditioning regimen.
For patients with relapsed/refractory T-ALL, there are currently no available antibody-based therapies outside of clinical trials. Conventional salvage chemotherapy, using a non-cross resistant regimen (e.g. Hyper-CVAD), may be used, or nelarabine. The latter is a prodrug of ara-G which is converted to ara-GTP, after which it is then incorporated into DNA, resulting in cytotoxicity. It has demonstrated single agent activity in relapsed/refractory T-ALL, with a 31% CR rate and 41% ORR. 151 However, responses are not durable, and require subsequent allogeneic HSCT if treated with creative intent. Major toxicities of nelarabine include myelosuppression and neurotoxicity. Neurotoxic effects may be either central or peripheral, and may be severe and irreversible.
# Recommendations for Relapsed ALL:
Based on the two pivotal TOWER and INO-VATE trials, patients with relapsed or refractory BCR-ABL negative B-ALL should be treated with either blinatumomab or inotuzumab as salvage therapy.
Although there are no clear recommendations with respect to the choice of agent, inotuzumab would generally be preferred in patients with higher disease burdens (> 50% BM blasts), based on higher responses rates in this group. In patients with lower disease burden, blinatumomab with be preferred for patients who are intended to proceed to subsequent allogeneic HSCT, due to the risk of VOD/SOS with inotuzumab.
For patient who receive inotuzumab with an intention to proceed to HSCT, patients should optimally not receive more than 2 cycles, and dual alkylator HSCT conditioning regimens should subsequently be avoided. Inotuzumab may also be preferred in patients who are intended to proceed to subsequent CAR-T therapy using an anti-CD19 construct (see below), in order to minimize the risk of preselection of a CD19 negative subclone. However, conventional chemotherapy or blinatumomab may be preferred in patients who are at risk of VOD/SOS (patients who are early post-HSCT or have pre-existing liver issues).
Patients with relapsed BCR-ABL positive B-ALL on imatinib may be reinduced with a second generation TKI such as dasatinib + chemotherapy. Mutational analysis should be performed at relapse and, if a T315I mutation is detected, ponatinib should be used. Those failing a second generation TKI, should be treated with either inotuzumab or blinatumomab, optimally combined with ponatinib.
Patients with relapsed/refractory T-ALL should receive either salvage chemotherapy with a non-cross resistant regimen (e.g. Hyper-CVAD) or nelarabine.
Regardless of salvage therapy, subsequent relapse is inevitable unless the patient proceeds to allogeneic HSCT or CAR T-cell therapy (see below).
# CAR T-Cell Therapy
Chimeric antigen receptor (CAR) T-cell therapy is a treatment in which T lymphocytes are removed from a patient via apheresis, transfected ex vivo with a gene rendering them immunogenic against certain cancer cells, grown and subsequently reinfused into the patient. The activated T-cells then circulate, attack and kill the cancer cells. This treatment has demonstrated considerable activity in patients with relapsed and refractory B-ALL.
Most studies to date have utilized anti-CD19 CAR T-cells. Tisagenlecleusel is the first such therapy to be approved in children and young adults up to age 25 with relapsed/refractory B-ALL. Complete remission rates of 81% were reported, 152 with a one-year event-free survival (EFS) of 50%, in a cohort of multiple relapsed patients, many of whom had previously received allogeneic HSCT.
Another study of 53 multiply relapsed and refractory B-ALL patients, including many older patients age 30-70 years, from Memorial Sloan Kettering Cancer Center (MSKCC) using a similar anti-CD19 CAR T-cell product, demonstrated an 83% CR rate, a median EFS of 6.1 months and OS of 12.9 months (Park et al, 2021). In this study, patients with a low disease burden (defined as 5% BM blasts at time of infusion. The ZUMA-3 study, using a different anti-CD19 CAR T-cell product, reported a CR rate of 83% and a median remission duration of 17.6 months (Shah et al, 2021).
CAR T-cell therapy is associated with significant early toxicities, including cytokine release syndrome (CRS), sometimes requiring ICU support +/-tocilizumab, and neurotoxicity; patients therefore require close monitoring in the first two weeks. The MSKCC group 153 and others have reported that the severity of these toxicities is greater in patients with higher tumour burden at the time of CAR-T infusion.
CAR T-cell therapy has become available in Alberta as of 2021, in both Edmonton and Calgary, using both commercial and local investigational products. It is currently being used for patients who have failed at least two different treatment regimens; however, the field is rapidly evolving, and it is likely that it will be evaluated at earlier stages of disease. As some patients relapse with CD19-negative disease, other studies are investigating the use of dual anti-CD19/CD22 CAR-T products.
Potential candidates for this treatment should be referred early for apheresis, prior to administering salvage immunosuppressive chemotherapy, so as not to negatively interfere with the quality of the apheresis product. Most patients will the need some bridging cytoreductive therapy. The latter has a dual purpose: (1) to prevent clinical deterioration while the CAR T product is being prepared, and (2) to reduce the disease burden, potentially reducing the toxicity of the procedure and the risk of subsequent relapse. Optimal cytoreductive strategies are unclear; depending on the patient, it may include non-intensive chemotherapy, inotuzumab or blinatumomab. The latter, although less toxic than other treatments, could potentially increase the risk of emergence of a CD19 negative subclone, so most experts recommend avoiding this if possible. Inotuzumab should be avoided in patients at higher risk of VOD/SOS, including those who are early post-HSCT or who have pre-existing liver disease.
# Recommendations for CAR-T:
CAR T-cell therapy is indicated for fit patients with B-ALL who have relapsed after allogeneic HSCT, are not otherwise candidates for HSCT, or who have refractory disease. Early referral to the centre's Cellular Therapy Program is recommended. Patient should not receive salvage T-cell depleting immunosuppressive therapies such as corticosteroids or cyclophosphamide until after apheresis, so as not to impair the quality of the collection. Following apheresis, bridging/cytoreductive therapy should be given, particularly for high tumour burden or rapidly progressive disease, with an aim to control disease-related complications and reduce the overall tumour burden, while avoiding excessive treatment-related toxicities.
# Future directions
The treatment landscape of ALL has undergone major changes in the past 5 years, and it is likely that further changes will occur as new information becomes available.
A number of multicenter randomized clinical trials have been evaluating the role of blinatumomab and inotuzumab, in combination with standard frontline chemotherapy regimens, in both younger and older patients with B-ALL. Results from these trials should be available in the next 2-3 years and, if positive, may move these agents into frontline treatment protocols.
For BCR-ABL positive ALL, the combination of ponatinib with Hyper-CVAD chemotherapy has shown very favourable results, without transplant, compared with historical cohorts who had received first of second generation TKI's. 133 More intriguingly, chemo-free protocols, using blinatumomab combined with either dasatinib or ponatinib, have shown very encouraging results in early studies. 134,154 If successful, these may fundamentally change how these patients are treated in the future, and may render transplants unnecessary.
As described above, CAR-T cell therapy has shown considerable activity in multiply relapsed and refractory B-ALL. Dual CAR-T constructs, targeting both CD19 and CD22, are in clinical trials, and offer the promise of lowering relapse rates. Moreover, CAR-T therapies will be evaluated in earlier stages of the disease, after first relapse and, eventually, in first CR for high-risk patients with MRD positive disease. This may, if successful, potentially replace the need for allogeneic HSCT for many patients, thereby eliminating the problems associated with GVHD.
Appendix A: Original DFCI Protocol 91-01 (Used for pediatric patients) 92 Phase of Therapy Time Period Chemotherapy Induction 28 Days Vincristine 1.5 mg/m2/dose IV, maximum 2 mg, days 3, 10, 17, 24; prednisone 40 mg/m2/d IV/PO for 28 days; doxorubicin 30 g/m2/dose IV, days 1 and 2 methotrexate 4 g/m2 IV for one dose on day 3 IT cytarabine, dosed by age, one dose on day 0 IT cytarabine, dosed by age, one dose on day 17 CNS Therapy 3 Weeks SR girls: IT methotrexate/cytarabine for 4 doses during 2 weeks, then every 18 weeks SR boys and all HR patients: cranial XRT 18 Gy, randomly assigned to hyperfractionated (0.9 Gy bid) or conventional (1.8 Gy daily) with IT methotrexate/cytarabine for 4 doses during 2 weeks Intensification Every 3 weeks for 30 weeks SR: vincristine (2 mg/m2 IV every 3 weeks, maximum 2 mg); dexamethasone 6 mg/m2/d PO for 5 days; methotrexate 30 mg/m2 IV or IM every week; mercaptopurine,randomly assigned to high-dose 1,000 mg/m2 IV for 20 hours, weeks 1 and 2) or conventional 50
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Hematology Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, hematologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Hematology Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2016.
# Levels of Evidence | # Background
Acute Lymphoblastic Leukemia (ALL) is a highly aggressive hematological -malignancy resulting from the proliferation and expansion of lymphoid blasts in the blood, bone marrow and other organs. 1 ALL occurs with a bimodal distribution with an early peak in children 4 -5 years old followed by a second peak at ~ 50 years of age 2 with the worldwide incidence being ~ 1 -4.75/100,000 individuals with a male:female prevalence of roughly 1•3:1. 1 It is the most common childhood acute leukemia accounting for ~ 80% of the pediatric leukemias but contributing to only 20% of adult leukemias. Although significant progress has been made in treating adult ALL the overall survival amongst adults 18 to 60 years old is only 35% in contrast to childhood ALL in which overall survival at five years is more than 80%. 1 Over the past two decades the treatment of adult ALL has changed significantly with the introduction of pediatric protocols for the treatment of adolescents and young adults, the addition of tyrosine kinase (TKI) inhibitors for the treatment of Philadelphia positive/BCR-ABL positive ALL, a reevaluation of the role of allogeneic stem cell transplantation for standard risk ALL patients, the incorporation of minimal residual disease into risk assessments and most recently the introduction of novel agents such blinatumomab, inotuzumab and chimeric antigen receptor -T cell therapy for relapsed/refractory ALL.
Guideline Questions
# Search Strategy
The PubMed database was searched for relevant studies, guidelines and consensus documents published using the search term 'Acute Lymphoblastic Leukemia'. Clinical trials, clinical practice guidelines, systematic reviews and meta analyses written in English were included.
# Target Population
The following recommendations apply to adult cancer patients with suspicion or diagnosis of ALL. 2. Pre-treatment risk stratification should be ascertained for all patients using age and cytogenetics/FISH and/or molecular studies.
# Summary of Recommendations
# 3.
Post-treatment risk stratification should include the outcomes of minimal residual disease assessment using either flow cytometry or PCR (see below)
Principles of Treatment Initiation 1. Induction therapy should only be administered in a leukemia centre with physician and nursing expertise in the management of acute leukemias.
2. Induction therapy should not be initiated until the BCR-ABL status is known. If the patient is symptomatic, a steroid pre-phase should be indicated.
# 3.
Initiation of induction therapy should be accompanied by tumour lysis syndrome (TLS) prophylaxis, including hydration, urate lowering agents and close monitoring of TLS chemistries.
Treatment of Ph/BCR-ABL negative ALL 1. Eligible adults under age 60 should be treated with a pediatric-based protocol. a. In Alberta the current standard regimen is the modified Dana Farber Cancer Institute (DFCI) protocol. b. Patients with co-morbidities, or those unable to tolerate the full DFCI protocol, may be treated with a less intensive regimen, such as the modified DFCI protocol for patients age 60 or over. 2. Fit adults age 60-75 should be treated with curative intent.
a. The Princess Margaret Hospital modified DFCI protocol for adults above age 60 has produced favourable results in this population compared to other regimens and may be used.
Other curative-intent regimens are also acceptable. 3. Patients over age 75, or those under age 75 with major co-morbidities precluding intensive chemotherapy, should be considered for palliative chemotherapy with corticosteroids and vincristine +/-low-dose asparaginase, followed by low-dose maintenance chemotherapy if CR is achieved.
Treatment of Ph/BCR-ABL positive ALL 1. Ph/BCR-ABL positive patients who are fit for chemotherapy should be treated with a BCR-ABL tyrosine kinase inhibitor (TKI) combined with induction and post-remission therapy. a. A less intensive induction regimen with corticosteroids, vincristine and TKI (e.g. Chalandon protocol) is preferred for initial induction, as it produces higher CR rates due to lower induction mortality. In younger, fit patients, this should be followed by intensification (e.g. HyperCVAD Part B + TKI, as per the Chalandon protocol).
b. Patients achieving a hematologic CR should be continued on post-remission chemotherapy + TKI. This may consist of the modified Princess Margaret Hospital DFCI CNS, intensification and maintenance phases, or HyperCVAD + TKI. Asparaginase should not be used due to increased toxicity when used concurrently with TKI. c. Imatinib (600 -800mg per day), is currently the standard first line TKI drug. i. Patients with intolerance to, or not achieving an adequate response to, imatinib should be switched to a second generation TKI such as dasatinib ii. Ponatinib should be used in patients with a T315I mutation iii. For patients with CNS disease at diagnosis, dasatinib should be used upfront due to its superior CNS penetration. d. Patients with Ph/BCR-ABL positive ALL who are elderly, or otherwise unfit for intensive chemotherapy or transplant, should be treated with the Chalandon induction protocol cycle A, or corticosteroids + TKI, followed by low-dose maintenance chemotherapy + TKI. e. TKIs should be continued indefinitely in patients who are not transplanted. f. Patients not transplanted should be closely monitored for disease progression with serial PCR testing every 3 months. Reappearance of PCR positivity, if confirmed, should prompt a change in TKI and referral for allogeneic HSCT, if a potential candidate. g. Patients with persistence of, or reappearance of BCR-ABL transcripts by PCR, should have mutational testing, specifically to look for the presence of a T315I mutation.
# Role of MRD (minimal or measurable residual disease) assessments
1. Ph/BCR-ABL negative patients should have MRD assessments following induction chemotherapy, or by week 16, by flow cytometry or molecular techniques.
a. MRD positive B-ALL patients, defined as > 0.1% of mononuclear cells by flow (>10 -3 ), should receive immuno-therapy using 1-2 cycles of blinatumomab with an intent to achieve MRD negativity. b. MRD positive T-ALL patients should receive intensified chemotherapy with an intent to achieve MRD negativity.
c. MRD positive patients post-intensive induction or at week 16, defined as > 0.1% of mononuclear cells by flow, should be considered for allogeneic HSCT in CR1, as these patients are at higher risk of relapse.
2. Ph/BCR-ABL positive patients should have MRD assessments following induction chemotherapy, or by week 16, by quantitative PCR.
a. Patients who are MRD positive by PCR at the end of a two-cycle induction using the Chalandon protocol, or by week 16 using other protocols, should be switched to a second generation TKI such as dasatinib. If already on a 2 nd generation TKI, the patient should be switched to ponatinib. The TKI should be combined with either chemotherapy or blinatumomab. b. MRD positive patients at these timepoints should be referred for allogeneic HSCT in CR1, as per below.
Role of allogeneic stem cell transplantation 1. Allogeneic HSCT should not be routinely performed in patients with Ph/BCR-ABL negative ALL in CR-1. However, patients with the following high-risk features should be considered for HSCT: i. t(4;11) with MLL (KMT2A) rearrangement ii. Early T-cell precursor (ETP) ALL iii. Lack of attainment of hematologic CR with first induction iv. MRD positivity at end of induction or by week 16, as per above. v. Inability to deliver sufficient asparaginase dosing during intensification therapy a. There is no clear evidence that other cytogenetic abnormalities, or specific cell surface markers, constitute high risk features when using a pediatric-based regimen b. It is also not clear whether patients with a high-risk feature at baseline who achieve MRD negativity after induction therapy require a transplant. 2. Fit BCR-ABL positive patients up to age 70 may be considered for allogeneic HSCT in CR-1.
a. Patients with BCR-ABL positivity by PCR, either post-induction or by week 16 (depending on the regimen), should be referred for allogeneic HSCT, as per 6.1.3. If an HLA matched related or unrelated donor is unavailable, a haploidentical transplant should be considered. b. Patients achieving early MRD negativity by PCR, either post-induction or by week 16 (depending on the regimen), may be continued on post-induction chemotherapy together with TKI without a transplant. Transplant is also an option in these patients. c. Reappearance of PCR positivity with monitoring, if confirmed, should prompt a referral for allogeneic HSCT, if a potential candidate, as per above.
# CNS prophylaxis 1.
Intrathecal chemotherapy: All patients should receive intrathecal chemotherapy prophylaxis, starting with the initiation of induction therapy, and continuing through maintenance therapy, for 11-12 total doses. a. If the initial CSF is positive, intrathecal chemotherapy should be administered twice weekly until CSF clearance is confirmed on at least 3 occasions.
# 2.
Cranial Radiation: Cranial radiation may be omitted from CNS prophylaxis, unless there is evidence of fixed CNS disease.
# Relapsed
# CAR T-Cell Therapy:
1. Indicated for fit B-ALL patients relapsing after allogeneic HSCT, refractory to 2 induction regimens, or relapsed and not considered suitable candidates for HSCT.
# 2.
Patients should be referred for apheresis prior to administering salvage immunosuppressive chemotherapy such as corticosteroids or cyclophosphamide, to avoid interfering with the quality of the product.
# 3.
Patients should in most cases receive bridging/cytoreductive therapy following apheresis, to prevent clinical deterioration due to disease progression and to achieve cytoreduction prior to CAR T infusion. This may consist of either chemotherapy or antibody-based therapy.
# Discussion and Recommendations
Pathogenesis ALL is thought to arise from interactions between exogenous or endogenous exposures, genetic susceptibility, and chance. Infection was the first suggested causal exposure for childhood acute lymphoblastic leukemia. After the Hiroshima and Nagasaki atomic detonations, ionizing radiation quickly became established as an exposure leading to childhood ALL. 3 Chromosomal translocations occurring in utero during fetal hematopoiesis have been suggested as the primary cause for pediatric ALL while postnatal genetic events are considered secondary contributors. 4,5 Many of these chromosomal rearrangements disrupt genes that regulate normal haematopoiesis and lymphoid development (e.g. RUNX1, ETV6), activate oncogenes (eg, MYC), or constitutively activate tyrosine kinases (e.g. ABL1). Patients with trisomy 21, Klinefelter's syndrome and inherited diseases with excessive chromosomal fragility such as Fanconi's anemia, Bloom's syndrome and ataxiatelangiectasia have a higher risk of developing ALL. 6 However, in the majority of ALL patients no gross chromosomal alteration is noted suggesting that additional submicroscopic genetic alterations likely contribute to leukaemogenesis. 5 Genome-wide association studies of childhood 5 have noted common allelic variants in IKZF1, ARID5B, CEBPE, and CDKN2A which have been significantly and consistently associated with childhood ALL. 5 Others have investigated the associations of genetic polymorphisms in folate pathway and DNA repair genes with susceptibility to ALL. 7 Although several genetic alterations have well established roles in leukemogenesis (e.g. activating mutations in NOTCH1) the roles of many others remains elusive.
# Clinical Manifestations, Diagnosis, and Work-up
Clinical manifestations of ALL are highly variable. At presentation patients may have a multitude of constitutional symptoms, easy bruising, bleeding, dyspnea, dizziness, and infections due to anemia, thrombocytopenia and neutropenia. Extremity and joint pain may be the only presenting symptoms in some patients. 8 Lymphadenopathy, splenomegaly and/or hepatomegaly are seen on physical examination in approximately 20% of patients. 8 Abdominal masses from gastrointestinal involvement or chin numbness from cranial nerve involvement may be seen but are more suggestive of mature B-ALL. Less than 10% of patients have symptomatic central nervous system (CNS) involvement. Tlineage ALL with a mediastinal mass can cause stridor and wheezing, pericardial effusions, and superior vena cava syndrome. Testicular involvement is rare in adults. 9 The diagnosis of ALL begins with an evaluation of the peripheral blood film which may identify the presence of blasts. Patients presenting with only a mediastinal mass or lymphadenopathy require a tissue biopsy. All patients should have a bone marrow examination. As per the 2008 and 2016 WHO classifications, in contrast to myeloid malignancies, there is no agreed-upon lower limit for the percentage of blasts required to establish a diagnosis of lymphoblastic leukemias. 10 Despite this, some guidelines suggest that the diagnosis of ALL requires demonstration of > 20% blasts in the bone marrow aspirate/biopsymaterial. 8 By convention the term lymphoma is used when the process is confined to a mass lesion with no or minimal evidence of peripheral blood and bone marrow involvement. Based on morphologic, genetic and immunophenotypic features, lymphoblastic lymphoma is indistinguishable from ALL, and is in fact not distinguished in the WHO 2016 classification.
The assessment of immunophenotype by flow cytometry is essential to establishing the diagnosis. 9 The initial immunophenotyping panel should be comprehensive enough to establish a leukemia associated phenotype (LAP) to allow for use in minimal disease monitoring (MRD). Cytogenetic examination with examination of metaphases and/or fluorescence in situ hybridization (FISH) is crucial (eg, for BCR-ABL and MLL-AF4) particularly in cases in which cytogenetics are unavailable or have failed. Screening by polymerase chain reaction (PCR) for the BCR-ABL transcripts is also essential as it significantly impacts treatment. Determination of the BCR-ABL breakpoint is also required for subsequent molecular monitoring. Some labs also evaluate blast cells with molecular methods for the detection of patient-specific immunoglobulin and T-cell receptor (Ig/TCR) rearrangements 9 ; however, this is not routinely performed within Alberta. If bone marrow transplant is a consideration, tissue typing of both the patient and siblings should also be performed at diagnosis. If there are no HLA-matched siblings, consideration should be given to prompt initiation of an unrelated donor search.
# Recommendations:
The initial work-up of patients with ALL should include a thorough history and physical examination as well as baseline laboratory investigations including complete blood count, chemistry with extended electrolytes, tests of renal and liver function including amylase and lipase, a disseminated intravascular coagulation panel, and a tumour lysis panel. Cardiac imaging e.g. echocardiogram, multigated acquisition (MUGA) scan or cardiac MRI should be undertaken for all patients due to the use of anthracyclines.
Bone marrow studies or peripheral blood studies incorporating, as noted above, immunophenotyping, cytogenetics, and molecular studies should be completed. Ideally results of BCR-ABL testing should be available prior to the initiation of induction therapy, and should be available within 5 days. Lastly, patients eligible for allogeneic stem cell transplantation, and their siblings should have human leukocyte antigen (HLA) typing performed.
# Classification and Prognostication
# Classification of ALL:
The WHO 2016 classification is largely based on recurrent cytogenetic abnormalities, but also includes molecular markers such at KMT2A and BCR-ABL (Table 1). There is also a new provisional entity encompassing the BCR-ABL-like genotype (described later), which is not to this point readily diagnosed using routine testing. B-lymphoblastic leukemia/lymphoma NOS encompasses all subtypes not otherwise defined by one of the recognized abnormalities.
It is notable that this classification does not primarily distinguish between different immunophenotypic features, apart from the provisional T cell entities. It also does not distinguish between Tlymphoblastic lymphoma and T-ALL, acknowledging the widely held view that these are different clinical presentations of the same disease, and should be managed similarly. On the other hand, early T-cell precursor (ETP) lymphoblastic leukemia has been identified as a distinct subtype with unque biologic and clinical characteristics.
# Prognostic Factors in ALL:
Prognostic models for ALL have been refined continuously with improvements in therapy rendering some prognostic variables invalid. 9 The following represent clinical, cytogenetic and important molecular risk factors. It is important to note that many of these factors were defined using adultbased protocols and more studies are needed to evaluate their significance with pediatric based protocols.
# Clinical Prognostic Factors:
# Age, Gender and Ethnicity
Age is an important prognostic factor in ALL. In children age (infant or ≥10 years old) is an unfavourable risk group especially those younger than 6 months old. 5,17 Regardless of the treatment protocol utilized older adults are regarded as a prognostically unfavorable group. One study noted that the outcomes of patients aged over 55 had a probability of survival of 20% at 3 years while others have noted that patients over the age of 35 have poorer outcomes. [11][12][13][14][15] Recent data suggest that adolescents and young adults benefit with improved overall survival if treated according to pediatric protocols. 1 Several studies have suggested that the influence of age may relate to the increased prevalence of poor-risk features while others have suggested that it is independent of cytogenetic and molecular aberrations. 16,17 The ability to tolerate chemotherapy likely plays an important role. 13,18,19 Together with age, male gender and race (Hispanic or of African descent) have been considered negative prognostic factors in pediatric ALL Inaba, 2013 #20. Racial differences in prognosis have been linked to socioeconomic factors but also to differences in genomic variations. For example, germline single nucleotide polymorphisms of PDE4B and ARID5B are associated with Native American genetic ancestry and somatic CRLF2 were over-represented in children with a Hispanic background.
# White Blood Cell Count
In children, a presenting leucocyte count (≥50 × 10⁹/L) has been associated with a worse prognosis. 17 In many, but not all adult studies of ALL, high-risk ALL has been defined as WBC ≥ 30 x 10 9 /L for Bcell ALL and ≥100x10 9 /L for T-cell ALL. 1,11,[13][14][15] Although most early studies identifying this factor used adult-based protocols, subgroup analyses in larger studies show that these continue to be important prognostic factors with pediatric-inspired regimens Brandwein, 2011 #51;Boissel, 2003 #357. In their study of the DFCI protocol in adults a high WBC (>30 x 10 9 /L for Pre-B ALL or >100 x 10 9 /L for T-ALL) was associated with inferior RFS and OS. 20 However, subsequent studies incorporating early MRD detection into multivariate models have demonstrated that baseline WBC was no longer an independent predictor of relapse (see section on MRD). 21
# Immunophenotype
The SEER database demonstrated a better prognosis with B cell as compared with T cell immunophenotype in patients < age 20 years; while in patients ≥ 20 years of age, T cell immunophenotype was more favorable. 22 This was confirmed in a metanalysis by Kako 23 Amongst adults T-cell ALL accounts for 14-22% of adult ALL 24 and is thought to be of favourable prognosis. In both the LALA 87 and the UKALL/EGOG 2993 trial, T-ALL was associated with male gender, age <35 -39 years old, CNS involvement and a high WBC count. The LALA-87 investigators also noted a higher incidence of a mediastinal mass and anemia. 15,24 In this study for patients age <40 treated with chemotherapy alone 3 year DFS was superior in the group with a T-cell phenotype relative to a B-ALL phenotype (59% vs. 20%). No difference in DFS was seen in patients with B-or T-ALL patients treated with allo-or auto -HSCT. 24 Similarly, Both Rowe et al. and Larson et al. noted that improved OS in patients with T-cell antigen expression relative to B-lineage antigens. 13,18 Kantarjian et al. using Hyper-CVAD noted similar results. 12 Using the pediatric Dana Farber Cancer Institute (DFCI) protocol a trend toward improved clinical outcomes was observed in adolescents 25 and adults 20,26 with T-ALL. The GRAALL study group 94 noted that when using a pediatric protocol at 42 months, EFS was estimated to be 62% (95% CI, 50% to 72%) in T-ALL patients and 52% (95% CI, 42% to 59%) in BCP-ALL patients (p=0.09). Within the T-cell ALL subset the prognosis is worse for pro-, pre-and mature-T subtypes (CD1a-, CD3-/CD3+) compared with the CD1a+ cortical/thymic phenotype. The early T-cell precursor ALL which retains stem cell-like features is associated with a dismal prognosis with conventional chemotherapy 27 in both adult and pediatric T-ALL. 28 As noted above, several studies have suggested that patients with B-cell phenotype fare worse than those with T-ALL. Patients with a CD10-negative pro-B phenotype are considered as high-risk particularly when associated with t(4;11)/abn q23. 1,26 The pre-B subtype expressing cytoplasmic heavy chains has a bad outlook when harboring MLL rearrangements. The CD20 antigen is expressed in nearly half of B-cell ALL and its impact on clinical outcomes is controversial. Maury et al. when using the pediatric GRAALL 2003 protocol in adults aged 15-60 years old with Ph-negative ALL noted that CD 20 expression did not influence achievement of complete remission but was associated with a higher cumulative incidence of relapse (CIR) and lower EFS at 42 months (42% vs. 29%) in patients with a WBC ≥ 30 ×10 9 /L (P=0.006). Thomas et al. also noted an inferior survival in CD20 positive patients using the adult-based hyper-CVAD protocol. 29 In contrast, a retrospective analysis by the Princess Margaret Hospital groups in adult patients, most of whom had received a pediatricbased regimen, did not find any association between CD20 expression and outcome 30 and in-fact there appeared to be a trend towards a favourable EFS in those showing CD20 positivity.
# Cytogenetic Studies
Karyotype is an important prognostic factor with a number of cytogenetic abnormalities being associated with altered prognosis in ALL (Table 2). The frequency of cytogenetic aberrations varies between adult and childhood ALL and may partially explain the differences in clinical outcomes between patient populations. 8 Whether cytogenetic abnormalities remains important with the use of pediatric protocols in adult patients remains unclear; some studies suggest that most abnormalities are not independent predictors of outcome in adults treated with such protocols, with the exception of KMT2A-associated abnormalities. 20,21,26 The Philadelphia chromosome, characterized by the t(9;22) translocation resulting in production of a BCR-ABL1 fusion gene and protein, is the most common cytogenetic and molecular abnormality in adult ALL. The frequency is age-dependent, being present in approximately 8-10% of adolescents, 15-30% of younger and middle aged adults, and 40-50% of elderly ALL patients. 9 Over two-thirds have the p190 gene, with the remaining harbouring the p190 gene.
Until recently the BCR-ABL1 fusion gene marked the most unfavourable subgroup of adult ALL. With chemotherapy alone the CR rate was 75%-80%, median DFS about 10 months and 5-year survival below 10-20%. 26,31,32 Most studies demonstrated superior outcomes with allogeneic HSCT compared to chemotherapy alone. 26,31,32 Combinations of tyrosine kinase inhibitors (TKIs) with chemotherapy have produced superior outcomes to chemotherapy alone, as will be discussed later.
The t(4;11) is present in up to 60 % of infants younger than 12 months but is uncommon in adult patients, constituting 5-10% of cases. When rearranged, the MLL (now called KMT2A) gene has been found to be associated with inferior RFS and OS in adult patients when using a pediatric protocol. 20 The t(1;19) is uncommon in adults; its prognostic significance is unclear, with conflicting data. Garg et al. noted that adults treated with Hyper CVAD had a significantly better CRD and OS compared with all other patients. 33 However, Foa et al. found that this abnormality is frequently associated with early treatment failure, and recommended that these patients should be considered for intensified treatment strategies. 34 The t(12;21) abnormality leading to ETV6-RUNX1 fusion is detectable in about 25 % of children and 3 % of adults with B-ALL. Patients generally have a favorable prognosis. 35,36 Hyperdiploidy (>50 chromosomes) is seen in approximately 25% -30% of paediatric cases and 7% of adults and represents the most common chromosomal abnormality in children. It is associated with a favourable prognosis regardless of age and leukocyte count at presentation. 37,38 Its characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21, with individual trisomies or tetrasomies being seen in over 75% of cases. The individual structural abnormalities do not appear to influence outcome in patients with hyperdiploidy except for the t(9;22), which is associated with a poor prognosis. 39 The favourable prognosis may reflect an increased propensity of these cells to undergo apoptosis. 17 In contrast, 5 % to 6 % of ALL patients, independent of age, have the loss of various chromosomes, resulting in a hypodiploid clone with fewer than 44 -46 chromosomes. These patients generally have a poor prognosis, especially those with near-haploid and low-hypodiploid clones. 17,36,40 Recent data suggest that complex karyotypes (≥ five chromosomal abnormalities) occur more frequently with increasing age and may be associated with inferior survival. 15,26,41 Intrachromosomal amplification of chromosome 21 (iAMP21) occurs at an incidence up to 2 % in older children with B-cell precursor ALL Harrison, 2005 #1056 and is defined by at least three copies of the RUNX1 gene (Children's Oncology Group, COG, definition for iAMP21). iAMP21 has been shown to be linked to a dismal outcome when patients are treated with standard therapy, because it is associated with an increased risk of both early and late relapses. 36,[42][43][44] It is rare in adults.
Many of these prognostic factors may be regimen dependent. Many older studies used adult-based protocol. In contrast, using pediatric based regimens, most of these cytogenetic abnormalities have not been found to be of prognostic importance in adults, with the notable exception of t(4;11). [45][46][47]
# Molecular Studies
Molecular genetics has identified several gene mutations, translocations and amplifications that may have prognostic significance in ALL. IKZF1 encodes IKAROS which has been established as one of the most clinically relevant tumor suppressors in ALL. It is a DNA-binding zinc finger transcription factor that regulates the development and function of the immune system and acts as a master regulator of normal hematopoietic differentiation and proliferation, particularly in lymphoid lineage. 48 Deletion of a single IKZF1 allele or mutations of a single copy of IKZF1 were first detected in 15 % of pediatric B-cell ALL and in more than 80 % of Ph+ ALL cases, either de novo Ph+ ALL or chronic myeloid leukemia at progression to lymphoid blast crisis suggesting a critical role in the pathogenesis of Ph+ ALL. [49][50][51][52] The incidence in adults is about 50% in B-cell ALL and about 65% when BCR-ABL positive. Recent data further suggest that together with Ph+ve ALL, mutations in IKZF1 are also a hallmark of 'BCR-ABL1-like ALL. 5 Alteration of the IKAROS gene is associated with increased risk of treatment failure and relapse in both BCR-ABL1-positive and BCR-ABL1-negative disease independent of commonly used risk stratification features such as age, sex, white cell count, and levels of minimal residual disease (MRD). 21,52 PAX5 encodes a transcription factor known as B-cell specific activator protein, that plays a key role in B-cell commitment by activating essential components of the B-cell receptor signaling and repressing the transcription of genes necessary for T-lymphopoiesis. 53 Monoallelic deletion of PAX5 have been observed in about 30 % of children and adults 54,55 and have been demonstrated to not influence treatment outcome. 36,55,56 The CDKN2A/B locus encodes for the INK4-class cyclin dependent kinase inhibitors p15INK4B, p16INK4A and for p14ARF. CDKN2A and CDKN2B deletions have been identified in 29 % and 25 % of BCR-ABL1-positive ALL patients, respectively. 57 The association with prognosis is still controversial. 36,57,58 Four independent groups in late 2009 and early 2010 identified that up to 50 % of BCR-ABL1-like ALL cases have dysregulated expression of CRLF2, the gene encoding the cytokine receptor-like 2 factor. 56,[59][60][61] Overall aberrant expression of CRLF2 was found in 12. Mutations of NOTCH1, a transmembrane receptor-encoding gene that regulates normal T-cell development, have been detected in in about 60% of T-ALL. 63 Early studies in paediatric T-ALL showed that NOTCH1 mutations may be associated with a favourable prognosis. 21,[63][64][65][66][67][68] Similarly, in adult T-ALL patients, studies have demonstrated a better prognosis for patients with NOTCH1 and/or FBXW7 mutations, 67,69 but this could not be validated in a series of 88 patients treated in the MRC UKALLXII/ECOGE2993 protocol 70 or by the Zhu et al who in fact noted that Chinese adult TALL patients with mutated NOTCH1 had poorer survival compared with those with wild-type NOTCH1. 71 Overall these studies seem to suggest that NOTCH activation is associated with improved early therapeutic response. However, this early benefit translates into improved overall survival only in some series, probably due to differences in therapy. 63 Gene Expression Profiling:
# BCR-ABL like ALL
Mullighan and colleagues identified some patients with Ph-negative ALL which had a gene expression profile almost identical to Ph+ ALL and which were termed Ph-like ALL. 54,56,72 This genesignature has been noted in approximately 15% of pediatric cases, but the frequency is as high as 33% in adults with B-ALL. 73 Genetic alterations of activating kinases or cytokine receptor signaling, incuding ABL, JAK2, CSF1 and EPOR, are commonly observed in addition to overexpression of cytokine receptor-like factor 2 (CRLF2) and frequent deletions of IKZF1. 54,56,72,74 Some studies have found higher levels of MRD after induction therapy, 74,75 increased relapse rates and inferior overall survival. 8 However, reliable testing for this genotype is not routinely available in most laboratories, including in Alberta.
# Early T-cell precursor acute lymphoblastic leukaemia (ETP -ALL)
ETP -ALL accounts for 12% of paediatric T-ALL. It is an aggressive leukaemia characterised by an immature immunophenotype with lack of CD1a and CD8 expression, weak CD5 expression 76 and aberrant expression of myeloid and stem cell markers (CD117, CD34, HLA-DR, CD13, CD33, CD11b, or CD65) on at least 25% of lymphoblasts. 8 The long-term response to therapy is one of the worst among recognized high-risk forms of childhood ALL. 27 In one study, the 10 year OS was 19% compared with 84% in the non-ETP ALL. 27 Similarly inferior outcomes have been reported in adults with ETP-ALL. 77,78 The mutational spectrum in ETP-ALL is similar to myeloid tumours with a high frequency of activating mutations in the cytokine receptor and RAS signaling pathways including NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3, and BRAF, raising the possibility that addition of myeloid-directed therapies might improve the outcome of ETP ALL. 79 Given the poor outcomes with conventional ALL regimens, most ETP-ALL patients are referred for allogeneic HSCT in CR1, where there are data suggesting a survival benefit. 78
Other Factors:
# Pharmacogenetics and pharmacogenomics
Genome-wide analyses have identified specific gene signatures which may be prognostically relevant when associated with drug resistance e.g. polymorphism of genes metabolizing thiopurines, methotrexate, and cytarabine all of which have been associated with variable treatment response and are a mechanisms of drug resistance. 1 Rocha et al noted that the glutathioneS-transferasel1(GSTM1) non-null genotype was associated with a higher risk of recurrence, which was increased further by the thymidylate synthetase (TYMS) 3/3 genotype. Others have observed that hyperdiploid cells accumulate more methotrexate polyglutamates as they possess extra copies of the gene encoding reduced folate carrier, an active transporter of methotrexate. Hareedy et al found significant associations between variants in genes coding for enzymes and transporters related to the 6mercaptopurine pathway and clinical outcomes as well as hematological toxicity (neutropenia, agranulocytosis and leukopenia) in pediatric patients with acute lymphoblastic leukemia. 80 The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. Gregers et al. noted statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL. 81
# iAMP of chromosome 21
Poor prognosis 2% of older children with B-ALL.
# Hyperdiploidy
Favourable prognosis 25-30% of cases; nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21; The favourable prognosis may reflect an increased propensity of these cells to undergo apoptosis.
# Hypodiploidy
Poor prognosis 5-6% of ALL patients; near haploid and lowhypodiploid have the worst prognosis.
# Complex Karyotype
Poor prognosis More than 5 chromosomal abnormalities.
# Molecular Genetics IKZF1 mutations
Poor prognosis Most commonly present in BCR-ABL + ALL or BCR-ABL like ALL.
# Abnormality Clinical Impact Notes PAX5
No effect on treatment outcomes 30% of adults and paediatric patients.
# CDKN2A/B
# Pre-Treatment Risk Stratification
Over the past twenty years there has been continued debate regarding the risk stratification of patients with ALL with different groups using the above clinical, immunophenotype, cytogenetics and molecular tests to variably group patients into those that are standard risk, high risk or very high risk of having a leukemia relapse. As discussed, many of these discrepancies may be related to the type of treatment reigmens used (adult vs pediatric-based), and whether MRD analysis is taken into consideration in risk stratification.
Recent studies have found that, using pediatric-based protocols, most cytogenetic abnormalities are not independent predictors except for certain abnormalities, such as KMT2A-based abnormalities, t(9;22) and possibly hypodiploidy. 21,45 Given the poor prognosis of patients with Ph+ve ALL, the initial risk stratification for all patients should be based on the presence or absence of t(9;22)/BCR-ABL1. Amongst Ph-ve patients the NCCN considers those with hypodiploidy (<44 chromosomes), t(v;11q23)/KMT2A rearrangements or complex karyotype (≥5 chromosomal abnormalities) as high risk. 8 Although prior studies have shown that a WBC > 30 for B-cell ALL and >100 for T-cell ALL were important risk factors, 20 MRD has since been demonstrated to be a more important predictor on multivariate analysis (discussed below). However, age remains an important predictor of outcome in nearly all studies, with patients > age 30-35 having worse outcomes than so-called AYA (adolescent and young adult) patients. 20 Recent evidence suggests that molecular profiling, and specifically the detection of a Ph-like genetic signature as discussed, may be the most important pre-treatment predictor of outcome in adults and children with BCR-ABL negative B-ALL. However, detection is time consuming and labour intensive, and is not routinely available at most centres, including in Alberta.
# Recommendations:
All patients should be classified as having B-cell or T-cell ALL based upon immunophenotyping results. Although some of the above noted prognostic factors are beyond the scope of routine clinical laboratories, all patients, should undergo cytogenetic evaluation and, if unsuccessful, FISH for the determination of the most clinically significant abnormalities, in particular BCR-ABL and MLL gene rearrangements. There is no convincing evidence that other cytogenetic abnormalities or cell surface markers add to risk-stratification when using paediatric or paediatric inspired protocols. Given the increasing recognization of minimal residual assessments, all patients should have immunophneotyping performed. This can be used to guide post-induction treatment.
# Post-Treatment Risk Stratification
# Role of MRD Assessments in the Management of Patients with ALL:
Measurable (or minimal) residual disease (MRD) refers to the detection of small amounts of residual disease, undetectable by morphology. Techniques for MRD detection include multiparameter flow cytometry (MPFC) or molecular techniques. For BCR-ABL+ ALL, molecular detection is readily performed by qRT-PCR for BCR-ABL1, and is regarded as the gold standard for MRD detection. For BCR-ABL negative ALL, many European studies have used immunoglobulin gene rearrangements for MRD detection; however, this technique is labour intensive and requires detection of the specific rearrangement for each patient. Consequently, MPFC is widely used for MRD detection due to its ease, and has a sensitivity of 10 -3 -10 -4 ; it is the technique used in Alberta.
Based on the paediatric literature, a number of studies over the past 15 years have explored the role of MRD in adults with ALL. Most of these have suggested that MRD may be the single most important factor predicting clinical outcomes. 9 A number of investigators have described differences in patterns and dynamics of clearance of MRD between adult and childhood ALL as well as between B-and T-cell ALL. Foroni et al. noted that MRD decreased faster in children than in adults particularly in the first 6 months of CR 96 while Parekh et al. noted that MRD clearance was slower with T-ALL. 97 Bruggemann and colleagues measured MRD at 9 different time points ranging from 11 days post-induction up to to 52 weeks post induction. 98 Only a minority of patients had undetectable MRD at day +11 while at 6 weeks approximately 50% had undetectable MRD.
Several groups have explored the prognostic value of MRD in adult ALL patients. Bruggman and colleagues noted that a combination of MRD measurements at day 11, day 24 and 16 weeks could classify patients into those with a low likelihood of ALL relapse (MRD -ve at day 11 and day 24), high likelihood of relapse (MRD + at week 16) or intermediate risk of relapse (all others). 98 Similar findings were noted by Bassan and colleagues who measured MRD at week 10 and week 22 post induction chemotherapy. 46 Regardless of whether they were SR, HR or VHR by traditional criteria, patients who were MRD negative had significantly better DFS relative to those that were MRD positive.
Whether treatment intensification can negate the negative effects of residual disease has also been investigated by several investigators. Bassan and colleagues assessed MRD at week, week 16 and week 22. 46 Patients that were MRD negative or with unknown MRD status but standard risk by traditional criteria received maintenance treatment only while patients that were MRD positive or with unknown MRD but high risk or very high risk by traditional criteria received an allogeneic SCT or autologous blood stem cell harvest/reinfusion with subsequent maintenance therapy. MRD positive patients receiving either SCT or intensive chemotherapy had improvements in DFS with no significant difference between those that received SCT and intensive chemotherapy. Moreover, patients who became MRD negative had improved DFS relative to those who remained MRD positive. Similar results were noted by Gokbuget et al. where 5 year CCR improved for MRD positive patients undergoing an allo SCT. 99 Ribera and colleagues noted that allo SCT in MRD -ve patients was unnecessary and counterproductive as it led to worse DFS and overall survival both in the whole series and an intention to-treat-analysis. 100 Beldjord et al. assessed 423 adult patients with Ph-negative ALL treated with a pediatric protocol. 21 MRD1 was evaluated at 6 weeks after induction initiation and MRD2 after the first consolidation phase i.e. 12 weeks after induction initiation. A study by the GRAALL group, using a pediatric inspired protocol for adults with B-ALL, evaluated the role of allogeneic HSCT according to MRD response with induction therapy. 47 Patient who were MRD positive, defined as a level > 10 -3 following induction therapy, had a significantly higher relapse rate and inferior OS as compared to those who achieved a level < 10 -3 . Furthermore, those with MRD levels > 10 -3 who underwent subsequent HSCT in CR1 had a significantly superior RFS and OS as compared to those who were not transplanted. In contrast, those with MRD levels < 10 -3 following induction did not benefit from HSCT. These effects were seen for both B-ALL and T-ALL.
The Edmonton group subsequently analyzed outcomes following DFCI induction therapy. Between 2013-2019 patients with BCR-ABL negative ALL underwent induction therapy with this protocol, and MRD postinduction was assessed by multiparameter flow cytometry, with a sensitivity of 0.1%. Of 46 patients who achieve CR, 26 (57%) were MRD negative and 43% were MRD positive. The cumulative incidence of relapse was 45% in patients who were MRD positive at a level of >0.1%, as compared with 12% in MRD negative patients (p=0.05) (unpublished data). These results essentially mirror those reported by the GRAALL group as described above.
These data further support the conclusion that patients who fail to achieve a 3 log reduction in MRD levels with intensive induction therapy represent a high-risk group for relapse, and that these patients should be considered for HSCT in CR1. In contrast, those who achieve who achieve a >3 log reduction with induction can be successfully managed by chemotherapy alone with a low relapse risk and favourable prognosis. A subsequent German study (Herold et al, 2017) found a strong association between MRD positivity and a Ph-like genotype; Ph like B-ALL patients only achieved a 33% MRD negativity rate, as comparted with 79% for Ph negative and non-Ph-like B-ALL patients (p=0.02) Therefore, MRD may represent a surrogate marker for a more resistant disease biology which is more destined to relapse with conventional chemotherapy.
# Treatment of MRD positive B-ALL:
Blinatumomab is a bispecific tumour-engaging (BiTE) antibody with an anti-CD19 domain that binds to B-cells, including B-ALL cells, and an anti-CD3 domain that engages T lymphocytes to lyse the B cells. A large European study 101 was recently published, evaluating the role of blinatumomab in 116 B-ALL patients in hematologic CR with MRD positivity, defined as a level > 0.1% by qRT-PCR.
Patients were permitted to received up to 4 treatment cycles, and could undergo allogeneic HSCT at any time after the first cycle. Overall, 78% of patients achieved an MRD negative state, with a sensitivity of 10 -4 , after one blinatumomab treatment cycle. Two additional patients achieved this after 2 cycles. Of patient in first CR, 83% achieved MRD negativity. The treatment was well-tolerated.
The median OS of the patients who achieved MRD negativity was 38.9 months, vs. 12.5 months in those who did not achieve MRD negativity (p=0.002); corresponding RFS were 23.6 vs. 5.7 months, respectively (p=0.002). With a median follow-up of 24 months, 49% of patient who underwent subsequent HSCT remained in continuous CR, as compared with 25% who did not undergo HSCT. By comparison, in Edmonton BCR-ABL negative B-ALL patients who were MRD positive at a level > 0.1% by flow cytometry after DFCI induction therapy were treated with intensified chemotherapy, using cycles 1A and 1B of Hyper-CVAD, between 2013-2018. Of 13 patients, only 5 (38%) were able to achieve MRD negativity; treatment was associated with considerable toxicity, including severe myelosuppression and mucositis.
These data indicate that (1) blinatumomab is able to induce a high rate of MRD negativity, usually after one cycle, with good tolerance, (2) patients who achieve MRD negativity have superior outcomes compared with those who do not, (3) patients who subsequently undergo allogeneic HSCT have favourable outcomes as compared with those who do not, and (4) intensified chemotherapy is less effective at inducing MRD negativity but is associated with considerably more toxicity. The use of blinatumomab for MRD positive B-ALL has now been widely incorporated into standard ALL protocols in Europe and North America.
# Recommendations:
Taken together, these data indicate that MRD assessment provides critical prognostic information in adults with ALL. There is convincing evidence in pediatric and adult ALL that a high level of MRD at the end of induction therapy is associated with a higher relapse rate. Furthermore, the persistence of MRD during consolidation and maintenance therapy, or its the re-emergence, all seem to herald relapse. In contrast, negative MRD results are associated with a favorable prognosis. It is therefore recommended that all patients have MRD ascertained at the end of intensive induction therapy, or early during intensification. Patients with persistent MRD at a level > 0.1% should receive further treatment with an intent to achieve MRD negativity; for B-ALL the treatment of choice is blinatumomab, while for T-ALL intensified chemotherapy would be appropriate. Furthermore, these patients should be referred for allogeneic HSCT if suitable candidates, optimally after achieving MRD negativity. In contrast, patient achieving MRD negativity do not appear to benefit from transplant, provided they can successfully complete the subsequent treatment protocol.
# Treatment Approaches in ALL
In general, the treatment of ALL is complex consisting of several different chemotherapy cycles and, for some patients, stem-cell transplantation. 1 A number of different approaches have been used as discussed below.
# Adult Multidrug Regimens:
Starting in the 1960s, researchers at St. Jude Children's Research Hospital designed combination therapies of available anti-leukemia drugs that were delivered in a sequence of extended courses of therapy. 9 Since then several multidrug combinations have been developed centered on a vincristine, prednisone, and anthracycline combination, with or without asparaginase and cyclophosphamide. This concept was modified in children to the Berlin-Frankfurt Munster (BFM) ALL model and later, by Hoelzer et al., to adult ALL. 11,102 Studies using this approach are presented in Table 5. Despite variations in chemotherapy regimens, variable use of allogeneic SCT or auto SCT the 5 year overall survivals ranged from 35 -60% in various subgroups with induction mortality ranging of 5-10%.
The second treatment model pioneered at the M.D. Anderson Cancer Center consists of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and cytarabine (Hyper-CVAD). The regimen consists of a total of eight courses: four courses of hyper-CVAD (courses 1, 3, 5, and 7) alternate with four courses of MTX and HIDAC (courses 2, 4, 6, and 8). 103,104 In the original report the mortality was 6% and the overall CR rate was 91%. The estimated median survival time was 35 months with a 5-year estimated survival of 39%. Younger age was associated with better survival (age <30 had estimated 5-year survival rate of 54% vs. age > 60 estimated 5-year survival rate of 25%). In an updated report of patients aged 15 -92 years old, the CR rate for patients age ≤30 years was 99% and for patients age ≥60 years 80%, mostly because of a higher induction mortality. Kantarjian, 2004 #710. The addition of rituximab was associated with CCR and OS rates of 60% and 58%, respectively. Treatment with Rituximab-hyper-CVAD was associated with improvement in 3-year CRD rates compared with hyper-CVAD (78% vs. 53%). In patients age < 60 improvements in 3-year OS (75% v47%; P 0=.003) rates favoring rituximab were observed. 105 The Pediatric Approach: A third approach was the adoption of pediatric protocols or "pediatric inspired"regimens particularly for adolescents and young adults variably defined as patients 15 to 35-45 years old. 1, 106 These regimens have common features, including significantly increasing the non-myelosuppressive agents such as vincristine and steroids, using much higher cumulative doses of asparaginase for prolonged asparagine depletion, and administering very early and extended intrathecal methotrexate together with high-dose systemic methotrexate. Several studies from Europe and the USA reported that pediatric inspired approaches are feasible in adolescents and adults (Table 6 and 7). These studies have shown that prolonged administration of non-myelosupressive agents such as asparaginase, vinca alkaloids and steroids is feasible and tolerated in a substantial portion of adults. Based on these studies, pediatric based regimens have now been widely accepted as the standard of care for younger adults with ALL.
# CNS Prophylaxis and Treatment:
Because of the high risk (up to 50%) of CNS relapse, CNS prophylaxis is an essential part of any treatment regimen for ALL. Standard approaches include the use of repeated (11)(12) doses of intrathecal (IT) chemotherapy. This has been demonstrated in many studies to reduce the risk of CNS relapse to 10% or less. Although many protocols use triple intrathecal chemotherapy with methotrexate, cytarabine and corticosteroids, a recent pediatric randomized study did not show any difference in CNS relapse rates between this approach and single-agent methotrexate. 112 A baseline LP is required to rule out CSF disease at diagnosis. If positive, the usual approach is to administer intrathecal chemotherapy twice weekly until the CSF has been adequately cleared (as evidenced by 3 consecutive negative results). Although the standard cerebrospinal fluid (CSF) diagnostic approach consists of morphologic analysis of a cytospin preparation, studies have shown that flow cytometry of CSF provides greater sensitivity, 113 and may thus be a more reliable indicator of blast clearance.
Most older treatment protocols incorporated prophylactic cranial radiation; however, this adds significant short-term and potential long-term toxicities. Recent pediatric studies have demonstrated that routine cranial radiation can be safely deleted without adversely impacting CNS relapse rates; 114 this is particularly the case if high-dose intravenous methotrexate, which has good CNS penetration, is used. However, if evidence of fixed leptomeningeal disease is present based on the presence of focal neurologic symptoms and corresponding MRI findings, CNS radiotherapy is indicated as intrathecal chemotherapy alone is usually insufficient.
# Provincial Recommendations for Treatment of ALL
# Adolescents and Young Adults (AYA):
Adolescents and young adults have been variably defined as those aged 15 -35 (40) years old. A multitude of accumulating evidence suggests that this group of patients is best treated with a pediatric or a pediatric inspired protocol. Ram et al. conducted a systematic review of 11 studies that compared adult and pediatric protocols. 115 Overall, all-cause mortality, relapse rates and non-relapse mortality were lower in the pediatric groups whereas CR rates and EFS were higher in the pediatric groups. It is important to note that in many of these studies the median age ranged from 12.9 -31 with only two studies including patients over age 55. The native E. coli asparaginase used in the DFCI 91-01 protocols is no longer available in Canada, and has been replaced by pegylated asparaginase (Pegaspargase). This should be given no more frequently than once every 3 weeks in adults due to its long half-life (see Appendix C and D).
# Patients Aged 35(40)-60:
The use of pediatric protocols for the treatment of adolescents has inspired some groups to explore the use of pediatric protocols in older adults however the data are not clear whether this represents a significant difference relative to adult protocols. When using the paediatric GRAALL-2003 protocol improvemnets in EFS and OS were noted at 42 months but only for patients <age 45. 94 Similarly, Storring and colleagues, when using a modified DFCI paediatric regimen 20
# Recommendations for Patients Aged 35(40)-60:
These data suggest that although results in patients 30-60 years old may be inferior to those in adolescents and young adults a use of a pediatric protocol may benefit these patients with 3-5 year OS improving from an historic 35-40% to 50-70%. The lower OS observed in some studies may be related to the preferential use of allo-SCT in this cohort of patients. Nonetheless, we recommend that patients in this age range continue to be treated with the DFCI protocol (Appendix A-C). However, given the increased toxicities seen in middle-aged adults, some patients, particularly those age 50-60, may require changing to a less toxic regimen such as the modified DFCI protocol for older patients (see below).
# Patients Aged >60:
The outcome of patients above age 60 treated with standard ALL chemotherapy has been generally poor. Larson et al. using the CALGB 8811 protocol noted a 3 year OS of only 17% with a median survival of only 1 month. 82 Brandwein et al. noted similar results when using a multitude of different adult based chemotherapy regimens. 116 In their study the 3 year OS was only 18.4%. Using the HyperCVAD protocol Kantarjian et al. noted a 5 year OS of 17%. 12 Thus, it appears that the majority of older patients with ALL will succumb to their disease although some older patients may remain long-term survivors.
Whether a paediatric inspired regimen might benefit this older subset of patients was investigated by Martell et al. who evaluated the outcomes of 51 patients treated with a modified DFCI paediatric regimen at the PMH (Appendix B). 109 Modifications from the full-dose DFCI 91-01 protocol during induction included the substitution of dexamethasone for two 4-d pulses instead of daily prednisone, reduction of the methotrexate dose from 4 g/m2 to 40 mg/m2, reduction in the asparaginase dose from 25 000 to 12 000 iu/m 2 and removal of one vincristine dose. In the CNS prophylaxis phase cranial radiation was removed. In the intensification phase seven cycles were given instead of 10, the dexamethasone dose was reduced to 6 mg PO BID and the asparaginase reduced to 6000 iu/m 2 from 12500 iu/m 2 . In the maintenance phase parenteral methotrexate was switched to oral, and the dexamethasone dose was again reduced from 6 mg/m 2 BID to 6 mg PO BID. For patients who developed progressive grade ≥2 neuropathy, intravenous vinblastine 10 mg was substituted for vincristine. Median age was 65 (60 -79), 12 patients were over the age of 70, 35 patients were BCR-ABL negative and 16 were BCR -ABL positive. CR rate was 75% for the entire cohort with 20% induction mortality. Interestingly CR rate was 81% in BCR -ABL positive patients and 71% in BCR -ABL1 negative patients. The estimated 5-year OS was 40.5% for the BCR-ABL1 negative patients, and 47.3% for the BCR-ABL1+ patients but there was no significant difference in OS between these two groups. The estimated 5-year OS for BCR-ABL1 negative patients presenting with low WBC (defined as <30 x 10 9 /L for B-ALL or <100 x 10 9 /L for T-ALL) was 44.3% respectively.
# Recommendations for Patients Aged >60:
Given that some medically fit patients above age 60 may be cured of ALL we recommend that eligible patients over age 60 be treated with curative intent therapy. Although, there are no randomized studies, based upon data from the PMH group, the modified DFCI provided superior results relative to historical controls. We therefore recommend that the modified DFCI protocol be used for older ALL patients (Appendix C). A more recent report from the Spanish PETHEMA group also showed reasonably good activity with their protocols, although relapse rates remained high. 117 Patients over age 75, or those age 60-75 with major co-morbidities precluding intensive chemotherapy, should be considered for palliative chemotherapy with corticosteroids and vincristine +/-low-dose asparaginase. Such patients should continue to receive central nervous system prophylaxis and may benefit from incorporation of a CNS phase. Patients not tolerating DFCI-type intensification, or judged to be unfit for such treatment, may be moved directly to the DFCI maintenance phase.
# Philadelphia Chromosome or BCR-ABL Positive ALL:
Tyrosine kinase inhibitors (TKI's) have become the standard of care for Ph+/BCR-ABL+ ALL and have led to improvements in the outcomes for all age groups. 1 The earliest TKI used in ALL was imatinib. Although, different chemotherapy regimens and schedules of imatinib have been assessed, all showed improvements in overall survival and reduction in the relapse rate. [118][119][120] In the first large study done by the French GRAAPH-2003 group, the combination of imatinib with induction and postremission therapy 121 led to higher estimated OS (65% vs. 39%), lower CIR (30% vs. 49%) and improved DFS (51% vs. 31%) at 18 months in comparison to historical controls treated with the LALA-94 protocol. An Italian study also reported 5-year OS of 38% and DFS of 39% with imatinib combined with chemotherapy and again these results were significantly superior to a historical cohort receiving chemotherapy alone. 122 In the large UKALL/ECOG2993 trial investigators reported an improved post-induction CR rate with imatinib, improved 4 year OS, EFS and a considerable reduction in relapse risk in the imatinib cohort. 123 Lastly, The M.D. Anderson group also combined imatinib with their standard hyper-CVAD protocol and reported CR rates of 93% as well as results that were substantially superior to their retrospective results with chemotherapy. 124 Second and third generation TKI's have also been assessed in Ph+ ALL. [125][126][127][128] Kim et al evaluated the outcomes of Nilotinib with multiagent chemotherapy for adult patients with newly diagnosed Ph+ve ALL. After achieving CR, subjects received either 5 courses of consolidation, followed by 2year maintenance with nilotinib, or allo-HCT. Amongst the 90 evaluable subjects the CR rate was 91%, the 2-year RFS was 72% and the 2-year OS was 72%. Unlike nilotinib, dasatinib has the ability to peneterate the CNS. Single agent dasatinib is associated with short-term cytogenetic remission and median relapse free survivals of only 3.3 months. Studies of dasatinib in combination with chemotherapy, however, have been associated with excellent response rates approaching 100% with minimal toxicity. 72,125 Ponatinib was evaluated in Ph+/BCR-Abl+ by Jabbour and colleagues for patients up to age 60 with previously untreated Ph +ve ALL. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously each subsequent cycle of hyper-CVAD. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The 2-year EFS rate was 81% (95% CI for the 37 patients enrolled in the study. 128 Several investigators have combined TKI's with paediatric based regimens used for the treatment of adult patients. Thyagu et al. evaluated the outcomes of 32 ALL patients age 18-60 with Philadelphia positive ALL treated between 2001 and December 2008 with imatinib. Ninety-four percent of patients (94%) achieved a CR and, of the 28 patients proceeding to intensification therapy, 16 received a HSCT. The 3-year OS was 56% in the transplanted group vs. 50% in the non-transplanted group. 129 They also noted increased rates of peripheral neuropathy, ileus, myopathies, deconditioning, infections and abnormal liver enzymes in a high proportion of patients. Therefore, a number of modifications were made to the original DFCI protocol. 129 Using an unmodified DFCI protocol, Deangelo et al. reported similar results amongst 18 Ph +ve patients treated with imatinib, 11 of whom went on to transplant. The 4 year DFS was 54% and 4 year OS was 53%. 95 Martell et al. also treated 16 BCR-ABL positive patients aged 62 -75 with a modified DFCI protocol together with imatinib. The CR rate was 81% with an induction mortality of 19% and the estimated 5-year OS was 47.3% for the BCR-ABL1+ patients. 109 Monotherapy with TKI has been explored in several studies particularly in elderly patients, who had an extremely poor outcome with chemotherapy alone. Ottmann et al evaluated imatinib monotherapy in 27 patients older than 55 years of age, and observed CR in 26 patients and a partial remission in the remaining patient. 130 Vignetti et al. treated patients aged 61 to 83 years with Ph-+ ALL with a 45day induction of imatinib 800 mg daily plus prednisone (40 mg/m 2 daily). Post-remission therapy was not specified. All 29 assessable patients (100%) experienced a CR. At 12 months, the OS and DFS probabilities were 74% and 48%, respectively. 131 The French GRAALL group conducted a large randomised controlled trial comparing a reduced intensity induction with imatinib, vincristine and dexamethasone (Arm A) to standard imatinib/hyper-CVAD A part (Arm B) in 268 adults with Ph+ve ALL up to age 60; both arms then received a second cycle with Hyper-CVAD B part. 132 The CR rate was higher in arm A than in arm B (98% vs 91%), mainly related to a lower induction death rate in Arm A, whereas the MMolR rate was similar in both arms (66% vs 64%). The OS was superior in the patients that subsequently proceeded to allogeneic HSCT; however, on subgroup analysis, patients who had achieved MRD negativity (defined as a >4 log reduction in BCR-ABL transcripts by PCR) by the end of the second induction cycle had a similar RFS with or without allogeneic HSCT. In contract patients who were MRD positive at that timepoint had a significantly better RFS with allogeneic HSCT, compared to those who were not transplanted. Therefore, MRD assessment with this regimen could be used to help identify a high-risk cohort for whom HSCT was beneficial.
Foa et al. evaluated a similar regimen consisting of dasatinib (70 mg twice daily for 84 days) together with prednisone 60 mg/m 2 daily for 32 days plus two doses of intrathecal methotrexate in untreated patients with Ph +ve ALL. 125 Post remission therapy was not defined with two patients receiving no further therapy, 19 continuing on TKI only (16 dasatinib, 2 imatinib and 1 imatinib-dasatinib), 10 receiving intensive chemotherapy with TKI, 4 having an auograft and 18 receiving an allogeneic HSCT. Overall, 53 patients aged 24 -76 were treated. A CR rate of 100% was seen with 92.5% by day 22 and no deaths occurred during induction. Of the patients that had MRD measured by PCR 10 achieved levels lower than 10 -3 and 8 had a complete molecular remission. Twenty-three patients relapsed after completing induction with 12/17 relapsing patients showing a T315I mutation. This trial demonstrated impressive remission rates for dasatinib and steroids only but at the same time underscored the importance of adding intensive chemotherapy and/or HSCT to maintain durable remissions.
More recent studies suggest that the treatment landscape is changing. The MD Anderson group evaluated the use of ponatinib + Hyper-CVAD chemotherapy in fit patients with BCR-ABL+ ALL. 133 The 3-year EFS of 69% and OS of 84%, without transplant, were significantly superior to a historical group that had received dasatinib + Hyper-CVAD. These results suggest that using ponatinib with intensive chemotherapy upfront may potentially circumvent the need for transplant in CR1 for most patients. More recently the Italian GIMEMA group reported on a chemo-free regimen using dasatinib + blinatumomab. 134 The CR rate was 98%, with 70-80% eventually achieving a complete molecular response; at a median follow-up of 18 months, the OS was 95% and DFS 88%. The MD Anderson group is currently using a combination of ponatinib + blinatumomab for 4 cycles, followed by ponatinib maintenance therapy, as their standard frontline regimen; the CR rate was 100% and 86% achieved a complete molecular response 154 . While very promising, follow-up is brief, and these treatments are not currently approved as upfront therapy for BCR-ABL+ ALL.
# Recommendations Philadelphia Chromosome or BCR-ABL Positive ALL:
All patients with Ph+/BCR-ABL+ve ALL should receive a TKI combined with chemotherapy. No randomized studies are available comparing different TKI's in adults; therefore, a firm recommendation regarding the choice of TKI upfront cannot be made. Currently, only imatinib (600-800 mg daily) is approved as first line therapy. Patients intolerant to imatinib should be switched to another TKI such as dasatinib; dasatinib may also be preferred for patients with CNS disease due to its excellent CNS penetration. Patients with documented T315I BCR-ABL mutations, or those refractory to or progressing on, a 2 nd generation TKI, should be treated with ponatinib.
Fit BCR-ABL+ve ALL patients should be treated with a TKI combined with induction and postremission chemotherapy. Given recent studies showing higher remission rates and decreased mortality using corticosteroids, TKI + vincristine during induction, this combination is recommenedd as initial induction therapy (see Appendix F); however, such patients require additional intensive chemotherapy +/-HSCT to maintain a durable remission.
Given data suggesting increased toxicity of asparaginase and vincristine with TKI, asparaginase should be deleted, and vinblastine substituted for vincristine, in the post-remission phases.
Patients above age 65, particularly, those with major co-morbidities, poor performance status or ineligible for SCT should be treated with steroid and TKI +/-vincristine or vinblastine. Post induction therapy should be individualized based upon patient tolerance. Patients not transplanted should continue TKI indefinitely.
BCR-ABL monitoring by quantitative RT-PCR should be performed in all patients, post-induction and then every 3 months. Patients with inadequate response or loss of response should be switched to a second or third generation TKI as indicated and, depending on circumstances, may require switching from chemotherapy to blinatumomab.
# Role of Allogeneic Stem Cell Transplantation
# Ph-/BCR-ABL-ALL:
In the largest adult ALL trial to date (MRC-ECOG UKALLXII/E2993) patients in first complete remission < 50 years were assigned to alloHCT if they had a compatible sibling donor while others were randomized to consolidation/maintenance therapy for 2.5 years or to autologous transplant and no further therapy. Patients were considered to be high-risk if they had age >35, WBC >30,000/ mL for B-lineage or WBC >100,000/mL for T-ALL, Philadelphia chromosome positivity, t(4;11), t(8;14), complex karyotype, low hypodiploidy or triploidy. All other patients were considered standard risk. In a donor versus no-donor analysis, patients with a sibling donor had improved OS than those with no donor (53% vs. 45%). In the standard risk group, the OS at 5 years was 62% for patients with a donor compared to 52% for patients with no donor (P=.02). In contrast, for high-risk patients OS was 41% for those with a donor vs. 35% for those without a donor (p=0.2) likely due to the high non-relapse mortality. The 10 year relapse rate was substantially lower in patients with a donor (24% for standard risk and 37% for high-risk) versus those without a donor (49% standard risk and 37% high-risk). 19 The Spanish PETHEMA group reported similar findings in their cohort of high-risk patients defined as those with age 30-50 years old, WBC count >25,000/ mL, Ph +ve, t(4;11)/other 11q23 rearrangements, or t(1;19). 87 In contrast, two French studies both reported that there was an advantage for high-risk patients having a donor. 86,135 A meta-analysis of 7 studies that included 1274 patients also noted improvements in overall survival for patients with donors relative to those in the no-donor groups undergoing allogeneic stem-cell transplantation. When only high-risk patients were analyzed, the survival advantage was greater. 136 More recently, Gupta et al. conducted a meta-analysis using individual patient data from a total of 20 trials that included a donor no-donor comparison. Overall survival at 5 years was significantly better in the donor arm (49.9% vs 42.7%, p=.003). However, because TRM was much higher in those age >35 both in the donor and no-donor arms there was no difference in OS in this age group. Interestingly, unlike in previous studies and using standardized definitions of high/standard risk, there was no evidence that survival differed by risk category. It was therefore concluded that patients age<35 benefit from an allo-SCT regardless of risk group. Furthermore, by reducing TRM, RIC has the potential to extend the benefit of allo-SCT to those age>35.
Despite the above data, it remains unclear whether adult patients treated with paediatric protocols would gain a benefit from SCT. In their study of a 156 BCR-ABL -ve patients treated with the DFCI protocol the 5 year OS amongst patients receiving an allogeneic SCT was 44% while for those not undergoing a SCT the survival was 74% with the difference possibly related to transplant related mortality. Seftel and colleagues compared 422 Ph-ve ALL patients aged 18-50 years with 108 patients receiving DFCI chemotherapy 155 . Expectedly, treatment related mortality was higher in those receiving a SCT (37% vs. 6%). At 4 years, the incidence of relapse was similar for those receiving SCT and chemotherapy (24% vs. 23%), however, both DFS and OS were improved for those receiving chemotherapy alone (40% vs. 71% for DFS and 45% vs. 73% for OS). Dhedin and colleagues further assessed the the role of allogeneic stem cell transplantation in Ph-ve ALL adult patients with at least 1 conventional high-risk factor treated with the paediatric inspired GRAALL 2003 and 2005 protocols. 47 In all, 522 patients age 15 to 55 years old were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission while 240 (46%) did not. As with previous studies, the lower CIR observed in the SCT was counterbalanced by a higher NRM. When analyzing SCT in CR1 as a time-dependent event RFS and OS were not significantly improved in the SCT cohort. No significant effect of SCT on RFS was noted in patients younger or older than age 45 or on any prespecified baseline risk factor. RFS and OS were significantly longer, however, in patients who presented with morphologic poor early BM blast clearance or in late CR patients. Furthermore, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) >10 -3 but not in good MRD responders.
For pediatric-based protocols, asparaginase is a critical agent in achieving the high cure rates reported. There is evidence in both pediatric and adult studies with the DFCI protocol that the inability to deliver the intended asparabinase dosing during intensification (defined as >80%) is associated with a higher relapse rate. 20,137 Therefore, the inability to deliver effective asparaginase dosing (e.g. due to pancreatitis) places the patients in a higher risk category and warrants consideration of allogeneic HSCT.
# Recommendations for Ph-/BCR-ABL-ALL:
These data suggest that patients with Ph-/BCR-ABL -ve ALL treated with a paediatric protocol who attain an MRD negative complete remission are at low risk of subsequent relapse and will not benefit from an allogeneic SCT. It is therefore recommended that such patients not proceed with allogeneic SCT, unless they are unable to complete the protocol. Given that patients with MLL (KMT2A) rearrangements remain a high-risk group with pediatric based regimens, SCT may be a reasonable recommendation for younger ALL patients with this abnormality. Failure to achieve a complete hematologic remission after the first induction cycle is also generally considered a high risk features; transplantation is also recommended for these patients. Although high presenting WBC has been identified in the past as a high-risk feature, its prognostic value is superceded by MRD based on data from GRAALL. Failure to deliver effective asparaginase dosing during intensification should also warrant consideration of allogeneic SCT.
Patients who are MRD +ve at >10 -3 (or >0.1%) after induction therapy, or >10 -4 (<0.01%) at 16-18 weeks, are at higher risk of relapse and may benefit from transplant. Such patients should be considered for allogeneic HSCT, optimally after receiving further cytoreduction to attain an MRD negative state prior to transplant.
# Role of SCT in Patients with Ph/BCR-ABL Positive ALL:
The UKALLXII/ECOG 2993 study evaluated the outcome of allo-SCT in Ph+/BCR-ABL+ patients younger than 55 years of age achieving complete remission with an adult ALL protocol. Of the 267 patients, 76 (28%) proceeded to alloHSCT in first CR (45 with cells from a sibling and 31 with cells from a MUD) whereas 86 received chemotherapy alone. The median EFS for all 267 Ph+ patients was 9 months and the median OS was 13 months. At 10 years, OS was 39% for sib alloHSCT, 31% for MUD alloHSCT, and 13% for chemotherapy. Comparing the outcome after any alloHSCT with the outcome after chemotherapy alone, OS, EFS, and RFS were all significantly superior for patients receiving any alloHSCT over those receiving chemotherapy alone. Whereas the leading cause of death in chemotherapy treated patients was relapse, the leading cause of death after transplantation was TRM, which was 27% after sib HSCT and 39% after MUD HSCT. 31 Limited information is available comparing adult Ph+ patients receiving a paediatric protocol with those undergoing an allo SCT. Thyagu et al. treated 32 patients with Ph+ ALL with DFCI protocol together with imatinib. Of the 28 patients proceeding to intensification therapy, 16 underwent an allo-SCT. The 3 year OS was 56% in the transplanted group and 50% in the non-transplanted group. 129 Recent studies in the pediatric setting noted that children receiving intensive multidrug chemotherapy with imatinib had a survival higher than 80% compared to 35% in historical controls, and even better than related or unrelated HSCT (>60%). In the recent US Children's' Oncology Group study, the outcomes at 3 years were not significantly different for those treated with chemotherapy plus imatinib compared with those assigned to alloHSCT. 138 However, limited patient numbers precluded rigorous subgroup analysis.
Recent studies in adults are also demonstrating the impact of molecular status on relapse risk in Ph+ ALL. The MD Anderson Cancer Center 139 found that molecular positivity at a variety of time points was associated with a significantly higher cumulative incidence of relapse. The French GRAAPH study 132 found that the benefit of alloHCT in CR1 was restricted to patients who were molecularly positive post-induction chemotherapy. On subgroup analysis, patients who had achieved MRD negativity (defined as a >4 log reduction in BCR-ABL transcripts by PCR) by the end of the second induction cycle had a similar RFS with or withour allogeneic HSCT. In contract patients who were MRD positive at that timepoint had a significantly better RFS with allogeneic HSCT, compared to those who were not transplanted. Therefore, MRD assessment with this regimen could be used to help identify a high risk cohort for which HSCT was clearly indicated.
In contrast, a study using nilotinib plus chemotherapy 140 found that overall survival was superior in patients undergoing HSCT regardless of MRD status; however, 60% of patients achieving molecular negativity remained free of relapse at 30 months without a transplant. Taken together, these data suggest that some patients who achieve MRD negativity early on may remain relapse-free with continuing chemotherapy + TKI, potentially sparing them the toxicity associated with transplant.
# Recommendations for the Role of SCT in Patients with Ph/BCR-ABL Positive ALL:
Although allogeneic HSCT remains the standard post-remission approach for many patients with BCR-ABL positive ALL, patients who achieve early MRD negativity by PCR (e.g. after induction with the Chalandon protocol) may be continued on post-induction chemotherapy + TKI without a transplant; these patients should continue with indefinite TKI and regular PCR monitoring. However, all patients with persistent molecular positivity should be referred for allogeneic HSCT if otherwise eligible. Consideration should be given to switching to a more potent TKI such as dasatinib or ponatinib in these MRD+ patients prior to transplant. Furthermore, patients with subsequent recurrence of MRD detectable disease by PCR should also be referred for transplant.
# Role of Cranial Radiation
CNS involvement at the time of presentation is uncommon in adults with ALL being reported in 5% to 7% of patients. 141 Before the use of central nervous system (CNS) prophylaxis, the CNS was the most frequently reported site of initial recurrence in children with ALL, accounting for up to 75% of cases. 141 Similarly, amongst adults with ALL, CNS recurrence occurs in approximately 30% of those in a hematological remission. 1 Aur et al. published the results of St. Jude Total Study V in 1971 demonstrating that 2,400 cGy cranial radiation and five doses of intrathecal methotrexate greatly diminished CNS relapse resulting in the first cures of childhood ALL. 142 Subsequently, widespread incorporation of CNS prophylaxis led to the largest single "step up" in 10-year survival from approximately 20% to 60% among those diagnosed from 1970 to 1972 versus 1972 to 1975. 142 Given the significant risk of CNS relapse current adult and pediatric protocols incorporate CNS prophylaxis with both systemic and intrathecal chemotherapy and/or radiation.
Cranial irradiation is an effective form of CNS-directed treatment, but its effectiveness is offset by substantial rates of secondary neoplasms, endocrinopathies, growth impairment, neurocognitive dysfunction, and neurotoxic effects. Amongst the pediatric population, Pui et al. found that prior cranial radiation was associated with a 20.9% cumulative risk of second neoplasms at 20 years in addition to a higher mortality and a greater likelihood of being unemployed when compared to an age matched general population. 142 Subsequently, multiple trials compared CNS prophylaxis using intrathecal chemotherapy and/or intravenous methotrexate with cranial radiation. These trials demonstrated the efficacy of IT/IV therapy without cranial radiation leading to use of cranial irradiation for patients at especially high risk of CNS relapse and elimination of cranial radiation for infants or very young children, irrespective of their presenting features Jeha, 2009 #199. More recently, in the St Jude Total XV and Dutch Childhood Oncology Group acute lymphoblastic leukaemia-9 protocols cranial irradiation is replaced by triple intrathecal chemotherapy with methotrexate, hydrocortisone, and cytarabine for all newly diagnosed patients. The 5 year cumulative risk of isolated CNS relapse was 2•7% with the St Jude and 2•6% with the Dutch Childhood Oncology Group protocol similar to the relapse rates observed with prophylactic cranial irradiation (1•5-4•5%). In the largest study to date Vora and colleagues 143 obtained data on 16623 patients aged 1 to 18 years old treated between 1996 and 2007 by 10 cooperative groups. In their analysis cranial radiation was associated with a reduced risk of relapse but only in patients with overt CNS disease at time of presentation. In other patients there was no difference in CNS relapse between those that received and did not receive cranial radiation. These data suggest that, in the context of a pediatric protocol prophylactic cranial irradiation can be safely omitted in patients in the context of effective intrathecal and systemic chemotherapy.
# Recommendations for the Role of Cranial Radiation:
Given the above data we recommend that cranial irradiation not be used for CNS prophylaxis in patients receiving a pediatric protocol such as the DFCI if intrathecal or systemic chemotherapy is used, unless there is evidence of fixed intracranial disease at presentation on MRI.
# Supportive Care
Supportive care remains an important aspect of the care of the ALL patient throughtout all phases of treatment. All patients should be transfused packed red blood cells as per institutional guidelines and particularly for symptomatic anemia. Similarly, platelets should be transfused to maintain platelet counts > 10 x 10 9 /L. All patients receive prophylaxis, and if indicated, treatment for tumour lysis syndrome with allopurinol and/or rasburicase during induction therapy. Disseminated intravascular coagulation should be treated aggressively with clotting factor replacement. Patients with signs and symptomns of febrile neutropenia should be managed with broad spectrum antibiotics and intensive care support as necessary. As corticosteroids may mask fevers in such patients, broad spectrum antibiotics should be instituted for clinical suspicion of sepsis (e.g. unexplained hypotension) even in the absence of fever. Antifungal prophylaxis against Candida is recommended during induction due to the risk of Candida septicemia.
Clinicians should be continuously aware of both the short-and long-term consequences of potential toxicities associated with specific agents used in ALL and use prevention, treatment or dose adjustment as necessary:
1.
# Treatment of Relapsed ALL
Adult ALL patients experiencing hematologic relapse have a poor prognosis with conventional chemotherapy salvage regimens. CR2 rates have been in the 30-50% range. Second remissions are invariably brief unless followed by allogeneic HSCT, and OS is in the 10-20% range. 147,148 Recent studies have demonstrated the superiority of antibody-based therapies for relapsed patients with B-ALL. Blinatumomab, a BiTE antibody construct described earlier (see MRD Section) ,was evaluated in the Phase III randomized TOWER trial 156 . Adult B-ALL patients with relapsed (CR1 < 12 months or > CR2) or refractory disease were randomized to receive either blinatumomab for 2 cycles, followed by up to 3 consolidation cycles, or conventional salvage chemotherapy. The CR rate was higher with blinatumomab (44% vs. 25%, p=0.001), and OS was significantly longer in the blinatumomab arm (7.7 months vs. 4 months, p=0.01). Responses in the blinatumomab arm were influenced by tumour burden: The CR rate was 65% in those with < 50% bone marrow blasts, vs. 34% in those with > 50% BM blasts; nevertheless, CR rates were higher in both subgroups as compared with the chemotherapy arm. Although this study only included patients with BCR-ABL negative ALL, a subsequent study demonstrated a 36% CR rate in patients with relapsed/refractory BCR-ABL+ B-ALL, all of whom had failed second or later generation TKI's. 149 Inotuzumab ozogamicin is an anti-CD22 antibody conjugated to the toxin calicheamycin. The immunoconjugate is internalized into CD22+ B-cells, followed by release of the calicheamicin, which induces DNA strand breaks. The INO-VATE trial was a Phase III randomized study in patients with relapsed/refractory CD22+ B-ALL. 150 Patients were randomized to receive inotuzumab or conventional salvage chemotherapy. The CR rate was significantly higher in the inotuzumab arm (81% vs. 29%, p<0.001); furthermore, nearly all CR's in the inotuzumab group were MRD negative. The PFS in the inotuzumab group was also significantly longer (5 mos vs. 1.8 mos, p<0.001), and the OS was also longer (7.7 mos vs. 6.7 mos, p=0.04). CR rates with inotuzumab were not influenced as much by tumour burden (86.7% for those with <50% BM blasts, vs. 78% for those with >50% BM blasts). Notably, this study included patients with BCR-ABL+ ALL, where a 79% CR rate was reported.
In addition to being more effective, both antibody drugs were well tolerated. The major toxicities of blinatumomab included cytokine release syndrome and neurologic toxicity, both of which were usually grade 1-2 and treated successfully with corticosteroids. The major toxicities of inotuzumab were nausea, febrile neutropenia and veno-occlusive disease (VOD/SOS) of the liver. The latter was a particular issue in patients who received >3 cycles and in those who subsequently proceeded to allogeneic HSCT using a duel alkyator conditioning regimen.
For patients with relapsed/refractory T-ALL, there are currently no available antibody-based therapies outside of clinical trials. Conventional salvage chemotherapy, using a non-cross resistant regimen (e.g. Hyper-CVAD), may be used, or nelarabine. The latter is a prodrug of ara-G which is converted to ara-GTP, after which it is then incorporated into DNA, resulting in cytotoxicity. It has demonstrated single agent activity in relapsed/refractory T-ALL, with a 31% CR rate and 41% ORR. 151 However, responses are not durable, and require subsequent allogeneic HSCT if treated with creative intent. Major toxicities of nelarabine include myelosuppression and neurotoxicity. Neurotoxic effects may be either central or peripheral, and may be severe and irreversible.
# Recommendations for Relapsed ALL:
Based on the two pivotal TOWER and INO-VATE trials, patients with relapsed or refractory BCR-ABL negative B-ALL should be treated with either blinatumomab or inotuzumab as salvage therapy.
Although there are no clear recommendations with respect to the choice of agent, inotuzumab would generally be preferred in patients with higher disease burdens (> 50% BM blasts), based on higher responses rates in this group. In patients with lower disease burden, blinatumomab with be preferred for patients who are intended to proceed to subsequent allogeneic HSCT, due to the risk of VOD/SOS with inotuzumab.
For patient who receive inotuzumab with an intention to proceed to HSCT, patients should optimally not receive more than 2 cycles, and dual alkylator HSCT conditioning regimens should subsequently be avoided. Inotuzumab may also be preferred in patients who are intended to proceed to subsequent CAR-T therapy using an anti-CD19 construct (see below), in order to minimize the risk of preselection of a CD19 negative subclone. However, conventional chemotherapy or blinatumomab may be preferred in patients who are at risk of VOD/SOS (patients who are early post-HSCT or have pre-existing liver issues).
Patients with relapsed BCR-ABL positive B-ALL on imatinib may be reinduced with a second generation TKI such as dasatinib + chemotherapy. Mutational analysis should be performed at relapse and, if a T315I mutation is detected, ponatinib should be used. Those failing a second generation TKI, should be treated with either inotuzumab or blinatumomab, optimally combined with ponatinib.
Patients with relapsed/refractory T-ALL should receive either salvage chemotherapy with a non-cross resistant regimen (e.g. Hyper-CVAD) or nelarabine.
Regardless of salvage therapy, subsequent relapse is inevitable unless the patient proceeds to allogeneic HSCT or CAR T-cell therapy (see below).
# CAR T-Cell Therapy
Chimeric antigen receptor (CAR) T-cell therapy is a treatment in which T lymphocytes are removed from a patient via apheresis, transfected ex vivo with a gene rendering them immunogenic against certain cancer cells, grown and subsequently reinfused into the patient. The activated T-cells then circulate, attack and kill the cancer cells. This treatment has demonstrated considerable activity in patients with relapsed and refractory B-ALL.
Most studies to date have utilized anti-CD19 CAR T-cells. Tisagenlecleusel is the first such therapy to be approved in children and young adults up to age 25 with relapsed/refractory B-ALL. Complete remission rates of 81% were reported, 152 with a one-year event-free survival (EFS) of 50%, in a cohort of multiple relapsed patients, many of whom had previously received allogeneic HSCT.
Another study of 53 multiply relapsed and refractory B-ALL patients, including many older patients age 30-70 years, from Memorial Sloan Kettering Cancer Center (MSKCC) using a similar anti-CD19 CAR T-cell product, demonstrated an 83% CR rate, a median EFS of 6.1 months and OS of 12.9 months (Park et al, 2021). In this study, patients with a low disease burden (defined as <5% BM blasts) at the time of CAR T infusion had a superior EFS and OS as compared with those who had >5% BM blasts at time of infusion. The ZUMA-3 study, using a different anti-CD19 CAR T-cell product, reported a CR rate of 83% and a median remission duration of 17.6 months (Shah et al, 2021).
CAR T-cell therapy is associated with significant early toxicities, including cytokine release syndrome (CRS), sometimes requiring ICU support +/-tocilizumab, and neurotoxicity; patients therefore require close monitoring in the first two weeks. The MSKCC group 153 and others have reported that the severity of these toxicities is greater in patients with higher tumour burden at the time of CAR-T infusion.
CAR T-cell therapy has become available in Alberta as of 2021, in both Edmonton and Calgary, using both commercial and local investigational products. It is currently being used for patients who have failed at least two different treatment regimens; however, the field is rapidly evolving, and it is likely that it will be evaluated at earlier stages of disease. As some patients relapse with CD19-negative disease, other studies are investigating the use of dual anti-CD19/CD22 CAR-T products.
Potential candidates for this treatment should be referred early for apheresis, prior to administering salvage immunosuppressive chemotherapy, so as not to negatively interfere with the quality of the apheresis product. Most patients will the need some bridging cytoreductive therapy. The latter has a dual purpose: (1) to prevent clinical deterioration while the CAR T product is being prepared, and (2) to reduce the disease burden, potentially reducing the toxicity of the procedure and the risk of subsequent relapse. Optimal cytoreductive strategies are unclear; depending on the patient, it may include non-intensive chemotherapy, inotuzumab or blinatumomab. The latter, although less toxic than other treatments, could potentially increase the risk of emergence of a CD19 negative subclone, so most experts recommend avoiding this if possible. Inotuzumab should be avoided in patients at higher risk of VOD/SOS, including those who are early post-HSCT or who have pre-existing liver disease.
# Recommendations for CAR-T:
CAR T-cell therapy is indicated for fit patients with B-ALL who have relapsed after allogeneic HSCT, are not otherwise candidates for HSCT, or who have refractory disease. Early referral to the centre's Cellular Therapy Program is recommended. Patient should not receive salvage T-cell depleting immunosuppressive therapies such as corticosteroids or cyclophosphamide until after apheresis, so as not to impair the quality of the collection. Following apheresis, bridging/cytoreductive therapy should be given, particularly for high tumour burden or rapidly progressive disease, with an aim to control disease-related complications and reduce the overall tumour burden, while avoiding excessive treatment-related toxicities.
# Future directions
The treatment landscape of ALL has undergone major changes in the past 5 years, and it is likely that further changes will occur as new information becomes available.
A number of multicenter randomized clinical trials have been evaluating the role of blinatumomab and inotuzumab, in combination with standard frontline chemotherapy regimens, in both younger and older patients with B-ALL. Results from these trials should be available in the next 2-3 years and, if positive, may move these agents into frontline treatment protocols.
For BCR-ABL positive ALL, the combination of ponatinib with Hyper-CVAD chemotherapy has shown very favourable results, without transplant, compared with historical cohorts who had received first of second generation TKI's. 133 More intriguingly, chemo-free protocols, using blinatumomab combined with either dasatinib or ponatinib, have shown very encouraging results in early studies. 134,154 If successful, these may fundamentally change how these patients are treated in the future, and may render transplants unnecessary.
As described above, CAR-T cell therapy has shown considerable activity in multiply relapsed and refractory B-ALL. Dual CAR-T constructs, targeting both CD19 and CD22, are in clinical trials, and offer the promise of lowering relapse rates. Moreover, CAR-T therapies will be evaluated in earlier stages of the disease, after first relapse and, eventually, in first CR for high-risk patients with MRD positive disease. This may, if successful, potentially replace the need for allogeneic HSCT for many patients, thereby eliminating the problems associated with GVHD.
#
Appendix A: Original DFCI Protocol 91-01 (Used for pediatric patients) 92 Phase of Therapy Time Period Chemotherapy Induction 28 Days Vincristine 1.5 mg/m2/dose IV, maximum 2 mg, days 3, 10, 17, 24; prednisone 40 mg/m2/d IV/PO for 28 days; doxorubicin 30 g/m2/dose IV, days 1 and 2 methotrexate 4 g/m2 IV for one dose on day 3 IT cytarabine, dosed by age, one dose on day 0 IT cytarabine, dosed by age, one dose on day 17 CNS Therapy 3 Weeks SR girls: IT methotrexate/cytarabine for 4 doses during 2 weeks, then every 18 weeks SR boys and all HR patients: cranial XRT 18 Gy, randomly assigned to hyperfractionated (0.9 Gy bid) or conventional (1.8 Gy daily) with IT methotrexate/cytarabine for 4 doses during 2 weeks Intensification Every 3 weeks for 30 weeks SR: vincristine (2 mg/m2 IV every 3 weeks, maximum 2 mg); dexamethasone 6 mg/m2/d PO for 5 days; methotrexate 30 mg/m2 IV or IM every week; mercaptopurine,randomly assigned to high-dose 1,000 mg/m2 IV for 20 hours, weeks 1 and 2) or conventional 50
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Hematology Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, hematologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Hematology Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2016.
# Levels of Evidence
| None | None |
c659d65820e035224c516ec2e500907b5cfbd73a | cma | None | The majority of adults and children with autoimmune rheumatic diseases (ARD) require immune modulating therapies for disease control. These therapies put people with ARD at higher risk for infections, particularly viral infections. 1 Immunosuppressed persons have a higher risk of poor outcomes with infections. 1,2 Although there is limited information about outcomes for people with ARD who develop COVID-19, one international study demonstrated that prednisone and an underlying diagnosis of lupus could be associated with worse outcomes and higher mortality. 3 Is COVID-19 immunization recommended for people with autoimmune rheumatic diseases? COVID-19 vaccines should be encouraged for people with autoimmune rheumatic diseases and are not contraindicated, including those who have had a COVID-19 infection. o Although the majority of patients with ARD who are immunosuppressed were excluded from clinical trials of the COVID-19 vaccines, the Canadian Rheumatology Association, 4 American College of Rheumatology 5 and British Rheumatology Association 6 have all released position statements strongly supporting the use of COVID-19 immunization in this population. o Experts agree that the potential benefits and anticipated desirable effects of COVID-19 immunization outweigh the potential harms in persons with ARD. While data specific to the safety and efficacy of the COVID-19 vaccines in people who take immunosuppressant or immunomodulating therapies is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 7 The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization.#
Is the COVID-19 vaccine efficacious and safe in patients with autoimmune rheumatic diseases?
Adults and children with ARD who take immunosuppressant/immunomodulating therapy were excluded in all of the trials for the COVID-19 vaccines currently approved in Canada. As per NACI, safety data in immunocompromised individuals, including those receiving immunosuppressive therapy, were available from observational studies in people who were taking immunosuppressive therapies. The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that of non-immunocompromised individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available.
There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 8 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. The safety of a third dose is unknown at this time for ARD, but in these small studies reactions were found to be similar to that of prior doses. The impact of additional doses on the worsening of underlying disease or on rare adverse events, including the risk of myocarditis and/or pericarditis, is unknown at this time. 9 Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the authorized COVID-19 vaccines, as well as a discussion about the emerging evidence on the safety of mRNA COVID-19 vaccines in these populations. The recommendations in this clinical guidance are based on these small observational studies, extrapolation of data from other viral infections, immunology of immunizations and from expert opinion.
When infected, people with ARD can exhibit high variability with respect to clinical presentation, organ involvement, disease severity, comorbidities and medications. If a patient has complicated disease or multiple medical conditions and health-care providers have questions, they are encouraged to reach out to the patient's rheumatologist for specific guidance.
As the majority of patients with ARD are on immune suppressing medications, there may be blunting of the magnitude and duration of vaccine response compared to the general population. 4,6,10 Regardless, the benefits of immunization are considered to outweigh the potential risks.
Are there any specific contraindications or exceptions for people with autoimmune rheumatic diseases?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 11 BCCDC has a list of the individual components and their purpose in COVID-19 Vaccines for People with Autoimmune Rheumatic Diseases Updated: April 18, 2023 the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Other than allergy, there are no specific contradictions or exceptions for people with ARD apart from the efficacy and safety considerations outlined above.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine including the seasonal influenza vaccine. Are there specific recommendations or considerations for safe and/or most effective administration?
Guidance from the Canadian Rheumatology Association 4 is to continue underlying immunosuppression and disease modifying agents without adjustment around COVID-19 immunization with the exception of Rituximab/Ocrelizumab, and high-dose prednisone as indicated below. Clinical advice to adjust Mycophenolate Mofetil around COVID-19 immunization (when the condition is stable) is derived from the American College of Rheumatology guidelines. 5 For patients on the following medications, there is no need to adjust or delay the medication: For patients on rituximab or ocrelizumab, the COVID-19 immunization should ideally be timed four to five months after their last infusion and two to four weeks prior to their next infusion, when possible, in order to optimize vaccine response. However, in patients who require immediate infusion or who are unable to optimize timing of infusion product and vaccine, it is likely more important to have the COVID-19 vaccine earlier than to delay based on timing of Bcell therapy.
- Adalimumab o Anakinra o Anifrolumab o Azathioprine o Belimumab o Canakinumab o Certolizumab o Cyclosporin o Etanercept o Golimumab o Gusulkumab o
For patients on mycophenolate mofetil, if the disease is stable, hold the medication for one week following a COVID-19 dose. 6 *For patients on prednisone 20mg/day or higher (or equivalent), consider waiting until the prednisone dose is tapered to below 20mg/d to receive both vaccine doses. Pediatric patients on high-dose steroids should consult with their pediatric rheumatologist to decide on the best time to receive the vaccine. 17 NOTE: The American College of Rheumatology 5 differs from the Canadian Rheumatology Association with adjustment recommendations for the medications as follows. The authors of this guidance document are aligned with the Canadian Rheumatology Association's recommendations, with the exception of mycophenolate mofetil as described above. However, the American College's recommendations are available here and provided below for reference:
- For patients on weekly methotrexate (MTX), an option is to skip the MTX dose the following week after each vaccine dose. o For patients on tofacitinib, baricitinib, upadacitinib, an option is to skip the medication for one week following each vaccine dose. o For patients on abatacept weekly injections, an option is to skip the abatacept one week before and one week after the first dose of vaccine. Continue abatacept through the second dose of vaccine. For IV abatacept, consider timing the first dose of vaccine four weeks post-dose and postpone next infusion by one week. No IV Abatacept adjustments are needed for the second vaccine dose. o For patients on intravenous cyclophosphamide, an option is to take each vaccine dose at least one week prior to the next cyclophosphamide infusion. | The majority of adults and children with autoimmune rheumatic diseases (ARD) require immune modulating therapies for disease control. These therapies put people with ARD at higher risk for infections, particularly viral infections. 1 Immunosuppressed persons have a higher risk of poor outcomes with infections. 1,2 Although there is limited information about outcomes for people with ARD who develop COVID-19, one international study demonstrated that prednisone and an underlying diagnosis of lupus could be associated with worse outcomes and higher mortality. 3 Is COVID-19 immunization recommended for people with autoimmune rheumatic diseases? COVID-19 vaccines should be encouraged for people with autoimmune rheumatic diseases and are not contraindicated, including those who have had a COVID-19 infection. o Although the majority of patients with ARD who are immunosuppressed were excluded from clinical trials of the COVID-19 vaccines, the Canadian Rheumatology Association, 4 American College of Rheumatology 5 and British Rheumatology Association 6 have all released position statements strongly supporting the use of COVID-19 immunization in this population. o Experts agree that the potential benefits and anticipated desirable effects of COVID-19 immunization outweigh the potential harms in persons with ARD. [4][5][6] While data specific to the safety and efficacy of the COVID-19 vaccines in people who take immunosuppressant or immunomodulating therapies is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 7 The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization.#
Is the COVID-19 vaccine efficacious and safe in patients with autoimmune rheumatic diseases?
Adults and children with ARD who take immunosuppressant/immunomodulating therapy were excluded in all of the trials for the COVID-19 vaccines currently approved in Canada. As per NACI, safety data in immunocompromised individuals, including those receiving immunosuppressive therapy, were available from observational studies in people who were taking immunosuppressive therapies. The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that of non-immunocompromised individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available.
There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 8 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. The safety of a third dose is unknown at this time for ARD, but in these small studies reactions were found to be similar to that of prior doses. The impact of additional doses on the worsening of underlying disease or on rare adverse events, including the risk of myocarditis and/or pericarditis, is unknown at this time. 9 Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the authorized COVID-19 vaccines, as well as a discussion about the emerging evidence on the safety of mRNA COVID-19 vaccines in these populations. The recommendations in this clinical guidance are based on these small observational studies, extrapolation of data from other viral infections, immunology of immunizations and from expert opinion.
When infected, people with ARD can exhibit high variability with respect to clinical presentation, organ involvement, disease severity, comorbidities and medications. If a patient has complicated disease or multiple medical conditions and health-care providers have questions, they are encouraged to reach out to the patient's rheumatologist for specific guidance.
As the majority of patients with ARD are on immune suppressing medications, there may be blunting of the magnitude and duration of vaccine response compared to the general population. 4,6,10 Regardless, the benefits of immunization are considered to outweigh the potential risks.
Are there any specific contraindications or exceptions for people with autoimmune rheumatic diseases?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 11 BCCDC has a list of the individual components and their purpose in COVID-19 Vaccines for People with Autoimmune Rheumatic Diseases Updated: April 18, 2023 the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Other than allergy, there are no specific contradictions or exceptions for people with ARD apart from the efficacy and safety considerations outlined above.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine including the seasonal influenza vaccine. [12][13][14][15] Are there specific recommendations or considerations for safe and/or most effective administration?
Guidance from the Canadian Rheumatology Association 4 is to continue underlying immunosuppression and disease modifying agents without adjustment around COVID-19 immunization with the exception of Rituximab/Ocrelizumab, and high-dose prednisone as indicated below. Clinical advice to adjust Mycophenolate Mofetil around COVID-19 immunization (when the condition is stable) is derived from the American College of Rheumatology guidelines. 5 For patients on the following medications, there is no need to adjust or delay the medication: For patients on rituximab or ocrelizumab, the COVID-19 immunization should ideally be timed four to five months after their last infusion and two to four weeks prior to their next infusion, when possible, in order to optimize vaccine response. However, in patients who require immediate infusion or who are unable to optimize timing of infusion product and vaccine, it is likely more important to have the COVID-19 vaccine earlier than to delay based on timing of Bcell therapy.
o Adalimumab o Anakinra o Anifrolumab o Azathioprine o Belimumab o Canakinumab o Certolizumab o Cyclosporin o Etanercept o Golimumab o Gusulkumab o
For patients on mycophenolate mofetil, if the disease is stable, hold the medication for one week following a COVID-19 dose. 6 *For patients on prednisone 20mg/day or higher (or equivalent), consider waiting until the prednisone dose is tapered to below 20mg/d to receive both vaccine doses. Pediatric patients on high-dose steroids should consult with their pediatric rheumatologist to decide on the best time to receive the vaccine. 17 NOTE: The American College of Rheumatology 5 differs from the Canadian Rheumatology Association with adjustment recommendations for the medications as follows. The authors of this guidance document are aligned with the Canadian Rheumatology Association's recommendations, with the exception of mycophenolate mofetil as described above. However, the American College's recommendations are available here and provided below for reference:
o For patients on weekly methotrexate (MTX), an option is to skip the MTX dose the following week after each vaccine dose. o For patients on tofacitinib, baricitinib, upadacitinib, an option is to skip the medication for one week following each vaccine dose. o For patients on abatacept weekly injections, an option is to skip the abatacept one week before and one week after the first dose of vaccine. Continue abatacept through the second dose of vaccine. For IV abatacept, consider timing the first dose of vaccine four weeks post-dose and postpone next infusion by one week. No IV Abatacept adjustments are needed for the second vaccine dose. o For patients on intravenous cyclophosphamide, an option is to take each vaccine dose at least one week prior to the next cyclophosphamide infusion. | None | None |
28f62d9d041a189bf207ba9fda74dfec61bd4df7 | cma | None | 1) Health Canada and the pharmaceutical industry have identified that there was a three-fold increase in the demand for salbutamol inhalers in the first 3 weeks of March 2020. 2) This has resulted in a Tier 3 shortage, which by definition is "a situation when a manufacturer/importer is unable to meet demand for the drug. A tier 3 shortage is a shortage with the greatest potential impact on the Canadian drug supply and healthcare systems by virtue of availability of alternate supplies, ingredients, or therapies." 3) Restrictions have been put in place by wholesalers and distributors to limit the supply of salbutamol which means that most patients will receive only one salbutamol inhaler or a one month supply at a time . 4) It is possible that the surge in demand relates to individuals and organizations projecting future need and purchasing product in advance of actual need .#
When refilling your inhaled medications, you should expect to receive only a 1-month supply. This is in response to inventory control measures put in place. You should carefully track doses of salbutamol by dose counting. You should use all salbutamol inhalers that you may have in various locations before refilling medication. If you have multiple salbutamol inhalers use the one with the earliest expiry date first.
# In the event that a patient's only option is to use an expired salbutamol inhaler:
Not discard recently expired inhalers (e.g., expired in the last 6 months) until they have obtained a replacement. If they need to use their reliever inhaler and only have an expired inhaler, be aware that it may be less potent. They should use the expired inhaler and if not getting relief, seek medical attention. Use the diskus inhaler even if it was removed from the wrapper more than 60 days ago.
# Mitigation strategy Step 2: Recommended options for Salbutamol MDI substitutions in the event of a shortage
The CTS COPD Assembly Steering Committee developed this rapid guidance for Canadian physicians treating patients with COPD for an emerging salbutamol inhaler shortage during the COVID-19 pandemic. The recommendations are evidence-based and expert-opinion, and we recommend that treatment decisions be individualized.
# List of Medication Substitutions for Salbutamol in COPD Substitution Comment
Preferred substitution: based on safety and efficacy when applied across the population recognizing that substitution decisions may be at the discretion of the community pharmacist without consultation by the primary care or specialty provider. Terbutaline 0.5mg Turbuhaler (Bricanyl)
- A direct substitution for salbutamol MDI or Diskus - 2 inhalations of salbutamol MDI are equivalent to 1 inhalation of terbutaline.
Terbutaline is delivered as a dry powder inhaler (Turbuhaler), rather than in an MDI or Diskus
# Patients will need instruction on the proper use of this inhaler device. Salbutamol 200ug Diskus (Ventolin Diskus)
- A direct substitute for salbutamol MDI.
- 1 inhalation of Salbutamol Diskus is the same as 2 inhalations of salbutamol MDI
# Patients will need instructions on the proper use of this inhaler device.
Ipratropium Bromide (20ug)/Salbutamol (100ug) (Combivent Respimat)
- A direct substitution for salbutamol - However, the dosing approved in Canada is 1 inhalation q4h up to a maximum of 6 inhalations a day.
- Combivent is delivered as a soft mist inhaler (Respimat)
# Patients will need instruction on the proper use of this inhaler device. Patient on a long-acting antimuscarinic (LAMA) should continue to use their maintenance medication as prescribed.
# Less Preferred
Ipratropium Bromide 20ug pMDI (Atrovent)
- This bronchodilator works by a different mechanism than salbutamol and has a slightly delayed onset of action when compared to salbutamol. - It is prescribed as a reliever medication but may not be as effective as salbutamol as an acute reliever medication due to the delayed onset of action. - It may be more effective for some patients when used in combination with salbutamol.
- 2 inhalations of 20 mcg would be approximately equivalent to 2 inhalations of 100 mcg salbutamol and should not be given closer than 4 hours apart. Maximum daily dose of ipratropium: 12 inhalations or 240 mcg.
# Patient on a long-acting anti-muscarinic (LAMA) should continue to use their maintenance medication as prescribed.
# Inhaler Devices
Many of the alternative options to salbutamol do not come in an MDI. If an alternative is required it is likely that the patient will be using a different type of inhaler device and it is imperative that proper instructions are given to ensure adequate deposition and efficacy ( /).
Nebulizers are not the preferred method of COPD medication delivery at any time due to decreased deposition and effectiveness (this is why higher dose is used in nebulization than MDI), and the need for less portable and more expensive equipment. Nebulizing medication is an aerosol generating procedure and risks disseminating viruses, such as the virus responsible for COVID-19 (SARS-CoV-2). Therefore, it is not recommended that nebulized medications are used in suspected or confirmed COVID19 cases in healthcare settings unless there are no other alternatives. In situations where nebulized medications are the best available option for a particular patient, they should be given using airborne precautions. If this needs to be administered in hospital, it should be done in a negative pressure room with staff wearing proper personal protective equipment. If nebulization were administered at home or in other locations, it should be highlighted to all that could be affected, that there is a risk of viral transmission. | 1) Health Canada and the pharmaceutical industry have identified that there was a three-fold increase in the demand for salbutamol inhalers in the first 3 weeks of March 2020. 2) This has resulted in a Tier 3 shortage, which by definition is "a situation when a manufacturer/importer is unable to meet demand for the drug. A tier 3 shortage is a shortage with the greatest potential impact on the Canadian drug supply and healthcare systems by virtue of availability of alternate supplies, ingredients, or therapies." 3) Restrictions have been put in place by wholesalers and distributors to limit the supply of salbutamol which means that most patients will receive only one salbutamol inhaler or a one month supply at a time . 4) It is possible that the surge in demand relates to individuals and organizations projecting future need and purchasing product in advance of actual need [Stockpiling].#
When refilling your inhaled medications, you should expect to receive only a 1-month supply. This is in response to inventory control measures put in place. You should carefully track doses of salbutamol by dose counting. You should use all salbutamol inhalers that you may have in various locations before refilling medication. If you have multiple salbutamol inhalers use the one with the earliest expiry date first.
# In the event that a patient's only option is to use an expired salbutamol inhaler:
Not discard recently expired inhalers (e.g., expired in the last 6 months) until they have obtained a replacement. If they need to use their reliever inhaler and only have an expired inhaler, be aware that it may be less potent. They should use the expired inhaler and if not getting relief, seek medical attention. Use the diskus inhaler even if it was removed from the wrapper more than 60 days ago.
# Mitigation strategy Step 2: Recommended options for Salbutamol MDI substitutions in the event of a shortage
The CTS COPD Assembly Steering Committee developed this rapid guidance for Canadian physicians treating patients with COPD for an emerging salbutamol inhaler shortage during the COVID-19 pandemic. The recommendations are evidence-based and expert-opinion, and we recommend that treatment decisions be individualized.
# List of Medication Substitutions for Salbutamol in COPD Substitution Comment
Preferred substitution: based on safety and efficacy when applied across the population recognizing that substitution decisions may be at the discretion of the community pharmacist without consultation by the primary care or specialty provider. Terbutaline 0.5mg Turbuhaler (Bricanyl)
• A direct substitution for salbutamol MDI or Diskus • 2 inhalations of salbutamol MDI are equivalent to 1 inhalation of terbutaline.
Terbutaline is delivered as a dry powder inhaler (Turbuhaler), rather than in an MDI or Diskus
# Patients will need instruction on the proper use of this inhaler device. Salbutamol 200ug Diskus (Ventolin Diskus)
• A direct substitute for salbutamol MDI.
• 1 inhalation of Salbutamol Diskus is the same as 2 inhalations of salbutamol MDI
# Patients will need instructions on the proper use of this inhaler device.
Ipratropium Bromide (20ug)/Salbutamol (100ug) (Combivent Respimat)
• A direct substitution for salbutamol • However, the dosing approved in Canada is 1 inhalation q4h up to a maximum of 6 inhalations a day.
• Combivent is delivered as a soft mist inhaler (Respimat)
# Patients will need instruction on the proper use of this inhaler device. Patient on a long-acting antimuscarinic (LAMA) should continue to use their maintenance medication as prescribed.
# Less Preferred
Ipratropium Bromide 20ug pMDI (Atrovent)
• This bronchodilator works by a different mechanism than salbutamol and has a slightly delayed onset of action when compared to salbutamol. • It is prescribed as a reliever medication but may not be as effective as salbutamol as an acute reliever medication due to the delayed onset of action. • It may be more effective for some patients when used in combination with salbutamol.
• 2 inhalations of 20 mcg would be approximately equivalent to 2 inhalations of 100 mcg salbutamol and should not be given closer than 4 hours apart. Maximum daily dose of ipratropium: 12 inhalations or 240 mcg.
# Patient on a long-acting anti-muscarinic (LAMA) should continue to use their maintenance medication as prescribed.
# Inhaler Devices
Many of the alternative options to salbutamol do not come in an MDI. If an alternative is required it is likely that the patient will be using a different type of inhaler device and it is imperative that proper instructions are given to ensure adequate deposition and efficacy ( https://ctssct.ca/covid-19/how-to-properly-use-an-inhaler/).
Nebulizers are not the preferred method of COPD medication delivery at any time due to decreased deposition and effectiveness (this is why higher dose is used in nebulization than MDI), and the need for less portable and more expensive equipment. Nebulizing medication is an aerosol generating procedure and risks disseminating viruses, such as the virus responsible for COVID-19 (SARS-CoV-2). Therefore, it is not recommended that nebulized medications are used in suspected or confirmed COVID19 cases in healthcare settings unless there are no other alternatives. In situations where nebulized medications are the best available option for a particular patient, they should be given using airborne precautions. If this needs to be administered in hospital, it should be done in a negative pressure room with staff wearing proper personal protective equipment. If nebulization were administered at home or in other locations, it should be highlighted to all that could be affected, that there is a risk of viral transmission. | None | None |
b190d7562c1fcfbdcadf9cd6671d21a798702857 | cma | None | The Canadian Rheumatology Association guideline panel suggests using a third dose of mRNA COVID-19 vaccination or mRNA-1273 (Moderna)] in persons aged 18 and older with autoimmune rheumatic disease.Remarks: - This recommendation is based on evidence for mRNA-1273 (Moderna). - The recommendation needs to be viewed in the context of any guidance or restrictions for vaccine use set by national or provincial bodies, that may change over time. This includes guidance in people who have had a mixed initial vaccine series (2 different vaccines). Primary justification: - The panel judged that for the majority of patients the potential benefits outweigh the potential harms in people with autoimmune rheumatic diseases, although this may vary considerably by person, based on their medications, age, other comorbidities. The recommendation was graded as conditional because of very low certainty of the evidence about effects in the population of interest. Primary implementation consideration for policy makers and providers: - Persons with autoimmune rheumatic diseases should be able to access a third vaccine dose if desired, and not be required to take additional steps to obtain their vaccination.The CRA panel decided on a conditional recommendation for a third dose of mRNA COVID-19 vaccination in persons aged 18 and older with autoimmune rheumatic disease. The panel balanced the#
very low certainty in the moderate benefits of a third dose (prevention of symptomatic infection) against the very low certainty of evidence for trivial harms. The panel discussed that the expected benefits are likely to vary considerably in individuals by current medications, age, and other comorbidities, but the expected harms are likely to be trivial. The decision to receive a third dose should be an individual discussion between a patient and their healthcare provider.
# Subgroup considerations
The benefits of a third dose will likely vary considerably between individuals. Subgroups of patients in whom serological protection has been shown to be lower would be expected to have the greatest potential benefit from a third dose. Evidence is being accumulated on clinical outcomes and serological responses to COVID vaccination in patients with ARDs in a living systematic review (Whittle SL, Hazlewood GS et al. 2021), and will inform updates to this guideline.
As of October 2021, the evidence supports the following:
- People taking rituximab: Studies have consistently shown lower immunogenicity from the initial 2 doses of COVID-19 vaccination in people taking rituximab, which is consistent with other vaccines (Papp, Haraoui et al. 2019). Third doses should ideally be administered ⩾4-5 months after the last dose and at least 4 weeks prior to the subsequent dose of rituximab. - People taking other DMARDs: There was a modest, but consistent reduction in serological response to COVID-19 vaccination in people with immune mediated inflammatory diseases across the six pooled case-control studies (see 'desirable effects' section of EtD). The evidence is less certain when analyzed by medication subgroups. In data from other (non-COVID) vaccines, methotrexate, mycophenolate mofetil, tofacitinib and prednisone (>= 10 mg/day) have been shown to attenuate vaccine-induced responses (Papp, Haraoui et al. 2019). A single small study with abatacept and influenza vaccine also showed decreased immunogenicity (Ribeiro, Laurindo et al. 2013). It is likely that some medications (hydroxychloroquine, sulfasalazine) have little effect on serological response.
# Implementation considerations
- As access to third doses is determined by provincial health authorities, it will be essential to ensure people with ARDs do not face unnecessary additional barriers. People with ARDs should not be required to obtain a physician letter as proof of an informed decision discussion. - People with ARDs may have mobility limitations and appropriate access to vaccine clinics should be ensured.
# Monitoring and evaluation
- Monitoring of vaccine uptake should occur in people with ARDs, including populations at risk of inequity. Low uptake may point to barriers to access or hesitancy. - The frequency of serious adverse events, disease flares, and COVID-19 infection/serious outcomes should be followed in patients with ARDs who do and do not receive the vaccine. - People with ARDs should be encouraged to track their immunization history using an online Canadian vaccination tracker, developed with funding support from the Public Health Agency of Canada (www.canimmunize.ca).
# Research priorities
- Randomized controlled trial evidence for the effect of a third dose in ARDs as compared with placebo - Observational evidence on the frequency of harms (in particular serious adverse events/serious disease flares) in people with ARD - Evidence comparing the frequency of serious adverse events and autoimmune adverse events in people with ARDs to those without ARD - Evidence on the benefits (both clinical outcomes and serological studies) in people with ARDs on different medications, including in pediatric populations - Evidence on patient values and preferences for the benefits and harms across different patient populations - Understanding vaccine hesitancy and barriers to vaccine access faced by persons with ARDs - Understanding vaccine benefits and harms in populations at risk for inequities. | The Canadian Rheumatology Association guideline panel suggests using a third dose of mRNA COVID-19 vaccination or mRNA-1273 (Moderna)] in persons aged 18 and older with autoimmune rheumatic disease.Remarks: • This recommendation is based on evidence for mRNA-1273 (Moderna). • The recommendation needs to be viewed in the context of any guidance or restrictions for vaccine use set by national or provincial bodies, that may change over time. This includes guidance in people who have had a mixed initial vaccine series (2 different vaccines). Primary justification: • The panel judged that for the majority of patients the potential benefits outweigh the potential harms in people with autoimmune rheumatic diseases, although this may vary considerably by person, based on their medications, age, other comorbidities. The recommendation was graded as conditional because of very low certainty of the evidence about effects in the population of interest. Primary implementation consideration for policy makers and providers: • Persons with autoimmune rheumatic diseases should be able to access a third vaccine dose if desired, and not be required to take additional steps to obtain their vaccination.The CRA panel decided on a conditional recommendation for a third dose of mRNA COVID-19 vaccination in persons aged 18 and older with autoimmune rheumatic disease. The panel balanced the#
very low certainty in the moderate benefits of a third dose (prevention of symptomatic infection) against the very low certainty of evidence for trivial harms. The panel discussed that the expected benefits are likely to vary considerably in individuals by current medications, age, and other comorbidities, but the expected harms are likely to be trivial. The decision to receive a third dose should be an individual discussion between a patient and their healthcare provider.
# Subgroup considerations
The benefits of a third dose will likely vary considerably between individuals. Subgroups of patients in whom serological protection has been shown to be lower would be expected to have the greatest potential benefit from a third dose. Evidence is being accumulated on clinical outcomes and serological responses to COVID vaccination in patients with ARDs in a living systematic review (Whittle SL, Hazlewood GS et al. 2021), and will inform updates to this guideline.
As of October 2021, the evidence supports the following:
• People taking rituximab: Studies have consistently shown lower immunogenicity from the initial 2 doses of COVID-19 vaccination in people taking rituximab, which is consistent with other vaccines (Papp, Haraoui et al. 2019). Third doses should ideally be administered ⩾4-5 months after the last dose and at least 4 weeks prior to the subsequent dose of rituximab. • People taking other DMARDs: There was a modest, but consistent reduction in serological response to COVID-19 vaccination in people with immune mediated inflammatory diseases across the six pooled case-control studies (see 'desirable effects' section of EtD). The evidence is less certain when analyzed by medication subgroups. In data from other (non-COVID) vaccines, methotrexate, mycophenolate mofetil, tofacitinib and prednisone (>= 10 mg/day) have been shown to attenuate vaccine-induced responses (Papp, Haraoui et al. 2019). A single small study with abatacept and influenza vaccine also showed decreased immunogenicity (Ribeiro, Laurindo et al. 2013). It is likely that some medications (hydroxychloroquine, sulfasalazine) have little effect on serological response.
# Implementation considerations
• As access to third doses is determined by provincial health authorities, it will be essential to ensure people with ARDs do not face unnecessary additional barriers. People with ARDs should not be required to obtain a physician letter as proof of an informed decision discussion. • People with ARDs may have mobility limitations and appropriate access to vaccine clinics should be ensured.
# Monitoring and evaluation
• Monitoring of vaccine uptake should occur in people with ARDs, including populations at risk of inequity. Low uptake may point to barriers to access or hesitancy. • The frequency of serious adverse events, disease flares, and COVID-19 infection/serious outcomes should be followed in patients with ARDs who do and do not receive the vaccine. • People with ARDs should be encouraged to track their immunization history using an online Canadian vaccination tracker, developed with funding support from the Public Health Agency of Canada (www.canimmunize.ca).
# Research priorities
• Randomized controlled trial evidence for the effect of a third dose in ARDs as compared with placebo • Observational evidence on the frequency of harms (in particular serious adverse events/serious disease flares) in people with ARD • Evidence comparing the frequency of serious adverse events and autoimmune adverse events in people with ARDs to those without ARD • Evidence on the benefits (both clinical outcomes and serological studies) in people with ARDs on different medications, including in pediatric populations • Evidence on patient values and preferences for the benefits and harms across different patient populations • Understanding vaccine hesitancy and barriers to vaccine access faced by persons with ARDs • Understanding vaccine benefits and harms in populations at risk for inequities. | None | None |
1a896756960095605be7687fccb2520f5fe75ef0 | cma | None | This guidance is intended for health-care providers. It is based on known evidence as of April 18, 2023. Asplenia can be anatomical (i.e. splenectomy) or functional (i.e., resulting from conditions that cause atrophy, infarction, infiltration, or engorgement of the spleen). 1,2 Patients who have had a splenectomy or have functional asplenia are immunocompromised and are at increased risk for severe and overwhelming bacterial infections, particularly from encapsulated bacteria. These bacterial infections are more likely to occur in patients with viral infections.COVID-19 vaccines should be encouraged for patients who have had a splenectomy or who have functional asplenia and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the NACI recommendation which has stated that immunosuppressed individuals should be offered the vaccine if the benefits of vaccine outweigh the potential risks. 3 # Are COVID-19 vaccines efficacious and safe for people with splenectomy or functional asplenia?
People who have had a splenectomy or who have functional asplenia are considered immunocompromised, and people immunocompromised due to disease or treatment were excluded from the clinical trials. Therefore, data on whether COVID-19 vaccines are efficacious in patients who have had a splenectomy or have functional asplenia is currently limited. As with most vaccines, there is a potential for blunted immune response in individuals who are immunocompromised due to their disease or treatment. 3 As a matter of informed consent, patients who are immunocompromised should be informed about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of authorized COVID-19 Clinical Guidance on COVID-19 Vaccines for People with Splenectomy or Functional Asplenia Updated: April 18, 2023 vaccines. 3 However, they should also be reassured that expert consensus is that immunization should proceed as the benefits outweigh the risks. There are data to suggest that the currently available COVID-19 vaccines have efficacy. 9 Following immunization, patients should continue with COVID-19 precautionary measures as outlined in the current advice from the B.C. Centre for Disease Control.
# Are there any specific contraindications or exceptions for people with splenectomy or functional asplenia?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 10 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Other than allergy, there are no specific contradictions or exceptions for people who have had a splenectomy or who have functional asplenia.
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other inactivated vaccine. For patients with these conditions due to a haematological malignancy, sickle cell disease, or thalassemia, please refer to the clinical guidance document for those conditions on the BCCDC website.
# Are there specific recommendations or considerations for safe and/or most effective administration?
There are no known studies regarding the timing of COVID-19 vaccine in patients with a splenectomy or who have functional asplenia.
Clinical Guidance on COVID-19 Vaccines for People with Splenectomy or Functional Asplenia Updated: April 18, 2023
Based on the 2013 Infectious Diseases Society of America guidelines, immunization timing is recommended as follows for asplenic patients 15 :
- Elective splenectomy patients should start immunizations approximately 10-12 weeks prior to surgery, so series can be completed at least 14 days prior to splenectomy - If vaccine series cannot be completed prior to splenectomy, series can be resumed 14 days after surgery for most patients. - It is not clear how COVID-19 and other immunizations for encapsulated organisms should be sequenced or timed. COVID-19 vaccines can be administered concomitantly with, or any time before after, any other live or inactivated vaccine. The risk of other causes of sepsis are high in patients with asplenia and in the case of emergency surgery, other vaccines should probably be prioritized. | This guidance is intended for health-care providers. It is based on known evidence as of April 18, 2023. Asplenia can be anatomical (i.e. splenectomy) or functional (i.e., resulting from conditions that cause atrophy, infarction, infiltration, or engorgement of the spleen). 1,2 Patients who have had a splenectomy or have functional asplenia are immunocompromised and are at increased risk for severe and overwhelming bacterial infections, particularly from encapsulated bacteria. These bacterial infections are more likely to occur in patients with viral infections.COVID-19 vaccines should be encouraged for patients who have had a splenectomy or who have functional asplenia and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the NACI recommendation which has stated that immunosuppressed individuals should be offered the vaccine if the benefits of vaccine outweigh the potential risks. 3 # Are COVID-19 vaccines efficacious and safe for people with splenectomy or functional asplenia?
People who have had a splenectomy or who have functional asplenia are considered immunocompromised, and people immunocompromised due to disease or treatment were excluded from the clinical trials. [4][5][6][7][8] Therefore, data on whether COVID-19 vaccines are efficacious in patients who have had a splenectomy or have functional asplenia is currently limited. As with most vaccines, there is a potential for blunted immune response in individuals who are immunocompromised due to their disease or treatment. 3 As a matter of informed consent, patients who are immunocompromised should be informed about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of authorized COVID-19 Clinical Guidance on COVID-19 Vaccines for People with Splenectomy or Functional Asplenia Updated: April 18, 2023 vaccines. 3 However, they should also be reassured that expert consensus is that immunization should proceed as the benefits outweigh the risks. There are data to suggest that the currently available COVID-19 vaccines have efficacy. 9 Following immunization, patients should continue with COVID-19 precautionary measures as outlined in the current advice from the B.C. Centre for Disease Control.
# Are there any specific contraindications or exceptions for people with splenectomy or functional asplenia?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 10 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Other than allergy, there are no specific contradictions or exceptions for people who have had a splenectomy or who have functional asplenia.
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other inactivated vaccine. [11][12][13][14] For patients with these conditions due to a haematological malignancy, sickle cell disease, or thalassemia, please refer to the clinical guidance document for those conditions on the BCCDC website.
# Are there specific recommendations or considerations for safe and/or most effective administration?
There are no known studies regarding the timing of COVID-19 vaccine in patients with a splenectomy or who have functional asplenia.
Clinical Guidance on COVID-19 Vaccines for People with Splenectomy or Functional Asplenia Updated: April 18, 2023
Based on the 2013 Infectious Diseases Society of America guidelines, immunization timing is recommended as follows for asplenic patients 15 :
• Elective splenectomy patients should start immunizations approximately 10-12 weeks prior to surgery, so series can be completed at least 14 days prior to splenectomy • If vaccine series cannot be completed prior to splenectomy, series can be resumed 14 days after surgery for most patients. • It is not clear how COVID-19 and other immunizations for encapsulated organisms should be sequenced or timed. COVID-19 vaccines can be administered concomitantly with, or any time before after, any other live or inactivated vaccine. The risk of other causes of sepsis are high in patients with asplenia and in the case of emergency surgery, other vaccines should probably be prioritized. | None | None |
4fba73cdb72c1f59fee5acaf9dd569fa15ef9668 | cma | None | Background: Exercise is widely regarded to improve pain and function in patients with knee osteoarthritis (OA) through building supportive muscle mass, facilitating weight loss, and through the other beneficial effects associated with it. Purpose: To explore literature that presents clinical guidelines for the use of exercise in the treatment of knee OA to inform an evidence-based position statement for the Arthroscopy Association of Canada. Study Design: Position statement. Methods: PubMed, MEDLINE, Embase, and Cochrane databases were searched for guidelines commenting on the role of exercise for knee OA. The search was limited to guidelines published in the last 10 years. Articles were screened for relevance, focusing on recently published research with clinical guidelines. Inclusion criteria involved all articles providing clinical guidelines for exercise and knee OA. Results: Eight guidelines were identified. All eight recommended exercise as an important component of treatment for knee OA, with 6/8 strongly recommending it. Conclusion: Exercise is an effective and important component of the non-pharmacological management of knee OA. The Arthroscopy Association of Canada strongly recommends the use of exercise in the management of knee OA.# BACKGROUND
Osteoarthritis (OA) is one of the most common chronic medical disorders worldwide. 26 Its prevalence is increasing globally and is associated with an aging population as well as increases in risk factors such as obesity and a sedentary lifestyle. 26 In Canada, OA is an unfortunately common chronic condition, affecting more than 10% of the population according to official Canadian estimates. 6 The productivity cost from loss of work associated with OA is rising and is estimated in a recent study to cost the Canadian economy $17.5 billion annually by 2031. 31 OA can occur in many joints, however the knee in particular is one of the most commonly affected, associated with 29% of all OA cases in Canadians. 17 Through appropriate treatment, knee OA symptoms can be managed to prevent disability, increase mobility, and reduce pain. 6 Knee OA is multifactorial -a complex interplay of various factors including joint integrity, genetic predisposition, local inflammation, joint loading forces, and cellular and biochemical processes. 19 For most patients, treatment is largely focused on managing symptoms through nonoperative therapies including weight loss, strength training, bracing, anti-inflammatory drugs, and injectable medications or therapies. Total knee joint replacement (arthroplasty) represents the only definitive treatment for end-stage knee OA and there are a few other relatively minor procedures that can be performed.
However, these options should generally be pursued after all nonoperative options have been exhausted.
The most common modifiable risk factor for knee OA is obesity, which increases risk through various mechanisms including increased joint loading forces, changing body composition which can increase inflammation, and changing behaviors such as decreased exercise subsequently leading to the loss of protective muscle strength. 19 Biomechanical studies demonstrate that every pound (0.45 kg) of body weight gained adds 2 lbs to 4 lbs (0.9 kg -1.8 kg) of load across the knee. 19 Studies have also demonstrated that physical activity is lower among patients with OA and it varies depending on the location of the affected 4 joint. 9 Patients with knee OA have an especially lower level of physical activity due to the physical limitations of the legs. 9 There are many reasons why incorporating exercise in treatment plans for patients with knee OA may be beneficial. First, exercise has repeatedly been shown to be associated with multiple health benefits and an overall better quality of life. Lack of physical activity has been shown to worsen maximal function of the heart, peripheral circulation, skeletal muscle strength, bone strength and more 30 . It is not surprising then that OA is among 40 chronic diseases which are associated with a higher incidence and worse progression in people who are physically inactive. 30 Second, certain strengthening exercises can increase the muscle mass of quadriceps, hamstrings, and peripheral muscles surrounding the knee which play a key role in stability. 9 It has been shown that exercise reduces pain, improves quality of life, and improves the physical function of the knee in patients with knee OA. 8 Finally, accompanied by a change in diet, exercise plays a role in weight loss and muscle strengthening which reduces joint load on the knee and may also improve its biomechanical function. When regular exercise is incorporated with a change in diet for weight loss in obese patients, more fat mass is lost and lean skeletal muscle mass is retained leading to improved cardiovascular fitness, strength, and functional capacity of joints required to perform regular daily activities. 22 There is sufficient evidence that suggests exercise is beneficial to incorporate in the treatment of knee OA. This systematic review evaluates the latest clinical guidelines surrounding the use of exercise as a treatment option for patients with knee OA to come to a position statement for the Arthroscopy Association of Canada (AAC).
# METHODS
This study was conducted using the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions. 11 The findings are presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 23 A single reviewer (SM) searched PubMed, MEDLINE, Embase, and Cochrane databases with the terms "guideline", "exercise", "knee", and "osteoarthritis", using the "related articles" function. The search was limited to articles published in the last 10 years (Aug 31, 2010 -Aug 28, 2020).
Articles were screened by a single reviewer (SM) for relevance, focusing on recently published research with clinical guidelines including systematic reviews, meta-analyses, and randomized controlled trials. Inclusion criteria involved all clinical articles that provided guidelines for exercise and knee OA. All basic science studies, case series, case reviews, studies reporting on OA in joints other than the knee, and studies with outdated guidelines were excluded (Figure 1).
# RESULTS
# Clinical Guidelines
From the ten included studies, eight clinical guidelines were found as one of the reporting bodies (Ottawa Panel) published their guideline over a three-part study assessing different categories of exercise. All clinical guidelines recommended that exercise be incorporated into the treatment regimen for knee OA, with six of them strongly recommending it. All of the guidelines recommended general aerobic and strength training exercises. The recommendations for the method of supervision were not unanimous across the guidelines.
All papers recommended exercise as beneficial over no exercise. The results of the clinical guidelines have been summarized in Table 1.
# Types of Exercise
General categories of exercises that were recommended have been summarized in Table 1. From all the guideline bodies, only the Ottawa Panel further investigated specific exercise programs for the management of knee OA. The Ottawa Panel included 46 studies on specific exercise programs from which 35 received at least one positive recommendation and were reported. 2 There were 12 programs that received a strong recommendation which included one mind-body program (out of four evaluated), eight strength training programs (out of 26 evaluated) , and three aerobic and strength combination programs (out of five evaluated). 2,3,4 The mind-body program is a Tai Chi program recommended for pain relief and improved physical function. 2 The eight strength training programs use a variety of different strategies to strengthen leg muscles and are recommended for pain relief, improved physical function, and improved quality of life. 3 The three combination programs combine aerobic exercises and strength training and are recommended for improved quality of life, pain relief, and improved physical function. 4 The details for all the strongly recommended exercise programs by the Ottawa Panel have been summarized in Table 2. While all of the programs evaluated and recommended by the Ottawa Panel are of a fixed-length, they acknowledge that to receive long-lasting benefits in the management of knee OA therapeutic exercise needs to be continued indefinitely. 3 diagnosis and therapy program with 10 repetitions every two to three hours. 3 It was noted that muscle strengthening exercises are recommended with or without other therapeutic types of exercises as being an effective non-pharmacological intervention for managing knee OA. 3 There are a variety of different ways strength training can be incorporated and these exercises were recommended for pain relief, improved physical function, and improved quality of life among patients with knee OA. 3 Aerobic exercises were evaluated as well by the Ottawa Panel for their potential to improve cardiopulmonary function and overall quality of life. From the five programs they evaluated, three were strongly recommended which were an eight-week individual or group aerobic and strengthening program with two one-hour sessions a week, a 10-week community physiotherapy exercise program with three to six 20 min physiotherapist intervention sessions over the 10 weeks, and a three-month aerobic and strength exercise and osteoarthritis educational program with three one-hour sessions a week. 4 It was noted that the aerobic exercises evaluated were in combination programs with strength training and that presently, no recommendations of aerobic-only exercise programs could be made. 4 These aerobic and strength combination programs may be beneficial for pain relief, improved physical function, and improved quality of life among patients with knee OA.
# Supervision
General supervision recommendations have been summarized in Table 1. From all the studies included, only EULAR and ACR further investigated the outcomes of interventions by various healthcare professionals on exercise treatment for knee OA. EULAR gave a total of 10 recommendations out of which the two strongest recommendations were to incorporate general self-directed physical activity (PA) in treatment plans and for healthcare providers (HCPs) to plan and deliver PA activity interventions that include behavioral and selfmonitoring techniques (e.g. physician provides an OA information and basic exercise program pamphlet to patient and follows-up with patient). 28 The rest of the eight recommendations were given a weaker strength due primarily to a lack of quality evidence to support them. 28 Briefly, these recommendations are that all HCPs should promote PA, PA interventions should be delivered by appropriate HCPs, PA level of patients should be routinely evaluated, general and disease specific contraindications should be considered, PA should be personalised to patient goals, general and disease specific barriers should be addressed, PA should be adapted (if there are adverse reactions), behavioral changing interventions should be used, and a variety of modes of delivery should be considered. 28 In addition, ACR determined that generally exercise programs are more effective if supervised either by a provider such as a physical therapist or in a class rather than performed individually at home. 18 However, ACR also mentions that exercise should be focused on patient preference and regardless of the mode of delivery exercise is beneficial over no exercise. 18 Finally, if a patient does not find a certain form of exercise acceptable, cannot afford it, or cannot arrange transport to take part in it then it will not be beneficial for them. 18
# DISCUSSION
From all eight guidelines evaluated, it is clear that the incorporation of exercise is beneficial in the management of knee OA. While there isn't enough evidence to support the recommendation of a specific exercise program, there are some findings from the literature that may guide clinical judgement for determining an exercise plan for patients.
From the many exercise programs strongly recommended by the Ottawa panel there were a few key findings. First, regularity of exercise seems to be associated with its beneficial effects. This was the specific variable that gave the 20 week Sun style Tai Chi program that had shorter but more frequent sessions a strong recommendation over the same program delivered over 12 weeks with fewer but longer sessions. 2 Second, aerobic exercise should be performed in combination with strengthening exercises as there is insufficient evidence to determine if aerobic only exercise has significant benefit to patients with knee OA. 4 Strength training exercises on the other hand have been shown to be effective regardless of whether they are combined with other exercises or not. 3 Finally, regardless of what exercise program patients follow, the retention of beneficial effects do not last if exercise is stopped. Therefore to retain these benefits long-term, regular exercise needs to be continued indefinitely. 3 All of these elements are useful when creating effective exercise programs for patients.
Another aspect to consider is mode of administration. There is some evidence to suggest that exercises delivered through healthcare providers such as physiotherapists may be more beneficial to patients. 18,28 Several factors may contribute to this including structure, motivation, access to specialized equipment and exercises, supervision to ensure correct form, and individual adjustments for maximal effects. However, there may be barriers related to accessing therapist-supervised exercise, chiefly financial and transport. A few more points to consider when determining both types of exercises and mode of delivery are the frailty of the patient, comorbidities, and risk of injury, especially in patients who are >60 years of age and who are morbidly obese. These factors need to be taken into consideration when determining if supervised exercise programs will be beneficial for patients.
The following general parameters for an effective exercise program can be inferred. First, there should be multiple sessions per week, at least 2-3 sessions/ week as frequency of exercise was observed by the Ottawa panel to be associated with its beneficial effects and almost all their strongly recommended programs had more than 2 sessions/week. 2 Second, the majority of exercises should be strength-training as all eight guideline bodies recommend strength training and the Ottawa Panel could not recommended any aerobic only programs, only as combination with strengthening exercises. 3 The strengthening exercises should be focused on the quadriceps and hamstring muscles as most of the strengthening exercises in programs strongly recommended by the Ottawa Panel target these muscles. 3,4 Third, there should be some aerobic exercise included (likely the warm-up component or a general incorporation). There are many reasons for this but a big one is because all eight guideline bodies also recommended aerobic exercises.
Many of the exercise programs strongly recommended by the Ottawa panel also had some aerobic component, commonly warm up on a stationary bike. 3,4 Additionally, many activities patients commonly enjoy (e.g. walking, biking, swimming) are aerobic which ACR notes should be a focus of treatment. 18 Also, EULAR strongly promotes general PA which includes many aerobic exercises. 28 Fourth, the strength exercises should consist of a variety of exercises including isometric, isotonic, WB, NWB, and therapeutic band resistance exercises such as leg extensions, leg press, leg lifts, stair climb, wall sit etc… All of these exercises were commonly used in strongly recommended exercise programs by the Ottawa Panel. 3,4 Fifth, there should be around 5-20 reps and 5-10 sets for strength exercises and a maximum of 50-60% onerepetition maximum (RM) for intense exercises as found in the literature from the strongly recommended exercise programs from the Ottawa panel. 7,12,14,15,24,29 These should be adjusted for total number of exercises, patient tolerance, and intensity of exercise. Finally, exercise programs should be supervised or have some HCP intervention as it has been noted by ACR and EULAR to be more effective and most of the Ottawa Panel programs had some type of HCP supervision. 2,3,4,18,28 While all of these parameters can be deduced, there isn't sufficient evidence across all eight guideline bodies to make a firm recommendation. As noted by the Ottawa panel, retention of beneficial effects does not last if exercise is stopped and ACR notes the best way to keep patients consistent is to have exercises focused on patient preference. 2,18 A rigid exercise program as described above can usually be sustained for a limited period and provide short-term improvement for symptoms of knee OA, as shown in all exercise programs strongly recommended by the Ottawa Panel. This has its place in immediately improving the patient's knee pain and function, allowing them to initially pursue a more concrete exercise program.
However, focusing on long-term benefits for patients requires an exercise regimen integrated into the patient's daily life.
In this systematic review all literature available containing clinical guidelines for the use of exercise in treating patients with knee OA was evaluated. Eight clinical guidelines were found which all recommended to incorporate exercise, with 6/8 strongly recommending it. In addition, specific exercises and methods of supervision were explored to find details that may be beneficial for clinical use, and the structure of an ideal exercise program was theorized. From this investigation, there is no conclusive evidence to recommend specific exercises or specific exercise programs beyond a combination of aerobic exercises and strength training targeting quadriceps and hamstring muscles. Exercise interventions should have multiple regularly scheduled sessions every week. The specific exercises should be something that the patient enjoys and can continue long-term to reap continual benefit from. If suitable for the patient, an exercise program that is supervised by a physical therapist or trainer may be beneficial. All of these factors should be discussed with the patient to create the most effective plan for them. The incorporation of any consistent exercise is better than none.
# POSITION STATEMENT
After evaluating all recent guidelines available, the Arthroscopy Association of Canada (AAC) strongly recommends incorporating a combination of aerobic and strength training exercises that work the quadriceps and hamstring muscles at regular intervals that can be continued long-term into treatment regimens for patients with knee OA. Whether self-directed or therapist supervised, exercise implemented alongside with patient education and other non-surgical treatments plays a significant role in managing the symptoms of knee OA. This position statement is endorsed by the Canadian Academy of Sport and Exercise Medicine (CASEM).
# LIMITATIONS
This review was carried out by a single reviewer. This review assessed papers that presented clinical guidelines regarding exercise and knee OA only. There was no risk of bias analysis performed. There were very few guidelines and a limited number of quality studies especially regarding specific of types of exercise and methods of supervision. Each guideline also used a different method to assign strength to their recommendation. | Background: Exercise is widely regarded to improve pain and function in patients with knee osteoarthritis (OA) through building supportive muscle mass, facilitating weight loss, and through the other beneficial effects associated with it. Purpose: To explore literature that presents clinical guidelines for the use of exercise in the treatment of knee OA to inform an evidence-based position statement for the Arthroscopy Association of Canada. Study Design: Position statement. Methods: PubMed, MEDLINE, Embase, and Cochrane databases were searched for guidelines commenting on the role of exercise for knee OA. The search was limited to guidelines published in the last 10 years. Articles were screened for relevance, focusing on recently published research with clinical guidelines. Inclusion criteria involved all articles providing clinical guidelines for exercise and knee OA. Results: Eight guidelines were identified. All eight recommended exercise as an important component of treatment for knee OA, with 6/8 strongly recommending it. Conclusion: Exercise is an effective and important component of the non-pharmacological management of knee OA. The Arthroscopy Association of Canada strongly recommends the use of exercise in the management of knee OA.# BACKGROUND
Osteoarthritis (OA) is one of the most common chronic medical disorders worldwide. 26 Its prevalence is increasing globally and is associated with an aging population as well as increases in risk factors such as obesity and a sedentary lifestyle. 26 In Canada, OA is an unfortunately common chronic condition, affecting more than 10% of the population according to official Canadian estimates. 6 The productivity cost from loss of work associated with OA is rising and is estimated in a recent study to cost the Canadian economy $17.5 billion annually by 2031. 31 OA can occur in many joints, however the knee in particular is one of the most commonly affected, associated with 29% of all OA cases in Canadians. 17 Through appropriate treatment, knee OA symptoms can be managed to prevent disability, increase mobility, and reduce pain. 6 Knee OA is multifactorial -a complex interplay of various factors including joint integrity, genetic predisposition, local inflammation, joint loading forces, and cellular and biochemical processes. 19 For most patients, treatment is largely focused on managing symptoms through nonoperative therapies including weight loss, strength training, bracing, anti-inflammatory drugs, and injectable medications or therapies. Total knee joint replacement (arthroplasty) represents the only definitive treatment for end-stage knee OA and there are a few other relatively minor procedures that can be performed.
However, these options should generally be pursued after all nonoperative options have been exhausted.
The most common modifiable risk factor for knee OA is obesity, which increases risk through various mechanisms including increased joint loading forces, changing body composition which can increase inflammation, and changing behaviors such as decreased exercise subsequently leading to the loss of protective muscle strength. 19 Biomechanical studies demonstrate that every pound (0.45 kg) of body weight gained adds 2 lbs to 4 lbs (0.9 kg -1.8 kg) of load across the knee. 19 Studies have also demonstrated that physical activity is lower among patients with OA and it varies depending on the location of the affected 4 joint. 9 Patients with knee OA have an especially lower level of physical activity due to the physical limitations of the legs. 9 There are many reasons why incorporating exercise in treatment plans for patients with knee OA may be beneficial. First, exercise has repeatedly been shown to be associated with multiple health benefits and an overall better quality of life. Lack of physical activity has been shown to worsen maximal function of the heart, peripheral circulation, skeletal muscle strength, bone strength and more 30 . It is not surprising then that OA is among 40 chronic diseases which are associated with a higher incidence and worse progression in people who are physically inactive. 30 Second, certain strengthening exercises can increase the muscle mass of quadriceps, hamstrings, and peripheral muscles surrounding the knee which play a key role in stability. 9 It has been shown that exercise reduces pain, improves quality of life, and improves the physical function of the knee in patients with knee OA. 8 Finally, accompanied by a change in diet, exercise plays a role in weight loss and muscle strengthening which reduces joint load on the knee and may also improve its biomechanical function. When regular exercise is incorporated with a change in diet for weight loss in obese patients, more fat mass is lost and lean skeletal muscle mass is retained leading to improved cardiovascular fitness, strength, and functional capacity of joints required to perform regular daily activities. 22 There is sufficient evidence that suggests exercise is beneficial to incorporate in the treatment of knee OA. This systematic review evaluates the latest clinical guidelines surrounding the use of exercise as a treatment option for patients with knee OA to come to a position statement for the Arthroscopy Association of Canada (AAC).
# METHODS
This study was conducted using the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions. 11 The findings are presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 23 A single reviewer (SM) searched PubMed, MEDLINE, Embase, and Cochrane databases with the terms "guideline", "exercise", "knee", and "osteoarthritis", using the "related articles" function. The search was limited to articles published in the last 10 years (Aug 31, 2010 -Aug 28, 2020).
Articles were screened by a single reviewer (SM) for relevance, focusing on recently published research with clinical guidelines including systematic reviews, meta-analyses, and randomized controlled trials. Inclusion criteria involved all clinical articles that provided guidelines for exercise and knee OA. All basic science studies, case series, case reviews, studies reporting on OA in joints other than the knee, and studies with outdated guidelines were excluded (Figure 1).
# RESULTS
# Clinical Guidelines
From the ten included studies, eight clinical guidelines were found as one of the reporting bodies (Ottawa Panel) published their guideline over a three-part study assessing different categories of exercise. All clinical guidelines recommended that exercise be incorporated into the treatment regimen for knee OA, with six of them strongly recommending it. All of the guidelines recommended general aerobic and strength training exercises. The recommendations for the method of supervision were not unanimous across the guidelines.
All papers recommended exercise as beneficial over no exercise. The results of the clinical guidelines have been summarized in Table 1.
# Types of Exercise
General categories of exercises that were recommended have been summarized in Table 1. From all the guideline bodies, only the Ottawa Panel further investigated specific exercise programs for the management of knee OA. The Ottawa Panel included 46 studies on specific exercise programs from which 35 received at least one positive recommendation and were reported. 2 There were 12 programs that received a strong recommendation which included one mind-body program (out of four evaluated), eight strength training programs (out of 26 evaluated) , and three aerobic and strength combination programs (out of five evaluated). 2,3,4 The mind-body program is a Tai Chi program recommended for pain relief and improved physical function. 2 The eight strength training programs use a variety of different strategies to strengthen leg muscles and are recommended for pain relief, improved physical function, and improved quality of life. 3 The three combination programs combine aerobic exercises and strength training and are recommended for improved quality of life, pain relief, and improved physical function. 4 The details for all the strongly recommended exercise programs by the Ottawa Panel have been summarized in Table 2. While all of the programs evaluated and recommended by the Ottawa Panel are of a fixed-length, they acknowledge that to receive long-lasting benefits in the management of knee OA therapeutic exercise needs to be continued indefinitely. 3 diagnosis and therapy program with 10 repetitions every two to three hours. 3 It was noted that muscle strengthening exercises are recommended with or without other therapeutic types of exercises as being an effective non-pharmacological intervention for managing knee OA. 3 There are a variety of different ways strength training can be incorporated and these exercises were recommended for pain relief, improved physical function, and improved quality of life among patients with knee OA. 3 Aerobic exercises were evaluated as well by the Ottawa Panel for their potential to improve cardiopulmonary function and overall quality of life. From the five programs they evaluated, three were strongly recommended which were an eight-week individual or group aerobic and strengthening program with two one-hour sessions a week, a 10-week community physiotherapy exercise program with three to six 20 min physiotherapist intervention sessions over the 10 weeks, and a three-month aerobic and strength exercise and osteoarthritis educational program with three one-hour sessions a week. 4 It was noted that the aerobic exercises evaluated were in combination programs with strength training and that presently, no recommendations of aerobic-only exercise programs could be made. 4 These aerobic and strength combination programs may be beneficial for pain relief, improved physical function, and improved quality of life among patients with knee OA.
# Supervision
General supervision recommendations have been summarized in Table 1. From all the studies included, only EULAR and ACR further investigated the outcomes of interventions by various healthcare professionals on exercise treatment for knee OA. EULAR gave a total of 10 recommendations out of which the two strongest recommendations were to incorporate general self-directed physical activity (PA) in treatment plans and for healthcare providers (HCPs) to plan and deliver PA activity interventions that include behavioral and selfmonitoring techniques (e.g. physician provides an OA information and basic exercise program pamphlet to patient and follows-up with patient). 28 The rest of the eight recommendations were given a weaker strength due primarily to a lack of quality evidence to support them. 28 Briefly, these recommendations are that all HCPs should promote PA, PA interventions should be delivered by appropriate HCPs, PA level of patients should be routinely evaluated, general and disease specific contraindications should be considered, PA should be personalised to patient goals, general and disease specific barriers should be addressed, PA should be adapted (if there are adverse reactions), behavioral changing interventions should be used, and a variety of modes of delivery should be considered. 28 In addition, ACR determined that generally exercise programs are more effective if supervised either by a provider such as a physical therapist or in a class rather than performed individually at home. 18 However, ACR also mentions that exercise should be focused on patient preference and regardless of the mode of delivery exercise is beneficial over no exercise. 18 Finally, if a patient does not find a certain form of exercise acceptable, cannot afford it, or cannot arrange transport to take part in it then it will not be beneficial for them. 18
# DISCUSSION
From all eight guidelines evaluated, it is clear that the incorporation of exercise is beneficial in the management of knee OA. While there isn't enough evidence to support the recommendation of a specific exercise program, there are some findings from the literature that may guide clinical judgement for determining an exercise plan for patients.
From the many exercise programs strongly recommended by the Ottawa panel there were a few key findings. First, regularity of exercise seems to be associated with its beneficial effects. This was the specific variable that gave the 20 week Sun style Tai Chi program that had shorter but more frequent sessions a strong recommendation over the same program delivered over 12 weeks with fewer but longer sessions. 2 Second, aerobic exercise should be performed in combination with strengthening exercises as there is insufficient evidence to determine if aerobic only exercise has significant benefit to patients with knee OA. 4 Strength training exercises on the other hand have been shown to be effective regardless of whether they are combined with other exercises or not. 3 Finally, regardless of what exercise program patients follow, the retention of beneficial effects do not last if exercise is stopped. Therefore to retain these benefits long-term, regular exercise needs to be continued indefinitely. 3 All of these elements are useful when creating effective exercise programs for patients.
Another aspect to consider is mode of administration. There is some evidence to suggest that exercises delivered through healthcare providers such as physiotherapists may be more beneficial to patients. 18,28 Several factors may contribute to this including structure, motivation, access to specialized equipment and exercises, supervision to ensure correct form, and individual adjustments for maximal effects. However, there may be barriers related to accessing therapist-supervised exercise, chiefly financial and transport. A few more points to consider when determining both types of exercises and mode of delivery are the frailty of the patient, comorbidities, and risk of injury, especially in patients who are >60 years of age and who are morbidly obese. These factors need to be taken into consideration when determining if supervised exercise programs will be beneficial for patients.
The following general parameters for an effective exercise program can be inferred. First, there should be multiple sessions per week, at least 2-3 sessions/ week as frequency of exercise was observed by the Ottawa panel to be associated with its beneficial effects and almost all their strongly recommended programs had more than 2 sessions/week. 2 Second, the majority of exercises should be strength-training as all eight guideline bodies recommend strength training and the Ottawa Panel could not recommended any aerobic only programs, only as combination with strengthening exercises. 3 The strengthening exercises should be focused on the quadriceps and hamstring muscles as most of the strengthening exercises in programs strongly recommended by the Ottawa Panel target these muscles. 3,4 Third, there should be some aerobic exercise included (likely the warm-up component or a general incorporation). There are many reasons for this but a big one is because all eight guideline bodies also recommended aerobic exercises.
Many of the exercise programs strongly recommended by the Ottawa panel also had some aerobic component, commonly warm up on a stationary bike. 3,4 Additionally, many activities patients commonly enjoy (e.g. walking, biking, swimming) are aerobic which ACR notes should be a focus of treatment. 18 Also, EULAR strongly promotes general PA which includes many aerobic exercises. 28 Fourth, the strength exercises should consist of a variety of exercises including isometric, isotonic, WB, NWB, and therapeutic band resistance exercises such as leg extensions, leg press, leg lifts, stair climb, wall sit etc… All of these exercises were commonly used in strongly recommended exercise programs by the Ottawa Panel. 3,4 Fifth, there should be around 5-20 reps and 5-10 sets for strength exercises and a maximum of 50-60% onerepetition maximum (RM) for intense exercises as found in the literature from the strongly recommended exercise programs from the Ottawa panel. 7,12,14,15,24,29 These should be adjusted for total number of exercises, patient tolerance, and intensity of exercise. Finally, exercise programs should be supervised or have some HCP intervention as it has been noted by ACR and EULAR to be more effective and most of the Ottawa Panel programs had some type of HCP supervision. 2,3,4,18,28 While all of these parameters can be deduced, there isn't sufficient evidence across all eight guideline bodies to make a firm recommendation. As noted by the Ottawa panel, retention of beneficial effects does not last if exercise is stopped and ACR notes the best way to keep patients consistent is to have exercises focused on patient preference. 2,18 A rigid exercise program as described above can usually be sustained for a limited period and provide short-term improvement for symptoms of knee OA, as shown in all exercise programs strongly recommended by the Ottawa Panel. This has its place in immediately improving the patient's knee pain and function, allowing them to initially pursue a more concrete exercise program.
However, focusing on long-term benefits for patients requires an exercise regimen integrated into the patient's daily life.
In this systematic review all literature available containing clinical guidelines for the use of exercise in treating patients with knee OA was evaluated. Eight clinical guidelines were found which all recommended to incorporate exercise, with 6/8 strongly recommending it. In addition, specific exercises and methods of supervision were explored to find details that may be beneficial for clinical use, and the structure of an ideal exercise program was theorized. From this investigation, there is no conclusive evidence to recommend specific exercises or specific exercise programs beyond a combination of aerobic exercises and strength training targeting quadriceps and hamstring muscles. Exercise interventions should have multiple regularly scheduled sessions every week. The specific exercises should be something that the patient enjoys and can continue long-term to reap continual benefit from. If suitable for the patient, an exercise program that is supervised by a physical therapist or trainer may be beneficial. All of these factors should be discussed with the patient to create the most effective plan for them. The incorporation of any consistent exercise is better than none.
# POSITION STATEMENT
After evaluating all recent guidelines available, the Arthroscopy Association of Canada (AAC) strongly recommends incorporating a combination of aerobic and strength training exercises that work the quadriceps and hamstring muscles at regular intervals that can be continued long-term into treatment regimens for patients with knee OA. Whether self-directed or therapist supervised, exercise implemented alongside with patient education and other non-surgical treatments plays a significant role in managing the symptoms of knee OA. This position statement is endorsed by the Canadian Academy of Sport and Exercise Medicine (CASEM).
# LIMITATIONS
This review was carried out by a single reviewer. This review assessed papers that presented clinical guidelines regarding exercise and knee OA only. There was no risk of bias analysis performed. There were very few guidelines and a limited number of quality studies especially regarding specific of types of exercise and methods of supervision. Each guideline also used a different method to assign strength to their recommendation. | None | None |
a3ed3b33e93ced8a6a5bfa3a77d430632df082f5 | cma | None | Follow-up V/P SPECT is ideally suited for use in the follow-up of PE because small and large emboli are recognized so that regression or progression of thrombotic disease can be studied in detail. Furthermore, the low radiation exposure allows repeated studies. It can be applied in all patients. Using the same method for diagnosis and for follow-up has great advantages. Perfusion-only scintigraphy may be chosen for control during the initial phase of treatment CANM endorses Fig. 3 -Algorithms for diagnostic imaging for acute PE suspected as published in Eur# CANM Guidelines for Ventilation/Perfusion (V/P SPECT) in Pulmonary
Embolism Executive Summary
Diagnostic approach for PE. Generally, predictive models based on clinical data for PE are poor. D-dimer has high NPV but low specificity for PE, and is not needed if the pretest probability for PE is other than low. V/P SPECT has at least the same or better accuracy for PE as CTPA, but much lower radiation dose especially regarding breast exposure. Also, there have been little or no reported adverse reactions.
Methodology V/P SPECT should be used instead of planar acquisition when available. Multidetector gamma-cameras with large FOV are preferred for V/P SPECT. A one-day ventilation and perfusion protocol where the ventilation precedes the perfusion is the norm. For ventilation, 99m Tc-Technegas is the best radio-aerosol, particularly in patients with COPD. Liquid aerosols produced in nebulizers such as 99m Tc-DTPA are inferior for SPECT and should not be used unless Technegas is not available. Lung perfusion is performed using 99m Tc-macroaggregated albumin (MAA). Suggested administered doses and acquisition parameters are presented in table 1 of attached document. Appropriate iterative reconstruction and display of transverse, sagittal and coronal projections are essential for interpretation.
Interpretation criteria and reporting Interpretation in probabilistic terms is not appropriate and must be avoided. Accordingly, all exams should be interpreted as either "PE present" or "PE absent" or other similar clear affirmative terms. Affirmative diagnosis of PE requires the presence of vascular type mismatches. PE is considered excluded if perfusion is normal, if there are only matched defects, non-vascular type mismatches or reverse mismatches. See document for explanations. Findings other than PE may be clinically pertinent, especially if symptoms include dyspnea or desaturation. All PEs should have a final control 3 months after diagnosis to assess final reperfusion and to benefit from the availability of a baseline exam in case of recurrent symptoms.
Other considerations In the pediatric population and during pregnancy, one should consider V/P SPECT as the first investigation for suspected PE due to better sensitivity, lower radiation, and no adverse reactions. As ventilation co-morbidities are unlikely, a perfusion-only study might suffice, with an optional ventilation study the next day if needed. However, V/P SPECT should be used in pregnant women with co-morbidities or a history of smoking. Due to a higher sensitivity and no adverse reactions, V/P SPECT should be the first investigation for the assessment of Chronic PE. Although we do not recommend performing SPECT-CT on a regular basis, it could be appropriate in more challenging and selected cases.
# Recommandations de l'ACMN pour les études de ventilation et de perfusion (V/P SPECT) dans l'embolie pulmonaire Résumé
Approche diagnostique De façon générale, les modèles pour établir la probabilité clinique d'embolie pulmonaire (EP) sont médiocres. Les D-dimères ont une valeur prédictive négative (VPN) élevée mais ne sont pas spécifiques d'EP et sont par ailleurs non-contributoires à moins d'une faible probabilité clinique pré-test. La scintitomographie pulmonaire (V/P SPECT) a une exactitude diagnostique au moins égale ou supérieure à l'angio-tomodensitométrie (Angio-TDM) et offre un taux de radiation nettement plus bas, en particulier au niveau des seins, et ne cause virtuellement aucune réaction adverse.
Méthodologie Lorsque disponible, l'acquisition en mode tomographique (SPECT) à l'aide d'une caméra scintigraphique multi-détecteurs à large champs devrait toujours être favorisée à la méthode planaire. Le protocole standard consiste à réaliser une étude ventilatoire suivie d'une étude perfusionnelle pendant la même session. Pour la ventilation, le meilleur agent est le 99m Tc-Technegas, à plus forte raison chez les sujets atteints de maladie pulmonaire obstructive chronique (MPOC). Les radio-aérosols liquides administrés par nébulisateur tel le 99m Tc-DTPA sont clairement inférieurs en mode SPECT et ne devraient être utilisés que si le Technegas n'est pas disponible. La perfusion est évaluée avec des macro-aggrégats d'albumine ( 99m Tc-MAA). Les doses recommandées ainsi que les paramètres d'acquisition sont énumérés au Tableau 1 du document ci-joint. Une méthode de reconstruction itérative des données et un affichage des coupes transverses, coronales et sagittales sont nécessaires pour une bonne interprétation.
Critères d'interprétation et compte-rendu Une interprétation en matière de probabilité d'EP est inadéquate et doit être évitée à tout prix. Conséquemment, tous les résultats d'examens doivent être rapportés en matière d'embolie pulmonaire "présente" ou "absente", ou autre terminologie équivalente. Un diagnostic affirmatif d'EP requiert la présence de déficits perfusionnels non-congruents (mismatches) de type vasculaire. L'embolie pulmonaire est éliminée lorsque la perfusion est normale, s'il n'y a que des déficits congruents ou non-congruents mais de type non-vasculaires ainsi qu'en présence de déficits ventilatoires non-congruents (reverse mismatches). Voir le document accompagnateur pour les détails. Outre la présence d'embolies pulmonaires, d'autres trouvailles sont à l'occasion pertinentes en particulier si les signes et symptômes incluent désaturation ou dyspnée. Un suivi scintigraphique (V/P SPECT) de contrôle devrait être obtenu 3 mois après un diagnostic initial d'EP, pour établir le degré final de reperfusion et à titre d'examen de référence en cas de suspicion d'une récidive.
Considérations additionnelles Chez la population pédiatrique et pendant la grossesse, la scintitomographie pulmonaire devrait être utilisée comme examen de première ligne en raison d'une meilleure sensibilité, moins d'exposition à la radiation et absence de réactions adverses. Les co-morbidités étant peu fréquentes chez ces populations, l'investigation peut se limiter à une étude perfusionnelle, avec l'option de procéder à une étude ventilatoire le lendemain si nécessaire. Cependant, une évaluation complète (V/P SPECT) est requise chez les patientes enceintes avec co-morbidités ou histoire de tabagisme. La scintitomographie pulmonaire est aussi l'examen de choix en première ligne dans l'embolie pulmonaire chronique, grâce à sa meilleure sensibilité et à l'absence de réactions adverses. Bien qu'une évaluation hybride de type SPECT-CT ne soit pas recommandée de façon routinière, ceci peut être utile pour certains cas plus complexes ou face à un diagnostic difficile.
# CANM Endorsement of the 2009 EANM Guidelines for Ventilation / Perfusion
Scintigraphy 1) Diagnostic approach to pulmonary embolism (PE) . Availability is the main determinant of use for MDCT vs V/P SPECT 8. Fetal dose is roughly equivalent for both V/P SPECT and MD-CTPA 9. Breast dose is much higher with MD-CTPA as compared to V/P SPECT 10. V/P SPECT carries less risk of allergic reaction associated with contrast agent injection 11. 99% of patients referred for V/P can undergo the exam.
# Referral criteria and assessment of clinical probability
# Imaging studies in PE
The diagnosis of PE relies upon imaging tests, notably V/P scan and MDCT. In many clinical studies, including recent ones, comparisons between V/P scan and MDCT have been based upon obsolete scintigraphic techniques and interpretation criteria. The lack of a satisfactory gold standard for the diagnosis of PE poses difficulties for the assessment of sensitivity, specificity and accuracy of all diagnostic methods for PE. V/P SPECT has at least the same or equal accuracy for PE as MDCT.
Additional diagnoses found on V/P SPECT include COPD, left heart failure and pneumonia. MDCT provides valuable information about diagnoses other than PE, such as aortic aneurysm, tumour, pleural effusion and pneumonia. A high number of patients are ineligible for MDCT due to kidney failure, allergy, ventilator support, recent MI and critical illness. 99% of patients referred for V/P can undergo the exam. CTPA is more readily available on a 24/7 basis and thus may be used more often.
# Radiation Doses
The effective radiation dose from V/P SPECT is 1.2-2 mSv. The absorbed dose to the female breast is estimated as 0.8 mGy. During the first trimester, the estimated dose for perfusion study (50 MBq) gives a fetal absorbed dose of 0.1-0.2 mGy .
For MDCT during the first trimester the absorbed fetal dose was estimated as 0.24-0.66 mGy and significantly higher later during gestation. Recent studies have shown that MDCT is often technically suboptimal during pregnancy. The rate of nondiagnostic MDCT studies was 27.5% during pregnancy, versus 7.5% in nonpregnant women.
Based upon data from ICRP reports, the effective dose for V/P SPECT with the recommended protocol is about 35-40% of the dose from MDCT. The dose to the female breast for V/P SPECT is only 4% of the dose from MDCT. During the first trimester of pregnancy the fetal dose from MDCT is greater than or equivalent to that of V/P SCAN. The advantage of V/P SPECT increases after the first trimester.
# Introduction
Planar ventilation/perfusion technique with probabilistic interpretation suffered disrepute since the PIOPED I study showed that 65% of scans were nondiagnostic for PE. Consequently, it has become an inferior technique for most clinicians and should be replaced by more advanced nuclear medicine imaging using SPECT acquisition whenever available. The following recommendations regarding the choice of radiopharmaceuticals and imaging strategies for V/P studies are based on the 2009 EANM guidelines, updated with the more recent literature.
# Radiopharmaceuticals Ventilation 81m
Kr (krypton) is currently the only gas appropriate for V/P SPECT. However, because of high costs and limited distribution, it is not readily available in Canada. The best widely available agent for ventilation is 99m Tc-Technegas, an aerosol of carbon nanoparticles (5-200 nm) generated in a high temperature furnace (Technegas Generator, Cyclomedica). Because of the very small particle size, this agent is distributed in the lungs almost like a gas and deposited in alveoli by diffusion, where they remain stable, thus providing the best possible images for ventilation SPECT. In practice, between 400-900 MBq (10-25 mCi) of 99m TcO4 in 0.15ml NS is vaporized in a graphite crucible at 2750 °C in an argon atmosphere. The resulting 99m Tc-Technegas is inhaled as soon as possible (<5 minutes) by the patient in a supine position, over the course of 2 to 5 inspirations. Activity over the lungs should be monitored, and administered activity should be around 30-50 MBq (0.8-1.4 mCi).
Liquid aerosols produced in nebulizers, such as 99m Tc-DTPA, are inferior for SPECT, and should not be used unless technegas is not available. Overall, technegas remains the best radio-aerosol, particularly in patients with obstructive lung disease. Another advantage is that only a few breaths are sufficient to achieve an adequate amount of activity in the lungs, reducing time and personnel exposure to radiation.
# Perfusion
Lung perfusion is performed using 99m Tc-macroaggregated albumin (MAA). These albumin particles average 10-90 um in size, which allows them to lodge in the pulmonary capillaries and properly define lung perfusion. Normally, about 400,000 particles are injected, but a reduction to between 100,000 and 200,000 is recommended in patients with severe pulmonary hypertension or after a single lung transplantation. A minimum of 60,000 particles is needed to obtain a uniform distribution. The suspension containing 99m Tc-MAA should be gently shaken immediately before use and then administered by slow i.v. bolus injection over several respiratory cycles while the supine patient breathes at normal tidal volumes. Withdrawal of blood into the syringe must be avoided to prevent aggregation artefacts. The administered dose is typically between 120-240 MBq (3-6 mCi) but actually depends on the count rate of the ventilation agent. The activity ratio between perfusion and ventilation should be at least 4:1. The EANM guidelines recommend doses at the low end of the range to keep radiation exposure low (< 2.5 mSv).
# Equipment and imaging protocols
A one-day ventilation and perfusion protocol where the ventilation precedes the perfusion is the norm. Ventilation is essential to maximize specificity and may help recognize alternate pathologies. A perfusion only protocol might be considered during pregnancy (with an optional day-after ventilation study if needed) or in the context of massive PE.
Planar acquisition should not be used anymore, unless SPECT is not feasible for some reason. In this case, six to eight projections are recommended for both ventilation and perfusion. The recommended matrix size is 256×256 in combination with a LEHR collimator, and acquisition time should be long enough to yield 500-1,000 kcounts per view.
Multidetector dual or triple head -cameras with large FOV are preferred for V/P SPECT. LEHR parallel collimators with 128 x 128 matrix size represents a good combination, but LEAP collimators with a 64 x 64 matrix are also adequate especially if one aims for lower doses and/or shorter acquisition times. It is important that the patient remains in the same supine position, carefully maintained between ventilation and perfusion acquisitions. A total acquisition time of 20-30 minutes (excluding dead time) is usually sufficient to complete both the ventilation and the perfusion SPECT scans. Ranges of acceptable doses and acquisition parameters are shown in Table 1 below. Ultimately the doses to be administered should be determined by each institution on the basis of the image quality obtained in a reasonable time, which is influenced by factors such as camera sensitivity, collimator choice, acquisition matrix size, processing parameters and local radiation protection guidelines. The added benefit of SPECT-CT is still debated, but the SPECT part acquisition parameters are similar, if there is a need to acquire CT data in selected cases.
# Reconstruction and display
Transverse, sagittal and coronal projections are generated using an OSEM (ordered-subset expectation maximization) or equivalent iterative reconstruction algorithm. The number of iterations, subsets and other parameters may vary according to the manufacturer's software used to this end, but overly noisy images should be avoided as they do not promote reproducible interpretations. A 3D post reconstruction filter is usually applied, and the final images can be reviewed in each of the orthogonal planes, preferably on a workstation with dedicated software. Pseudo-planar images can be generated using an angular summing technique and other methods. More advanced data processing can also be performed. Defect contrast on perfusion SPECT can be further enhanced by subtracting the background activity remaining from the preceding ventilation scan. Further, by examining the pixelbased V/P ratio, quotient images can be generated from the SPECT data. These parametric images can facilitate reporting and improve the demonstration of defect location and extent.
# 3) Interpretation criteria and reporting -
# Basic criteria -
Affirmative or negative w/r to PE -Other possible diagnoses -Follow-up recommendations _____________________________________ Interpretation Interpretation in probabilistic terms is not appropriate with VQ SPECT and should be abandoned. All images should be interpreted as either "PE present" or "PE absent" or other similar clear affirmative terms. A small number of "non-diagnostic or equivocal studies" is inevitable for various reasons but should not exceed 5% of the case load.
Affirmative diagnosis of PE requires the presence of vascular type mismatches. Vascular type perfusion defects have the following characteristics: moderate to severe defects, with clear borders, which are pleural based, wider at pleura than centrally, with an orientation compatible with pulmonary vascular anatomy. At the sub-segmental level, the shape is usually triangular. PE present: PE is diagnosed if there is at least one lobar or segmental vascular type mismatched defect (perfusion defect with preserved ventilation), or two sub-segmental vascular mismatches, regardless of other findings. PE absent: PE is considered excluded if perfusion is normal, if there are only matched defects (regardless of morphology), non-vascular type mismatches or reverse mismatches (perfusion preserved but ventilation absent).
A frequent cause of non-vascular mismatches is physiologically compressed lung. Typical locations are posterior para-mediastinal lung, costophrenic angles, the top of the great fissures and shallow posterior lung surfaces in cases of gravity dependant atelectasis. Other causes include penetration of ventilation agent in emphysema bullae or cystic space in severe fibrosis.
False positives interpretation may occur mainly in extrinsic vascular compression, pulmonary vein stenosis and rare cases of vasculitis.
The interpretation of an isolated vascular-type defect that is matched on ventilation and congruent with a radiographic opacity of similar size remains controversial because an isolated pulmonary infarct is a possibility (albeit not a frequent one). If symptoms are not acute (more than a few days), partial reperfusion of embolic disease can give atypical perfusion patterns. In difficult cases, consultation with the clinician is suggested.
# Other diagnoses
Other findings than PE may be clinically pertinent, especially if symptoms include dyspnea or desaturation.
-Cardiac failure: redistribution of perfusion to superior and anterior portions of the lungs (inversion of the normal gradient) associated with preserved normal ventilation gradient is highly suggestive of early cardiac failure and can be observed earlier than on chest X-ray. This redistribution of perfusion is often lost with more advanced failure and typical X-ray change of edema.
-COPD: The magnitude of changes observed on VQ SPECT correlates with COPD severity, which can be underestimated clinically. Changes are typically more severe on ventilation, which include varying degrees of heterogeneity, ventilation defects and aerosol deposition at various bronchi levels indicating turbulence.
-Reverse mismatch: indicates failure of the physiological pulmonary vasoconstriction in the presence of a ventilation defect. May contribute to hypoxemia because of right-to-left shunt effect. Frequent association with pneumonia and may also be seen in atelectasis, mucous plug or other causes of bronchi obstruction.
# Follow up
All PEs should have a final control 3 months after diagnosis to assess final reperfusion and benefit from the availability of a baseline exam in case of recurrent symptoms. Once a diagnosis of PE is made, a follow up exam is necessary to evaluate the degree of reperfusion. This has 2 purposes. First, incomplete reperfusion of a moderate to extensive PE is associated with the development of chronic pulmonary hypertension. Second, if there is a suspicion of new PE on follow up, it may be impossible to distinguish new PE from unresolved prior PE. If PE is extensive, routine early control 7-10 days after diagnosis is advisable since a substantial part of reperfusion may occur in the first week. If there is early suspicion of new PE, this early control may be invaluable for correct diagnosis in this group.
# Conclusions
In situations of Acute PE, Chronic PE, Pregnancy, Pediatrics, and the COPD population one can consider V/P SPECT, with or without low dose CT, as a first line investigation due to high sensitivity and specificity, low radiation, and no adverse reactions.
In situations of Pregnancy and Pediatrics due to the low likelihood of ventilation co-morbidities one could consider Perfusion only SPECT as a first line investigation. If co-morbidities exist then a full V/P SPECT should be performed. Also, V/P SPECT is not influenced by vascular volume changes during pregnancy as is CTPA.
In situations of COPD up to 31% of patients may have PE and up to 10% may die. Even those patients who have abnormal Chest X ray can still undergo V/P SPECT and in selected patients, V/P SPECT with low dose non-contrast CT could be considered. Technegas is considered the agent of choice in this population as there is less central airway deposition, better peripheral penetration, and it does not wash out as quickly as traditional aerosols.
Interpretation of new defects on control VQ SPECT has some known pitfalls. Sometimes, a partially occluding proximal defect may dissolve in several distal severe defects. Although those defects may seem impressive, they are not new. Also, clots located close to branching arteries may dissolve proximally and part of the clot may be drawn in the adjacent artery.
Additional considerations | Follow-up V/P SPECT is ideally suited for use in the follow-up of PE because small and large emboli are recognized so that regression or progression of thrombotic disease can be studied in detail. Furthermore, the low radiation exposure allows repeated studies. It can be applied in all patients. Using the same method for diagnosis and for follow-up has great advantages. Perfusion-only scintigraphy may be chosen for control during the initial phase of treatment CANM endorses Fig. 3 -Algorithms for diagnostic imaging for acute PE suspected as published in Eur# CANM Guidelines for Ventilation/Perfusion (V/P SPECT) in Pulmonary
Embolism Executive Summary
# 1.
Diagnostic approach for PE. Generally, predictive models based on clinical data for PE are poor. D-dimer has high NPV but low specificity for PE, and is not needed if the pretest probability for PE is other than low. V/P SPECT has at least the same or better accuracy for PE as CTPA, but much lower radiation dose especially regarding breast exposure. Also, there have been little or no reported adverse reactions.
# 2.
Methodology V/P SPECT should be used instead of planar acquisition when available. Multidetector gamma-cameras with large FOV are preferred for V/P SPECT. A one-day ventilation and perfusion protocol where the ventilation precedes the perfusion is the norm. For ventilation, 99m Tc-Technegas is the best radio-aerosol, particularly in patients with COPD. Liquid aerosols produced in nebulizers such as 99m Tc-DTPA are inferior for SPECT and should not be used unless Technegas is not available. Lung perfusion is performed using 99m Tc-macroaggregated albumin (MAA). Suggested administered doses and acquisition parameters are presented in table 1 of attached document. Appropriate iterative reconstruction and display of transverse, sagittal and coronal projections are essential for interpretation.
# 3.
Interpretation criteria and reporting Interpretation in probabilistic terms is not appropriate and must be avoided. Accordingly, all exams should be interpreted as either "PE present" or "PE absent" or other similar clear affirmative terms. Affirmative diagnosis of PE requires the presence of vascular type mismatches. PE is considered excluded if perfusion is normal, if there are only matched defects, non-vascular type mismatches or reverse mismatches. See document for explanations. Findings other than PE may be clinically pertinent, especially if symptoms include dyspnea or desaturation. All PEs should have a final control 3 months after diagnosis to assess final reperfusion and to benefit from the availability of a baseline exam in case of recurrent symptoms.
# 4.
Other considerations In the pediatric population and during pregnancy, one should consider V/P SPECT as the first investigation for suspected PE due to better sensitivity, lower radiation, and no adverse reactions. As ventilation co-morbidities are unlikely, a perfusion-only study might suffice, with an optional ventilation study the next day if needed. However, V/P SPECT should be used in pregnant women with co-morbidities or a history of smoking. Due to a higher sensitivity and no adverse reactions, V/P SPECT should be the first investigation for the assessment of Chronic PE. Although we do not recommend performing SPECT-CT on a regular basis, it could be appropriate in more challenging and selected cases.
# Recommandations de l'ACMN pour les études de ventilation et de perfusion (V/P SPECT) dans l'embolie pulmonaire Résumé
# 1.
Approche diagnostique De façon générale, les modèles pour établir la probabilité clinique d'embolie pulmonaire (EP) sont médiocres. Les D-dimères ont une valeur prédictive négative (VPN) élevée mais ne sont pas spécifiques d'EP et sont par ailleurs non-contributoires à moins d'une faible probabilité clinique pré-test. La scintitomographie pulmonaire (V/P SPECT) a une exactitude diagnostique au moins égale ou supérieure à l'angio-tomodensitométrie (Angio-TDM) et offre un taux de radiation nettement plus bas, en particulier au niveau des seins, et ne cause virtuellement aucune réaction adverse.
# 2.
Méthodologie Lorsque disponible, l'acquisition en mode tomographique (SPECT) à l'aide d'une caméra scintigraphique multi-détecteurs à large champs devrait toujours être favorisée à la méthode planaire. Le protocole standard consiste à réaliser une étude ventilatoire suivie d'une étude perfusionnelle pendant la même session. Pour la ventilation, le meilleur agent est le 99m Tc-Technegas, à plus forte raison chez les sujets atteints de maladie pulmonaire obstructive chronique (MPOC). Les radio-aérosols liquides administrés par nébulisateur tel le 99m Tc-DTPA sont clairement inférieurs en mode SPECT et ne devraient être utilisés que si le Technegas n'est pas disponible. La perfusion est évaluée avec des macro-aggrégats d'albumine ( 99m Tc-MAA). Les doses recommandées ainsi que les paramètres d'acquisition sont énumérés au Tableau 1 du document ci-joint. Une méthode de reconstruction itérative des données et un affichage des coupes transverses, coronales et sagittales sont nécessaires pour une bonne interprétation.
# 3.
Critères d'interprétation et compte-rendu Une interprétation en matière de probabilité d'EP est inadéquate et doit être évitée à tout prix. Conséquemment, tous les résultats d'examens doivent être rapportés en matière d'embolie pulmonaire "présente" ou "absente", ou autre terminologie équivalente. Un diagnostic affirmatif d'EP requiert la présence de déficits perfusionnels non-congruents (mismatches) de type vasculaire. L'embolie pulmonaire est éliminée lorsque la perfusion est normale, s'il n'y a que des déficits congruents ou non-congruents mais de type non-vasculaires ainsi qu'en présence de déficits ventilatoires non-congruents (reverse mismatches). Voir le document accompagnateur pour les détails. Outre la présence d'embolies pulmonaires, d'autres trouvailles sont à l'occasion pertinentes en particulier si les signes et symptômes incluent désaturation ou dyspnée. Un suivi scintigraphique (V/P SPECT) de contrôle devrait être obtenu 3 mois après un diagnostic initial d'EP, pour établir le degré final de reperfusion et à titre d'examen de référence en cas de suspicion d'une récidive.
# 4.
Considérations additionnelles Chez la population pédiatrique et pendant la grossesse, la scintitomographie pulmonaire devrait être utilisée comme examen de première ligne en raison d'une meilleure sensibilité, moins d'exposition à la radiation et absence de réactions adverses. Les co-morbidités étant peu fréquentes chez ces populations, l'investigation peut se limiter à une étude perfusionnelle, avec l'option de procéder à une étude ventilatoire le lendemain si nécessaire. Cependant, une évaluation complète (V/P SPECT) est requise chez les patientes enceintes avec co-morbidités ou histoire de tabagisme. La scintitomographie pulmonaire est aussi l'examen de choix en première ligne dans l'embolie pulmonaire chronique, grâce à sa meilleure sensibilité et à l'absence de réactions adverses. Bien qu'une évaluation hybride de type SPECT-CT ne soit pas recommandée de façon routinière, ceci peut être utile pour certains cas plus complexes ou face à un diagnostic difficile.
# CANM Endorsement of the 2009 EANM Guidelines for Ventilation / Perfusion
Scintigraphy 1) Diagnostic approach to pulmonary embolism (PE) . Availability is the main determinant of use for MDCT vs V/P SPECT 8. Fetal dose is roughly equivalent for both V/P SPECT and MD-CTPA 9. Breast dose is much higher with MD-CTPA as compared to V/P SPECT 10. V/P SPECT carries less risk of allergic reaction associated with contrast agent injection 11. 99% of patients referred for V/P can undergo the exam.
# Referral criteria and assessment of clinical probability
# Imaging studies in PE
The diagnosis of PE relies upon imaging tests, notably V/P scan and MDCT. In many clinical studies, including recent ones, comparisons between V/P scan and MDCT have been based upon obsolete scintigraphic techniques and interpretation criteria. The lack of a satisfactory gold standard for the diagnosis of PE poses difficulties for the assessment of sensitivity, specificity and accuracy of all diagnostic methods for PE. V/P SPECT has at least the same or equal accuracy for PE as MDCT.
Additional diagnoses found on V/P SPECT include COPD, left heart failure and pneumonia. MDCT provides valuable information about diagnoses other than PE, such as aortic aneurysm, tumour, pleural effusion and pneumonia. A high number of patients are ineligible for MDCT due to kidney failure, allergy, ventilator support, recent MI and critical illness. 99% of patients referred for V/P can undergo the exam. CTPA is more readily available on a 24/7 basis and thus may be used more often.
# Radiation Doses
The effective radiation dose from V/P SPECT is 1.2-2 mSv. The absorbed dose to the female breast is estimated as 0.8 mGy. During the first trimester, the estimated dose for perfusion study (50 MBq) gives a fetal absorbed dose of 0.1-0.2 mGy [47].
For MDCT during the first trimester the absorbed fetal dose was estimated as 0.24-0.66 mGy and significantly higher later during gestation. Recent studies have shown that MDCT is often technically suboptimal during pregnancy. The rate of nondiagnostic MDCT studies was 27.5% during pregnancy, versus 7.5% in nonpregnant women.
Based upon data from ICRP reports, the effective dose for V/P SPECT with the recommended protocol is about 35-40% of the dose from MDCT. The dose to the female breast for V/P SPECT is only 4% of the dose from MDCT. During the first trimester of pregnancy the fetal dose from MDCT is greater than or equivalent to that of V/P SCAN. The advantage of V/P SPECT increases after the first trimester.
# Introduction
Planar ventilation/perfusion technique with probabilistic interpretation suffered disrepute since the PIOPED I study showed that 65% of scans were nondiagnostic for PE. Consequently, it has become an inferior technique for most clinicians and should be replaced by more advanced nuclear medicine imaging using SPECT acquisition whenever available. The following recommendations regarding the choice of radiopharmaceuticals and imaging strategies for V/P studies are based on the 2009 EANM guidelines, updated with the more recent literature.
# Radiopharmaceuticals Ventilation 81m
Kr (krypton) is currently the only gas appropriate for V/P SPECT. However, because of high costs and limited distribution, it is not readily available in Canada. The best widely available agent for ventilation is 99m Tc-Technegas, an aerosol of carbon nanoparticles (5-200 nm) generated in a high temperature furnace (Technegas Generator, Cyclomedica). Because of the very small particle size, this agent is distributed in the lungs almost like a gas and deposited in alveoli by diffusion, where they remain stable, thus providing the best possible images for ventilation SPECT. In practice, between 400-900 MBq (10-25 mCi) of 99m TcO4 in 0.15ml NS is vaporized in a graphite crucible at 2750 °C in an argon atmosphere. The resulting 99m Tc-Technegas is inhaled as soon as possible (<5 minutes) by the patient in a supine position, over the course of 2 to 5 inspirations. Activity over the lungs should be monitored, and administered activity should be around 30-50 MBq (0.8-1.4 mCi).
Liquid aerosols produced in nebulizers, such as 99m Tc-DTPA, are inferior for SPECT, and should not be used unless technegas is not available. Overall, technegas remains the best radio-aerosol, particularly in patients with obstructive lung disease. Another advantage is that only a few breaths are sufficient to achieve an adequate amount of activity in the lungs, reducing time and personnel exposure to radiation.
# Perfusion
Lung perfusion is performed using 99m Tc-macroaggregated albumin (MAA). These albumin particles average 10-90 um in size, which allows them to lodge in the pulmonary capillaries and properly define lung perfusion. Normally, about 400,000 particles are injected, but a reduction to between 100,000 and 200,000 is recommended in patients with severe pulmonary hypertension or after a single lung transplantation. A minimum of 60,000 particles is needed to obtain a uniform distribution. The suspension containing 99m Tc-MAA should be gently shaken immediately before use and then administered by slow i.v. bolus injection over several respiratory cycles while the supine patient breathes at normal tidal volumes. Withdrawal of blood into the syringe must be avoided to prevent aggregation artefacts. The administered dose is typically between 120-240 MBq (3-6 mCi) but actually depends on the count rate of the ventilation agent. The activity ratio between perfusion and ventilation should be at least 4:1. The EANM guidelines recommend doses at the low end of the range to keep radiation exposure low (< 2.5 mSv).
# Equipment and imaging protocols
A one-day ventilation and perfusion protocol where the ventilation precedes the perfusion is the norm. Ventilation is essential to maximize specificity and may help recognize alternate pathologies. A perfusion only protocol might be considered during pregnancy (with an optional day-after ventilation study if needed) or in the context of massive PE.
Planar acquisition should not be used anymore, unless SPECT is not feasible for some reason. In this case, six to eight projections are recommended for both ventilation and perfusion. The recommended matrix size is 256×256 in combination with a LEHR collimator, and acquisition time should be long enough to yield 500-1,000 kcounts per view.
Multidetector dual or triple head -cameras with large FOV are preferred for V/P SPECT. LEHR parallel collimators with 128 x 128 matrix size represents a good combination, but LEAP collimators with a 64 x 64 matrix are also adequate especially if one aims for lower doses and/or shorter acquisition times. It is important that the patient remains in the same supine position, carefully maintained between ventilation and perfusion acquisitions. A total acquisition time of 20-30 minutes (excluding dead time) is usually sufficient to complete both the ventilation and the perfusion SPECT scans. Ranges of acceptable doses and acquisition parameters are shown in Table 1 below. Ultimately the doses to be administered should be determined by each institution on the basis of the image quality obtained in a reasonable time, which is influenced by factors such as camera sensitivity, collimator choice, acquisition matrix size, processing parameters and local radiation protection guidelines. The added benefit of SPECT-CT is still debated, but the SPECT part acquisition parameters are similar, if there is a need to acquire CT data in selected cases.
# Reconstruction and display
Transverse, sagittal and coronal projections are generated using an OSEM (ordered-subset expectation maximization) or equivalent iterative reconstruction algorithm. The number of iterations, subsets and other parameters may vary according to the manufacturer's software used to this end, but overly noisy images should be avoided as they do not promote reproducible interpretations. A 3D post reconstruction filter is usually applied, and the final images can be reviewed in each of the orthogonal planes, preferably on a workstation with dedicated software. Pseudo-planar images can be generated using an angular summing technique and other methods. More advanced data processing can also be performed. Defect contrast on perfusion SPECT can be further enhanced by subtracting the background activity remaining from the preceding ventilation scan. Further, by examining the pixelbased V/P ratio, quotient images can be generated from the SPECT data. These parametric images can facilitate reporting and improve the demonstration of defect location and extent.
# 3) Interpretation criteria and reporting -
# Basic criteria -
Affirmative or negative w/r to PE -Other possible diagnoses -Follow-up recommendations _____________________________________ Interpretation Interpretation in probabilistic terms is not appropriate with VQ SPECT and should be abandoned. All images should be interpreted as either "PE present" or "PE absent" or other similar clear affirmative terms. A small number of "non-diagnostic or equivocal studies" is inevitable for various reasons but should not exceed 5% of the case load.
Affirmative diagnosis of PE requires the presence of vascular type mismatches. Vascular type perfusion defects have the following characteristics: moderate to severe defects, with clear borders, which are pleural based, wider at pleura than centrally, with an orientation compatible with pulmonary vascular anatomy. At the sub-segmental level, the shape is usually triangular. PE present: PE is diagnosed if there is at least one lobar or segmental vascular type mismatched defect (perfusion defect with preserved ventilation), or two sub-segmental vascular mismatches, regardless of other findings. PE absent: PE is considered excluded if perfusion is normal, if there are only matched defects (regardless of morphology), non-vascular type mismatches or reverse mismatches (perfusion preserved but ventilation absent).
A frequent cause of non-vascular mismatches is physiologically compressed lung. Typical locations are posterior para-mediastinal lung, costophrenic angles, the top of the great fissures and shallow posterior lung surfaces in cases of gravity dependant atelectasis. Other causes include penetration of ventilation agent in emphysema bullae or cystic space in severe fibrosis.
False positives interpretation may occur mainly in extrinsic vascular compression, pulmonary vein stenosis and rare cases of vasculitis.
The interpretation of an isolated vascular-type defect that is matched on ventilation and congruent with a radiographic opacity of similar size remains controversial because an isolated pulmonary infarct is a possibility (albeit not a frequent one). If symptoms are not acute (more than a few days), partial reperfusion of embolic disease can give atypical perfusion patterns. In difficult cases, consultation with the clinician is suggested.
# Other diagnoses
Other findings than PE may be clinically pertinent, especially if symptoms include dyspnea or desaturation.
-Cardiac failure: redistribution of perfusion to superior and anterior portions of the lungs (inversion of the normal gradient) associated with preserved normal ventilation gradient is highly suggestive of early cardiac failure and can be observed earlier than on chest X-ray. This redistribution of perfusion is often lost with more advanced failure and typical X-ray change of edema.
-COPD: The magnitude of changes observed on VQ SPECT correlates with COPD severity, which can be underestimated clinically. Changes are typically more severe on ventilation, which include varying degrees of heterogeneity, ventilation defects and aerosol deposition at various bronchi levels indicating turbulence.
-Reverse mismatch: indicates failure of the physiological pulmonary vasoconstriction in the presence of a ventilation defect. May contribute to hypoxemia because of right-to-left shunt effect. Frequent association with pneumonia and may also be seen in atelectasis, mucous plug or other causes of bronchi obstruction.
# Follow up
All PEs should have a final control 3 months after diagnosis to assess final reperfusion and benefit from the availability of a baseline exam in case of recurrent symptoms. Once a diagnosis of PE is made, a follow up exam is necessary to evaluate the degree of reperfusion. This has 2 purposes. First, incomplete reperfusion of a moderate to extensive PE is associated with the development of chronic pulmonary hypertension. Second, if there is a suspicion of new PE on follow up, it may be impossible to distinguish new PE from unresolved prior PE. If PE is extensive, routine early control 7-10 days after diagnosis is advisable since a substantial part of reperfusion may occur in the first week. If there is early suspicion of new PE, this early control may be invaluable for correct diagnosis in this group.
# Conclusions
In situations of Acute PE, Chronic PE, Pregnancy, Pediatrics, and the COPD population one can consider V/P SPECT, with or without low dose CT, as a first line investigation due to high sensitivity and specificity, low radiation, and no adverse reactions.
In situations of Pregnancy and Pediatrics due to the low likelihood of ventilation co-morbidities one could consider Perfusion only SPECT as a first line investigation. If co-morbidities exist then a full V/P SPECT should be performed. Also, V/P SPECT is not influenced by vascular volume changes during pregnancy as is CTPA.
In situations of COPD up to 31% of patients may have PE and up to 10% may die. Even those patients who have abnormal Chest X ray can still undergo V/P SPECT and in selected patients, V/P SPECT with low dose non-contrast CT could be considered. Technegas is considered the agent of choice in this population as there is less central airway deposition, better peripheral penetration, and it does not wash out as quickly as traditional aerosols.
#
Interpretation of new defects on control VQ SPECT has some known pitfalls. Sometimes, a partially occluding proximal defect may dissolve in several distal severe defects. Although those defects may seem impressive, they are not new. Also, clots located close to branching arteries may dissolve proximally and part of the clot may be drawn in the adjacent artery.
# 4)
Additional considerations | None | None |
5c0e33dbcd0910ef20af6ad11b57d08002bade4d | cma | None | PURPOSE To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients. METHODS Recommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients. RESULTS There were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made. CONCLUSION We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps.# INTRODUCTION
Children and adolescents receiving intensive myelosuppressive chemotherapy and some pediatric hematopoietic stem-cell transplantation (HSCT) recipients are at high risk for invasive fungal disease (IFD) caused by yeasts and molds. In these patients, infections with Candida and Aspergillus species are most common. IFDs are important because they are associated with substantial morbidity, delayed cancer treatment, increased health services utilization, and treatmentrelated mortality. 5 Systemic antifungal prophylaxis can be an effective approach to reducing IFD. A clinical practice guideline (CPG) facilitates evidence-based clinical care by describing risks and benefits of different management options based on a systematic review of the literature. Risks and benefits are weighed against each other by a panel of experts to arrive at care recommendations. Previously published CPGs 6,7 addressing systemic antifungal prophylaxis in pediatric patients are . 5 years old and thus do not consider results of recent trials. In addition, those panels had limited regional and disease representation. Key representatives of two previously published CPGs for pediatric patients (T.L., E.C., L.L.D., A.H.G., E.R., M.S., A.W., P.D.R., and L.S.) 6,7 were brought together to arrive at a single harmonized CPG, thus improving consistency of recommendations internationally. The objective was to develop a CPG for systemic antifungal prophylaxis in pediatric patients with cancer and HSCT recipients.
# METHODS
# Panel Constitution
The panel included representatives from the fields of pediatric hematology/oncology, pediatric HSCT, pediatric infectious diseases, nursing, and pharmacy; a patient advocate; and a CPG methodologist (Data Supplement). Panel members were selected based on clinical and methodologic expertise and geographic representation. All panel members declared potential conflicts of interest, and none precluded participation in this CPG (Data Supplement).
# General CPG Development Approach
We used standard approaches to create this CPG, 8 including the Appraisal of Guidelines for Research and Evaluation II instrument, to direct development. 9 Financial support for CPG creation was provided by the Pediatric Oncology Group of Ontario. However, CPG development, drafting of recommendations and the manuscript, and the decision to submit for publication were independent from the funder.
The key clinical questions were developed by the panel and are listed in Table 1. The target population is children and adolescents (age 0-18 years) receiving chemotherapy for cancer or undergoing HSCT. Target users are physicians, microbiologists, nurse practitioners, nurses, pharmacists, antibiotic stewards, and other health care professionals who are concerned with infectious complications in pediatric patients receiving chemotherapy or undergoing HSCT.
Panel members identified and rated the importance of outcomes by consensus. Outcomes that were considered critical for decision making were proven or probable IFD, mold infection or yeast infection, fungal infection-related mortality, and overall mortality. Outcomes considered important were drug-related adverse effects and antifungal resistance. Empirical antifungal therapy was not considered important and, thus, not evaluated. Because changing diagnostic technologies can influence possible IFD events, possible IFD was included post hoc as an outcome.
To rate the level of evidence and to formulate recommendations, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used. 10 The level of evidence indicates the degree of certainty that estimates from the systematic review reflect effects of prophylaxis in our target population, namely pediatric patients with cancer and HSCT recipients. Evidence was rated as high, moderate, low, or very low. Rating was downgraded if there were limitations in study design, lack of consistency, or imprecision or if direct data were lacking. Considering the level of evidence, strong or weak recommendations were made. Strong recommendations were made where benefits clearly outweighed the risks or vice versa and, thus, patients should receive or not receive the intervention as a general policy. Weak recommendations were made where the benefits and risks were closely matched or where there was uncertainty in their estimates. Efficacy, toxicity, and resources, including costs, influenced recommendation formulation.
# Searching, Selecting, and Describing the Evidence
The evidence base used to create this CPG was founded on randomized clinical trials because they are generally less susceptible to bias in comparison with observational trials. 11 The literature search was performed with the assistance of a library scientist in the following databases: MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, and Embase. The Data Supplement shows the full search strategy. Inclusion criteria were fully published randomized trials with a parallel group design that compared the administration of a systemic antifungal agent to any control group as prophylaxis. At least 90% of study participants had to be patients with cancer receiving CONTEXT Key Objectives Which pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients should routinely receive systemic antifungal prophylaxis? Knowledge Generated Based on a systematic review, an international multidisciplinary guideline panel recommended systemic antifungal prophylaxis be administered to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. When systemic antifungal prophylaxis is warranted, an echinocandin or a mold-active azole should be used. Relevance This clinical practice guideline for systemic antifungal prophylaxis is important because of the impact of invasive fungal disease in pediatric patients with cancer and HSCT recipients and because of the presence of multiple approaches to invasive fungal disease prophylaxis, including no prophylaxis.
# Strength of Recommendation and Level of Evidence
Which pediatric patients with cancer and HSCT recipients should routinely receive systemic antifungal prophylaxis?
Acute myeloid leukemia 1. Administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia that is expected to result in profound and prolonged neutropenia.
# Strong recommendation; high-quality evidence
Remarks: This strong recommendation is based on the increasing benefit of systemic antifungal prophylaxis versus no prophylaxis to reduce proven or probable IFD as the risk for IFD increases. Although this recommendation advocates for a universal prophylaxis approach, future research should identify patient and treatment factors that may allow tailoring of prophylaxis to those at the highest risk for IFD.
Acute lymphoblastic leukemia 2. Consider administering systemic antifungal prophylaxis to children and adolescents with newly diagnosed and relapsed acute lymphoblastic leukemia at high risk for IFD.
# Weak recommendation; low-quality evidence
Remarks: Children and adolescents with acute lymphoblastic leukemia encompass a group with wide variability in IFD risk that is not solely accounted for by relapse status. Those with relapsed acute lymphoblastic leukemia receiving intensive myelosuppressive chemotherapy are most likely to warrant systemic antifungal prophylaxis, whereas greater uncertainty is present for those with newly diagnosed acute lymphoblastic leukemia. Given the heterogeneity in IFD risk across protocols overall and by phase of treatment, adaptation will be required for each protocol to recommend whether and when systemic antifungal prophylaxis should be administered.
- Do not routinely administer systemic antifungal prophylaxis to children and adolescents with acute lymphoblastic leukemia at low risk for IFD.
# Strong recommendation; low-quality evidence
Remarks: A low risk for IFD can be inferred based on absence of risk factors such as prolonged neutropenia and corticosteroid administration and observed IFD rates across different protocols. This group includes, for example, pediatric patients receiving maintenance chemotherapy for acute lymphoblastic leukemia.
Other malignancies including most patients with lymphomas and solid tumors 4. Do not routinely administer systemic antifungal prophylaxis to children and adolescents with cancer at low risk for IFD, such as most pediatric patients with lymphomas and solid tumors.
# Strong recommendation; moderatequality evidence
Remarks: In pediatric patients at low risk for IFD, the benefit of systemic antifungal prophylaxis is likely to be small and outweighed by the risk for adverse effects, costs, and inconvenience. Thus, systemic antifungal prophylaxis should not routinely be administered in this setting.
HSCT 5. Administer systemic antifungal prophylaxis to children and adolescents undergoing allogeneic HSCT pre-engraftment and to those receiving systemic immunosuppression for the treatment of graft-versushost disease.
# Strong recommendation; moderatequality evidence
Remarks: The panel recognized that these two phases of therapy are associated with different epidemiology of IFD. However, the nature of the trials included in the systematic review precluded the ability to make separate recommendations for them. This strong recommendation was influenced by the finding in the systemic prophylaxis versus no systemic prophylaxis stratified analysis that HSCT recipients experienced greater benefit in IFD reduction compared with chemotherapy recipients. In addition, the subgroup analysis showed that among the HSCT stratum, prophylaxis significantly reduced fungal infection-related mortality.
- We suggest that systemic antifungal prophylaxis not be used routinely in children and adolescents undergoing autologous HSCT.
# Weak recommendation; low-quality evidence
Remarks: This weak recommendation was based on the lower risk for IFD associated with autologous HSCT. There is less certainty in the setting of tandem transplantations where the cumulative duration of neutropenia may be longer.
If systemic antifungal prophylaxis is planned, which agents should be used?
- If systemic antifungal prophylaxis is warranted, administer a mold-active agent. Strong recommendation; high-quality evidence (continued on following page) chemotherapy or HSCT recipients. There was no restriction by language. We excluded studies of ketoconazole because both the US Food and Drug Administration and the European Medicines Agency have warned against its systemic use as a result of the risk for hepatic toxicities, adrenal suppression, and drug interactions. 12,13 The search included studies published from January 1, 1980, to November 18, 2019.
The primary outcome of the systematic review was proven or probable IFD. Other outcomes were proven or probable mold infection, proven or probable invasive aspergillosis (IA), proven or probable yeast infection, overall mortality, fungal infection-related mortality, and discontinuation of antifungal prophylaxis as a result of an adverse effect. For all IFD outcomes (namely IFD, mold infection, IA, and yeast infection), if the study used the European Organisation for Research and Treatment in Cancer (EORTC)/Mycosis Study Group criteria for categorization, proven or probable IFD outcomes were abstracted. If a study did not use the EORTC criteria, IFD outcomes were mapped to EORTC categories (2008 revised version) 14 by four investigators (T.L., P.P., P.D.R., and L.S.) by consensus where possible. These outcomes were considered missing if mapping was not possible.
We compared systemic antifungal prophylaxis, mold-active prophylaxis, and non-mold-active prophylaxis (fluconazole) versus no systemic prophylaxis, both by group and then stratified by specific agent evaluated. We next compared different systemic antifungal prophylaxis agents focusing on mold-active agents (amphotericin, mold-active azole, or echinocandin) versus fluconazole as a group and then broken down by subcategories and specific agents.
We also compared mold-active azole versus echinocandin.
Study and demographic characteristics were year of publication, country of study conduct, age of participants, cancer diagnosis or HSCT type, and number of randomly assigned participants. Study-level covariates were participant age group (adult, pediatric, or both), treatment group (chemotherapy only, HSCT only, or both chemotherapy and HSCT), and EORTC criteria use to classify IFD (yes or no). Age group was categorized as adult when all participants were older than 15 years of age, and it was categorized as pediatric when all participants were younger than 25 years of age or when the median or mean age was younger than 15 years. Agent dose and schedule, start and stop criteria, and use of therapeutic drug monitoring were also collected. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials was used. 15 Titles and abstracts of articles identified by the systematic review were screened, and articles potentially meeting eligibility criteria were evaluated at full text. All steps, including screening, full text review, and data abstraction, were performed in duplicate (V.F., P.P., or P.D.R.). If
# Strength of Recommendation and Level of Evidence
Remarks: This strong recommendation was based on the comparison of different systemic antifungal prophylaxis agents where mold-active agent versus fluconazole significantly reduced proven or probable IFD, mold infection, and IA, and reduced fungal infection-related mortality. Direct pediatric data were available, increasing quality of the evidence.
- In choosing a mold-active agent, administer an echinocandin or a mold-active azole. Strong recommendation; moderatequality evidence
Remarks: The choice of specific mold-active agent is influenced by multiple factors including local epidemiology, adverse effect profile, potential for drug interactions, costs, and jurisdictional availability. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested based on efficacy and adverse effects. In those 13 years of age and older, posaconazole also is an option.
# Do not use amphotericin routinely as systemic antifungal prophylaxis. Strong recommendation; low-quality evidence
Remarks: This strong recommendation was based on the finding that both conventional and lipid formulations of amphotericin were not more effective than fluconazole in reducing IFD. It is important to note that liposomal amphotericin was not included in studies comparing amphotericin versus fluconazole and, thus, there is less certainty about the benefits and risks of this formulation.
When should systemic antifungal prophylaxis be started and stopped?
- If systemic antifungal prophylaxis is warranted, consider administration during periods of observed or expected severe neutropenia. For allogeneic HSCT recipients, consider administration during systemic immunosuppression for graft-versus-host disease treatment.
# Weak recommendation; low-quality evidence
Remarks: There are limited data that inform the decision of when to initiate and discontinue systemic antifungal prophylaxis. This recommendation was based on the criteria used in the included randomized trials and the anticipated highest risk period.
Abbreviations: HSCT, hematopoietic stem-cell transplantation; IA, invasive aspergillosis; IFD, invasive fungal disease.
disagreement occurred, it was resolved by consensus or with arbitration by a third reviewer (T.L. or L.S.). Agreement in study inclusion was described using the kappa statistic. 16
# Statistical Analysis
Data synthesis used the risk ratio (RR) with the 95% CI to describe prophylaxis effects. In this analysis, RR , 1 indicates that the intervention is better than control. The Mantel-Haenszel random effects model in Review Manager 5.3 (Cochrane Collaboration, Nordic Cochrane Centre, London, United Kingdom) 17 was used to estimate treatment effects. Outcomes were synthesized where there were at least three studies for main analysis and where there were at least two studies for each stratum in stratified analysis. If the number of events was zero in both groups, that study was not included in synthesis, which is considered a standard approach in meta-analyses. 15 If a study included more than two randomized groups, the control group weight was proportionately divided between the different intervention groups, and all intervention versus control comparisons were included in the meta-analysis. 15 We also calculated the I 2 value, which is the percentage of total variation across studies as a result of heterogeneity rather than chance. 15 Stratified analysis focused on two comparisons and four outcomes to limit multiple testing. The two comparisons were systemic antifungal prophylaxis versus no systemic antifungal prophylaxis, and mold-active agent versus fluconazole. The four outcomes were proven or probable IFD, proven or probable mold infection, fungal infection-related mortality, and antifungal discontinuation as a result of adverse effect (only for mold-active agent v fluconazole comparison). Strata evaluated were study-level covariates and, in addition, the risk for IFD and mold in the control group (above and below the median value). P value for interaction (P int) was used to determine whether heterogeneity in the prophylaxis effect could be explained by study-level covariates; we did not focus on stratum-specific P values. 15 Funnel plots were used to explore the possibility of publication bias when at least 10 studies were available for an analysis. 15 Funnel plots are graphical displays of the effect measure on the x-axis and precision on the y-axis. An absence of studies in the right lower quadrant (for this specific analysis) may indicate publication bias. If there was a suggestion of publication bias, we used the trim and fill technique to describe its potential impact. In this event, we removed outlying studies (trim) and added hypothetical negative studies with equal weight (fill). 15 Analysis used Review Manager 5.3. 17 Formulating Recommendations, Assigning Quality of Evidence, and Manuscript Preparation
We drafted evidence tables based on the systematic review results. Recommendations were developed during a series of conference calls and an in-person meeting held in Lyon, France, on October 25, 2019. Deliberations also used the results of a recently published systematic review of risk factors for IFD. 4 Draft versions of the recommendations and manuscript were circulated until approved by all authors. We used the peer-review mechanism as an efficient approach to external review. We plan to update this CPG in 5 years or sooner in the event of important new information.
# RESULTS
The search strategy identified 68 randomized trials that were included in the systematic review. Agreement in study inclusion between reviewers was perfect (k 5 1.00). The Data Supplement illustrates the flow diagram of study identification, selection, and reasons for exclusion. Health questions, recommendations, strength of recommendation, level of evidence, and remarks are summarized in Table 1. Characteristics of the included trials are listed in Table 2, and study-level details are provided in the Data Supplement. Among the five trials of voriconazole and six trials of posaconazole, none used therapeutic drug monitoring to systematically guide dosing. Six studies were conducted solely in a pediatric population (Data Supplement).
Table 3 provides comparisons between systemic antifungal prophylaxis versus no systemic antifungal prophylaxis for all studies and stratified by mold-active agent and non-moldactive agent (fluconazole). The Data Supplement further stratifies these analyses by agent evaluated, namely amphotericin (all formulations), lipid amphotericin formulations, and itraconazole. Compared with no systemic prophylaxis, systemic antifungal prophylaxis significantly reduced proven or probable IFD (RR, 0.47; 95% CI, 0.36 to 0.60; P , .00001), proven or probable yeast infection (RR, 0.31; 95% CI, 0.22 to 0.44; P , .00001), and fungal infection-related mortality (RR, 0.57; 95% CI, 0.40 to 0.81; P 5 .002). The effects of mold-active agent and non-moldactive agent versus no systemic antifungal prophylaxis were similar to the overall analysis for the reduction of IFD, yeast infection, and fungal infection-related mortality. The Data Supplement shows stratified analyses of comparisons between systemic antifungal prophylaxis versus no systemic prophylaxis for the outcomes of proven or probable IFD, proven or probable mold infection, and fungal infectionrelated mortality. For the outcome of proven or probable IFD, significantly greater benefit was observed with increasing risk for IFD in the control group, both when the risk was dichotomized (P int 5 .03; Data Supplement) and when the risk was divided into quartiles (P int 5 .0009; Data Supplement). More specifically, the effect of prophylaxis was an RR of 0.72 (95% CI, 0.43 to 1.20) for those in the lowest quartile (smallest risk for IFD) compared with an RR of 0.25 (95% CI, 0.17 to 0.36) for those in the highest quartile (greatest risk for IFD). Benefit was also significantly greater in patients receiving HSCT only compared with chemotherapy only or chemotherapy plus HSCT (P int 5 .03). The effect of prophylaxis did not differ based on risk for mold infection in the control group (P int 5 .90). We also performed an analysis of amphotericin (conventional or lipid formulations) versus no systemic antifungal prophylaxis stratified by daily dosing versus nondaily dosing. Effects on IFD and fungal infection-related mortality were similar when comparing daily and nondaily dosing (Data Supplement). mold-active agent versus fluconazole; no significant interactions were observed.
The Data Supplement shows systemic antifungal prophylaxis initiation and discontinuation criteria by diagnosis or treatment group and also illustrates sensitivity analyses where publication bias was suggested in funnel plots. None substantially altered interpretation of the base analyses. In addition, the Data Supplement shows synthesis in which possible IFD, mold, or IA was reported. These did not substantially alter interpretation of the base analysis. Research gaps are outlined in Table 5.
# Recommendation 1
Administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia that is expected to result in profound and prolonged neutropenia (Evidence quality: high; Strength of recommendation: strong).
Explanation. This recommendation was informed by the systematic review of risk factors identifying that patients with acute myeloid leukemia are at high risk for IFD. The benefit of systemic antifungal prophylaxis was greater for those at higher risk for proven or probable IFD, leading to this strong recommendation.
# Recommendation 2
Consider administering systemic antifungal prophylaxis to children and adolescents with newly diagnosed and relapsed acute lymphoblastic leukemia at high risk for IFD (Evidence quality: low; Strength of recommendation: weak).
Explanation. The risk for IFD in pediatric acute lymphoblastic leukemia is protocol and phase specific. This risk is also dependent on remission status; chemotherapyrelated neutropenia; and corticosteroid formulation, dose, and duration of administration. On the basis of the systematic review of risk factors for IFD, 4 the panel believed that there are likely to be subgroups of pediatric patients with acute lymphoblastic leukemia who would benefit from systemic antifungal prophylaxis. However, the panel was unable to identify comprehensive baseline data on IFD incidence in the various acute lymphoblastic leukemia populations that would permit more specific recommendations. The panel also acknowledged that treatments for poor-risk acute lymphoblastic leukemia are changing. For example, immunotherapies are being used increasingly and may be associated with a lower risk for IFD compared with conventional, myelosuppressive chemotherapy. Given these factors, the panel did not make a strong recommendation for antifungal prophylaxis in pediatric patients with acute lymphoblastic leukemia. Rather, the panel made a weak recommendation with the understanding that protocol-specific recommendations adjusted to specific phases of therapy such as induction or reinduction are required. No synthesis possible because there were less than three studies with an event in at least one arm.
# Recommendation 3
Do not routinely administer systemic antifungal prophylaxis to children and adolescents with acute lymphoblastic leukemia at low risk for IFD (Evidence quality: low; Strength of recommendation: strong).
Explanation. For children and adolescents with acute lymphoblastic leukemia, a low risk for IFD can be inferred based on absence of risk factors such as prolonged neutropenia and corticosteroid administration, combined with observed IFD rates across different protocols and phases of therapy. This group includes, for example, pediatric patients receiving maintenance chemotherapy for acute lymphoblastic leukemia.
# Recommendation 4
Do not routinely administer systemic antifungal prophylaxis to children and adolescents with cancer at low risk for IFD, such as most pediatric patients with lymphomas and solid tumors (Evidence quality: moderate; Strength of recommendation: strong).
# Explanation.
In pediatric patients at low risk for IFD, benefit of systemic antifungal prophylaxis is likely to be small and outweighed by the risk for adverse effects, costs, and inconvenience. Thus, systemic antifungal prophylaxis should not routinely be administered in this setting. It is important to emphasize that some patients with lymphomas and solid tumors are at high risk for IFD, such as those with advanced Burkitt lymphoma and some infants with brain tumors. Thus, implementation must consider patient-and treatmentspecific risk factors rather than relying on diagnosis alone in deciding which populations merit antifungal prophylaxis.
# Recommendation 5
Administer systemic antifungal prophylaxis to children and adolescents undergoing allogeneic HSCT pre-engraftment and to those receiving systemic immunosuppression for the treatment of graft-versus-host disease (GVHD; Evidence quality: moderate; Strength of recommendation: strong).
Explanation. The panel recognized that pre-engraftment and during systemic immunosuppression for the treatment of GVHD were two distinct periods, each increasing the risk for IFD but with different epidemiology. The Data Supplement shows that many studies of allogeneic HSCT recipients included both periods, with few studies focusing on the period of immunosuppression for GVHD treatment. Thus, the panel felt this lack of granularity precluded separate recommendations for these two different periods.
This strong recommendation was influenced by the finding in the systemic prophylaxis versus no systemic prophylaxis stratified analysis that HSCT recipients experienced greater benefit in proven or probable IFD reduction compared with chemotherapy recipients (Data Supplement). In addition, the subgroup analysis showed that among the HSCT stratum, antifungal prophylaxis significantly reduced fungal infection-related mortality (Data Supplement). Although the adult data were clearer, these data may be less generalizable to pediatric patients because of different transplantation approaches such as stem-cell source. As a result, the evidence quality was reduced. The panel suggested that administration in patients receiving systemic treatment of GVHD was reasonable based on risk factors for IFD but could not provide more granularity around whether there is a subgroup in which GVHD treatment is sufficiently short as to not warrant antifungal prophylaxis.
# Recommendation 6
We suggest that systemic antifungal prophylaxis not be used routinely in children and adolescents undergoing autologous HSCT (Evidence quality: low; Strength of recommendation: weak).
Explanation. A lower risk for IFD associated with autologous HSCT can be inferred from the systematic review of IFD risk factors. 4 Consequently, systemic antifungal prophylaxis was not recommended for this group. However, there was less certainty in the setting of tandem transplantations where the cumulative duration of neutropenia may be longer. The degree of mucositis associated with specific conditioning regimens may also influence IFD risk and may affect the decision to administer antifungal prophylaxis.
# Recommendation 7
If systemic antifungal prophylaxis is warranted, administer a mold-active agent (Evidence quality: high; Strength of recommendation: strong).
Explanation. This strong recommendation was based on the comparison of different systemic antifungal prophylaxis agents (Table 4) where a mold-active agent versus fluconazole significantly reduced proven or probable IFD, mold infection, and IA, and reduced fungal infection-related mortality. Although a mold-active agent also increased adverse effects, the panel felt the benefits outweighed the negative aspects. Direct pediatric data were available, increasing quality of the evidence.
Trials comparing a mold-active agent versus fluconazole were presumably conducted in settings where there is an appreciable risk for mold infection. In settings where the risk for mold is sufficiently low, fluconazole may be an appropriate choice for prophylaxis.
# Recommendation 8
In choosing a mold-active agent, administer an echinocandin or a mold-active azole (Evidence quality: moderate; Strength of recommendation: strong).
Explanation. If systemic antifungal prophylaxis is warranted, the choice of which specific mold-active agent is influenced by multiple factors including local epidemiology, adverse effect profile, drug interaction potential, costs, and jurisdictional availability. All mold-active agents have disadvantages. For example, echinocandins must be administered intravenously daily, which may make this option less desirable for ambulatory populations. Use of moldactive azoles may be limited by drug interactions, hepatotoxicity, and adverse effects resulting in discontinuation of prophylaxis. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested based on efficacy, adverse effects, and availability of pediatric dosing information. In settings where all agents are available, either an echinocandin or voriconazole is favored based on toxicity profile. However, itraconazole may be used if other options are not available. Posaconazole may also be used in those 13 years of age and older. When using mold-active azoles, best practices with respect to therapeutic drug monitoring should be applied.
# Recommendation 9
Do not use amphotericin routinely as systemic antifungal prophylaxis (Evidence quality: low; Strength of recommendation: strong).
Explanation. This strong recommendation was based on the finding that amphotericin was not more effective than fluconazole in reducing proven or probable IFD but was associated with more adverse effects (Table 4). Stratified analysis did not reveal differential efficacy based on whether amphotericin was administered on a daily or nondaily schedule (Data Supplement).
# Recommendation 10
If systemic antifungal prophylaxis is warranted, consider administration during periods of observed or expected severe neutropenia. For allogeneic HSCT recipients, consider administration during systemic immunosuppression for GVHD treatment (Evidence quality: low; Strength of recommendation: weak).
Explanation. There are limited data that inform the decision of when to initiate and discontinue systemic antifungal prophylaxis. This recommendation was based both on criteria used in the included randomized trials and the anticipated highest risk periods.
# DISCUSSION
This CPG of systemic antifungal prophylaxis is important because of the impact of IFD in pediatric patients with cancer and HSCT recipients and uncertainty in the ideal approach. If systemic antifungal prophylaxis is warranted, the panel made a strong recommendation to administer a mold-active agent with an echinocandin or a mold-active azole. In choosing a specific agent, local epidemiology, adverse effect profile, potential for drug interactions, costs, and jurisdictional availability must be weighed against each other for specific settings. If all agents are available and appropriate from a microbiologic perspective, echinocandins may be favored when limiting adverse effects and hepatotoxicity are valued. Conversely, mold-active azoles may be favored when oral administration and convenience are favored.
It is possible that more broad-spectrum antifungal prophylaxis will change the choice of empirical antifungal therapy, and if the new choice has more adverse effects, the strategy could result in more toxicity overall. Future comparative effectiveness studies should evaluate the overall impact of antifungal prophylaxis selection on empirical antifungal choice and overall toxicities.
We found that fluconazole, when compared with no systemic antifungal prophylaxis, was associated with a reduction in fungal infection-related mortality but not overall mortality. It is possible that the reduction in fungal infection-related mortality occurred because these trials were conducted at a time when there were fewer IFD treatment options. It is also possible that this reduction is related to classification bias given the challenges in assigning cause of death. 5 As with all CPGs, a structured approach to local adaptation, implementation, and evaluation is a key consideration. Important factors in this process include a baseline understanding of local and disease-specific epidemiology, establishing a leadership team that will oversee the process, and appropriate engagement and education of key stakeholders. Pediatric acute lymphoblastic leukemia is a particularly challenging population in which to make universal recommendations regarding systemic antifungal prophylaxis because of the wide variability in treatment regimens, each with differing IFD risk patterns and limitations to specific antifungal agents. Implementation of this CPG will likely require protocol-specific recommendations for patients with acute lymphoblastic leukemia.
In summary, we created a CPG for systemic antifungal prophylaxis in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guidelineconcordant rates and impacts are important future steps.
# AFFILIATIONS | PURPOSE To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients. METHODS Recommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients. RESULTS There were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made. CONCLUSION We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps.# INTRODUCTION
Children and adolescents receiving intensive myelosuppressive chemotherapy and some pediatric hematopoietic stem-cell transplantation (HSCT) recipients are at high risk for invasive fungal disease (IFD) caused by yeasts and molds. [1][2][3][4] In these patients, infections with Candida and Aspergillus species are most common. [1][2][3] IFDs are important because they are associated with substantial morbidity, delayed cancer treatment, increased health services utilization, and treatmentrelated mortality. 5 Systemic antifungal prophylaxis can be an effective approach to reducing IFD. A clinical practice guideline (CPG) facilitates evidence-based clinical care by describing risks and benefits of different management options based on a systematic review of the literature. Risks and benefits are weighed against each other by a panel of experts to arrive at care recommendations. Previously published CPGs 6,7 addressing systemic antifungal prophylaxis in pediatric patients are . 5 years old and thus do not consider results of recent trials. In addition, those panels had limited regional and disease representation. Key representatives of two previously published CPGs for pediatric patients (T.L., E.C., L.L.D., A.H.G., E.R., M.S., A.W., P.D.R., and L.S.) 6,7 were brought together to arrive at a single harmonized CPG, thus improving consistency of recommendations internationally. The objective was to develop a CPG for systemic antifungal prophylaxis in pediatric patients with cancer and HSCT recipients.
# METHODS
# Panel Constitution
The panel included representatives from the fields of pediatric hematology/oncology, pediatric HSCT, pediatric infectious diseases, nursing, and pharmacy; a patient advocate; and a CPG methodologist (Data Supplement). Panel members were selected based on clinical and methodologic expertise and geographic representation. All panel members declared potential conflicts of interest, and none precluded participation in this CPG (Data Supplement).
# General CPG Development Approach
We used standard approaches to create this CPG, 8 including the Appraisal of Guidelines for Research and Evaluation II instrument, to direct development. 9 Financial support for CPG creation was provided by the Pediatric Oncology Group of Ontario. However, CPG development, drafting of recommendations and the manuscript, and the decision to submit for publication were independent from the funder.
The key clinical questions were developed by the panel and are listed in Table 1. The target population is children and adolescents (age 0-18 years) receiving chemotherapy for cancer or undergoing HSCT. Target users are physicians, microbiologists, nurse practitioners, nurses, pharmacists, antibiotic stewards, and other health care professionals who are concerned with infectious complications in pediatric patients receiving chemotherapy or undergoing HSCT.
Panel members identified and rated the importance of outcomes by consensus. Outcomes that were considered critical for decision making were proven or probable IFD, mold infection or yeast infection, fungal infection-related mortality, and overall mortality. Outcomes considered important were drug-related adverse effects and antifungal resistance. Empirical antifungal therapy was not considered important and, thus, not evaluated. Because changing diagnostic technologies can influence possible IFD events, possible IFD was included post hoc as an outcome.
To rate the level of evidence and to formulate recommendations, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used. 10 The level of evidence indicates the degree of certainty that estimates from the systematic review reflect effects of prophylaxis in our target population, namely pediatric patients with cancer and HSCT recipients. Evidence was rated as high, moderate, low, or very low. Rating was downgraded if there were limitations in study design, lack of consistency, or imprecision or if direct data were lacking. Considering the level of evidence, strong or weak recommendations were made. Strong recommendations were made where benefits clearly outweighed the risks or vice versa and, thus, patients should receive or not receive the intervention as a general policy. Weak recommendations were made where the benefits and risks were closely matched or where there was uncertainty in their estimates. Efficacy, toxicity, and resources, including costs, influenced recommendation formulation.
# Searching, Selecting, and Describing the Evidence
The evidence base used to create this CPG was founded on randomized clinical trials because they are generally less susceptible to bias in comparison with observational trials. 11 The literature search was performed with the assistance of a library scientist in the following databases: MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, and Embase. The Data Supplement shows the full search strategy. Inclusion criteria were fully published randomized trials with a parallel group design that compared the administration of a systemic antifungal agent to any control group as prophylaxis. At least 90% of study participants had to be patients with cancer receiving CONTEXT Key Objectives Which pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients should routinely receive systemic antifungal prophylaxis? Knowledge Generated Based on a systematic review, an international multidisciplinary guideline panel recommended systemic antifungal prophylaxis be administered to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. When systemic antifungal prophylaxis is warranted, an echinocandin or a mold-active azole should be used. Relevance This clinical practice guideline for systemic antifungal prophylaxis is important because of the impact of invasive fungal disease in pediatric patients with cancer and HSCT recipients and because of the presence of multiple approaches to invasive fungal disease prophylaxis, including no prophylaxis.
# Strength of Recommendation and Level of Evidence
Which pediatric patients with cancer and HSCT recipients should routinely receive systemic antifungal prophylaxis?
Acute myeloid leukemia 1. Administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia that is expected to result in profound and prolonged neutropenia.
# Strong recommendation; high-quality evidence
Remarks: This strong recommendation is based on the increasing benefit of systemic antifungal prophylaxis versus no prophylaxis to reduce proven or probable IFD as the risk for IFD increases. Although this recommendation advocates for a universal prophylaxis approach, future research should identify patient and treatment factors that may allow tailoring of prophylaxis to those at the highest risk for IFD.
Acute lymphoblastic leukemia 2. Consider administering systemic antifungal prophylaxis to children and adolescents with newly diagnosed and relapsed acute lymphoblastic leukemia at high risk for IFD.
# Weak recommendation; low-quality evidence
Remarks: Children and adolescents with acute lymphoblastic leukemia encompass a group with wide variability in IFD risk that is not solely accounted for by relapse status. Those with relapsed acute lymphoblastic leukemia receiving intensive myelosuppressive chemotherapy are most likely to warrant systemic antifungal prophylaxis, whereas greater uncertainty is present for those with newly diagnosed acute lymphoblastic leukemia. Given the heterogeneity in IFD risk across protocols overall and by phase of treatment, adaptation will be required for each protocol to recommend whether and when systemic antifungal prophylaxis should be administered.
3. Do not routinely administer systemic antifungal prophylaxis to children and adolescents with acute lymphoblastic leukemia at low risk for IFD.
# Strong recommendation; low-quality evidence
Remarks: A low risk for IFD can be inferred based on absence of risk factors such as prolonged neutropenia and corticosteroid administration and observed IFD rates across different protocols. This group includes, for example, pediatric patients receiving maintenance chemotherapy for acute lymphoblastic leukemia.
Other malignancies including most patients with lymphomas and solid tumors 4. Do not routinely administer systemic antifungal prophylaxis to children and adolescents with cancer at low risk for IFD, such as most pediatric patients with lymphomas and solid tumors.
# Strong recommendation; moderatequality evidence
Remarks: In pediatric patients at low risk for IFD, the benefit of systemic antifungal prophylaxis is likely to be small and outweighed by the risk for adverse effects, costs, and inconvenience. Thus, systemic antifungal prophylaxis should not routinely be administered in this setting.
HSCT 5. Administer systemic antifungal prophylaxis to children and adolescents undergoing allogeneic HSCT pre-engraftment and to those receiving systemic immunosuppression for the treatment of graft-versushost disease.
# Strong recommendation; moderatequality evidence
Remarks: The panel recognized that these two phases of therapy are associated with different epidemiology of IFD. However, the nature of the trials included in the systematic review precluded the ability to make separate recommendations for them. This strong recommendation was influenced by the finding in the systemic prophylaxis versus no systemic prophylaxis stratified analysis that HSCT recipients experienced greater benefit in IFD reduction compared with chemotherapy recipients. In addition, the subgroup analysis showed that among the HSCT stratum, prophylaxis significantly reduced fungal infection-related mortality.
6. We suggest that systemic antifungal prophylaxis not be used routinely in children and adolescents undergoing autologous HSCT.
# Weak recommendation; low-quality evidence
Remarks: This weak recommendation was based on the lower risk for IFD associated with autologous HSCT. There is less certainty in the setting of tandem transplantations where the cumulative duration of neutropenia may be longer.
If systemic antifungal prophylaxis is planned, which agents should be used?
7. If systemic antifungal prophylaxis is warranted, administer a mold-active agent. Strong recommendation; high-quality evidence (continued on following page) chemotherapy or HSCT recipients. There was no restriction by language. We excluded studies of ketoconazole because both the US Food and Drug Administration and the European Medicines Agency have warned against its systemic use as a result of the risk for hepatic toxicities, adrenal suppression, and drug interactions. 12,13 The search included studies published from January 1, 1980, to November 18, 2019.
The primary outcome of the systematic review was proven or probable IFD. Other outcomes were proven or probable mold infection, proven or probable invasive aspergillosis (IA), proven or probable yeast infection, overall mortality, fungal infection-related mortality, and discontinuation of antifungal prophylaxis as a result of an adverse effect. For all IFD outcomes (namely IFD, mold infection, IA, and yeast infection), if the study used the European Organisation for Research and Treatment in Cancer (EORTC)/Mycosis Study Group criteria for categorization, proven or probable IFD outcomes were abstracted. If a study did not use the EORTC criteria, IFD outcomes were mapped to EORTC categories (2008 revised version) 14 by four investigators (T.L., P.P., P.D.R., and L.S.) by consensus where possible. These outcomes were considered missing if mapping was not possible.
We compared systemic antifungal prophylaxis, mold-active prophylaxis, and non-mold-active prophylaxis (fluconazole) versus no systemic prophylaxis, both by group and then stratified by specific agent evaluated. We next compared different systemic antifungal prophylaxis agents focusing on mold-active agents (amphotericin, mold-active azole, or echinocandin) versus fluconazole as a group and then broken down by subcategories and specific agents.
We also compared mold-active azole versus echinocandin.
Study and demographic characteristics were year of publication, country of study conduct, age of participants, cancer diagnosis or HSCT type, and number of randomly assigned participants. Study-level covariates were participant age group (adult, pediatric, or both), treatment group (chemotherapy only, HSCT only, or both chemotherapy and HSCT), and EORTC criteria use to classify IFD (yes or no). Age group was categorized as adult when all participants were older than 15 years of age, and it was categorized as pediatric when all participants were younger than 25 years of age or when the median or mean age was younger than 15 years. Agent dose and schedule, start and stop criteria, and use of therapeutic drug monitoring were also collected. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials was used. 15 Titles and abstracts of articles identified by the systematic review were screened, and articles potentially meeting eligibility criteria were evaluated at full text. All steps, including screening, full text review, and data abstraction, were performed in duplicate (V.F., P.P., or P.D.R.). If
# Strength of Recommendation and Level of Evidence
Remarks: This strong recommendation was based on the comparison of different systemic antifungal prophylaxis agents where mold-active agent versus fluconazole significantly reduced proven or probable IFD, mold infection, and IA, and reduced fungal infection-related mortality. Direct pediatric data were available, increasing quality of the evidence.
8. In choosing a mold-active agent, administer an echinocandin or a mold-active azole. Strong recommendation; moderatequality evidence
Remarks: The choice of specific mold-active agent is influenced by multiple factors including local epidemiology, adverse effect profile, potential for drug interactions, costs, and jurisdictional availability. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested based on efficacy and adverse effects. In those 13 years of age and older, posaconazole also is an option.
# Do not use amphotericin routinely as systemic antifungal prophylaxis. Strong recommendation; low-quality evidence
Remarks: This strong recommendation was based on the finding that both conventional and lipid formulations of amphotericin were not more effective than fluconazole in reducing IFD. It is important to note that liposomal amphotericin was not included in studies comparing amphotericin versus fluconazole and, thus, there is less certainty about the benefits and risks of this formulation.
When should systemic antifungal prophylaxis be started and stopped?
10. If systemic antifungal prophylaxis is warranted, consider administration during periods of observed or expected severe neutropenia. For allogeneic HSCT recipients, consider administration during systemic immunosuppression for graft-versus-host disease treatment.
# Weak recommendation; low-quality evidence
Remarks: There are limited data that inform the decision of when to initiate and discontinue systemic antifungal prophylaxis. This recommendation was based on the criteria used in the included randomized trials and the anticipated highest risk period.
Abbreviations: HSCT, hematopoietic stem-cell transplantation; IA, invasive aspergillosis; IFD, invasive fungal disease.
disagreement occurred, it was resolved by consensus or with arbitration by a third reviewer (T.L. or L.S.). Agreement in study inclusion was described using the kappa statistic. 16
# Statistical Analysis
Data synthesis used the risk ratio (RR) with the 95% CI to describe prophylaxis effects. In this analysis, RR , 1 indicates that the intervention is better than control. The Mantel-Haenszel random effects model in Review Manager 5.3 (Cochrane Collaboration, Nordic Cochrane Centre, London, United Kingdom) 17 was used to estimate treatment effects. Outcomes were synthesized where there were at least three studies for main analysis and where there were at least two studies for each stratum in stratified analysis. If the number of events was zero in both groups, that study was not included in synthesis, which is considered a standard approach in meta-analyses. 15 If a study included more than two randomized groups, the control group weight was proportionately divided between the different intervention groups, and all intervention versus control comparisons were included in the meta-analysis. 15 We also calculated the I 2 value, which is the percentage of total variation across studies as a result of heterogeneity rather than chance. 15 Stratified analysis focused on two comparisons and four outcomes to limit multiple testing. The two comparisons were systemic antifungal prophylaxis versus no systemic antifungal prophylaxis, and mold-active agent versus fluconazole. The four outcomes were proven or probable IFD, proven or probable mold infection, fungal infection-related mortality, and antifungal discontinuation as a result of adverse effect (only for mold-active agent v fluconazole comparison). Strata evaluated were study-level covariates and, in addition, the risk for IFD and mold in the control group (above and below the median value). P value for interaction (P int) was used to determine whether heterogeneity in the prophylaxis effect could be explained by study-level covariates; we did not focus on stratum-specific P values. 15 Funnel plots were used to explore the possibility of publication bias when at least 10 studies were available for an analysis. 15 Funnel plots are graphical displays of the effect measure on the x-axis and precision on the y-axis. An absence of studies in the right lower quadrant (for this specific analysis) may indicate publication bias. If there was a suggestion of publication bias, we used the trim and fill technique to describe its potential impact. In this event, we removed outlying studies (trim) and added hypothetical negative studies with equal weight (fill). 15 Analysis used Review Manager 5.3. 17 Formulating Recommendations, Assigning Quality of Evidence, and Manuscript Preparation
We drafted evidence tables based on the systematic review results. Recommendations were developed during a series of conference calls and an in-person meeting held in Lyon, France, on October 25, 2019. Deliberations also used the results of a recently published systematic review of risk factors for IFD. 4 Draft versions of the recommendations and manuscript were circulated until approved by all authors. We used the peer-review mechanism as an efficient approach to external review. We plan to update this CPG in 5 years or sooner in the event of important new information.
# RESULTS
The search strategy identified 68 randomized trials that were included in the systematic review. Agreement in study inclusion between reviewers was perfect (k 5 1.00). The Data Supplement illustrates the flow diagram of study identification, selection, and reasons for exclusion. Health questions, recommendations, strength of recommendation, level of evidence, and remarks are summarized in Table 1. Characteristics of the included trials are listed in Table 2, and study-level details are provided in the Data Supplement. Among the five trials of voriconazole and six trials of posaconazole, none used therapeutic drug monitoring to systematically guide dosing. Six studies were conducted solely in a pediatric population (Data Supplement).
Table 3 provides comparisons between systemic antifungal prophylaxis versus no systemic antifungal prophylaxis for all studies and stratified by mold-active agent and non-moldactive agent (fluconazole). The Data Supplement further stratifies these analyses by agent evaluated, namely amphotericin (all formulations), lipid amphotericin formulations, and itraconazole. Compared with no systemic prophylaxis, systemic antifungal prophylaxis significantly reduced proven or probable IFD (RR, 0.47; 95% CI, 0.36 to 0.60; P , .00001), proven or probable yeast infection (RR, 0.31; 95% CI, 0.22 to 0.44; P , .00001), and fungal infection-related mortality (RR, 0.57; 95% CI, 0.40 to 0.81; P 5 .002). The effects of mold-active agent and non-moldactive agent versus no systemic antifungal prophylaxis were similar to the overall analysis for the reduction of IFD, yeast infection, and fungal infection-related mortality. The Data Supplement shows stratified analyses of comparisons between systemic antifungal prophylaxis versus no systemic prophylaxis for the outcomes of proven or probable IFD, proven or probable mold infection, and fungal infectionrelated mortality. For the outcome of proven or probable IFD, significantly greater benefit was observed with increasing risk for IFD in the control group, both when the risk was dichotomized (P int 5 .03; Data Supplement) and when the risk was divided into quartiles (P int 5 .0009; Data Supplement). More specifically, the effect of prophylaxis was an RR of 0.72 (95% CI, 0.43 to 1.20) for those in the lowest quartile (smallest risk for IFD) compared with an RR of 0.25 (95% CI, 0.17 to 0.36) for those in the highest quartile (greatest risk for IFD). Benefit was also significantly greater in patients receiving HSCT only compared with chemotherapy only or chemotherapy plus HSCT (P int 5 .03). The effect of prophylaxis did not differ based on risk for mold infection in the control group (P int 5 .90). We also performed an analysis of amphotericin (conventional or lipid formulations) versus no systemic antifungal prophylaxis stratified by daily dosing versus nondaily dosing. Effects on IFD and fungal infection-related mortality were similar when comparing daily and nondaily dosing (Data Supplement). mold-active agent versus fluconazole; no significant interactions were observed.
The Data Supplement shows systemic antifungal prophylaxis initiation and discontinuation criteria by diagnosis or treatment group and also illustrates sensitivity analyses where publication bias was suggested in funnel plots. None substantially altered interpretation of the base analyses. In addition, the Data Supplement shows synthesis in which possible IFD, mold, or IA was reported. These did not substantially alter interpretation of the base analysis. Research gaps are outlined in Table 5.
# Recommendation 1
Administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia that is expected to result in profound and prolonged neutropenia (Evidence quality: high; Strength of recommendation: strong).
Explanation. This recommendation was informed by the systematic review of risk factors identifying that patients with acute myeloid leukemia are at high risk for IFD. The benefit of systemic antifungal prophylaxis was greater for those at higher risk for proven or probable IFD, leading to this strong recommendation.
# Recommendation 2
Consider administering systemic antifungal prophylaxis to children and adolescents with newly diagnosed and relapsed acute lymphoblastic leukemia at high risk for IFD (Evidence quality: low; Strength of recommendation: weak).
Explanation. The risk for IFD in pediatric acute lymphoblastic leukemia is protocol and phase specific. This risk is also dependent on remission status; chemotherapyrelated neutropenia; and corticosteroid formulation, dose, and duration of administration. On the basis of the systematic review of risk factors for IFD, 4 the panel believed that there are likely to be subgroups of pediatric patients with acute lymphoblastic leukemia who would benefit from systemic antifungal prophylaxis. However, the panel was unable to identify comprehensive baseline data on IFD incidence in the various acute lymphoblastic leukemia populations that would permit more specific recommendations. The panel also acknowledged that treatments for poor-risk acute lymphoblastic leukemia are changing. For example, immunotherapies are being used increasingly and may be associated with a lower risk for IFD compared with conventional, myelosuppressive chemotherapy. Given these factors, the panel did not make a strong recommendation for antifungal prophylaxis in pediatric patients with acute lymphoblastic leukemia. Rather, the panel made a weak recommendation with the understanding that protocol-specific recommendations adjusted to specific phases of therapy such as induction or reinduction are required. No synthesis possible because there were less than three studies with an event in at least one arm.
# Recommendation 3
Do not routinely administer systemic antifungal prophylaxis to children and adolescents with acute lymphoblastic leukemia at low risk for IFD (Evidence quality: low; Strength of recommendation: strong).
Explanation. For children and adolescents with acute lymphoblastic leukemia, a low risk for IFD can be inferred based on absence of risk factors such as prolonged neutropenia and corticosteroid administration, combined with observed IFD rates across different protocols and phases of therapy. This group includes, for example, pediatric patients receiving maintenance chemotherapy for acute lymphoblastic leukemia.
# Recommendation 4
Do not routinely administer systemic antifungal prophylaxis to children and adolescents with cancer at low risk for IFD, such as most pediatric patients with lymphomas and solid tumors (Evidence quality: moderate; Strength of recommendation: strong).
# Explanation.
In pediatric patients at low risk for IFD, benefit of systemic antifungal prophylaxis is likely to be small and outweighed by the risk for adverse effects, costs, and inconvenience. Thus, systemic antifungal prophylaxis should not routinely be administered in this setting. It is important to emphasize that some patients with lymphomas and solid tumors are at high risk for IFD, such as those with advanced Burkitt lymphoma and some infants with brain tumors. Thus, implementation must consider patient-and treatmentspecific risk factors rather than relying on diagnosis alone in deciding which populations merit antifungal prophylaxis.
# Recommendation 5
Administer systemic antifungal prophylaxis to children and adolescents undergoing allogeneic HSCT pre-engraftment and to those receiving systemic immunosuppression for the treatment of graft-versus-host disease (GVHD; Evidence quality: moderate; Strength of recommendation: strong).
Explanation. The panel recognized that pre-engraftment and during systemic immunosuppression for the treatment of GVHD were two distinct periods, each increasing the risk for IFD but with different epidemiology. The Data Supplement shows that many studies of allogeneic HSCT recipients included both periods, with few studies focusing on the period of immunosuppression for GVHD treatment. Thus, the panel felt this lack of granularity precluded separate recommendations for these two different periods.
This strong recommendation was influenced by the finding in the systemic prophylaxis versus no systemic prophylaxis stratified analysis that HSCT recipients experienced greater benefit in proven or probable IFD reduction compared with chemotherapy recipients (Data Supplement). In addition, the subgroup analysis showed that among the HSCT stratum, antifungal prophylaxis significantly reduced fungal infection-related mortality (Data Supplement). Although the adult data were clearer, these data may be less generalizable to pediatric patients because of different transplantation approaches such as stem-cell source. As a result, the evidence quality was reduced. The panel suggested that administration in patients receiving systemic treatment of GVHD was reasonable based on risk factors for IFD but could not provide more granularity around whether there is a subgroup in which GVHD treatment is sufficiently short as to not warrant antifungal prophylaxis.
# Recommendation 6
We suggest that systemic antifungal prophylaxis not be used routinely in children and adolescents undergoing autologous HSCT (Evidence quality: low; Strength of recommendation: weak).
Explanation. A lower risk for IFD associated with autologous HSCT can be inferred from the systematic review of IFD risk factors. 4 Consequently, systemic antifungal prophylaxis was not recommended for this group. However, there was less certainty in the setting of tandem transplantations where the cumulative duration of neutropenia may be longer. The degree of mucositis associated with specific conditioning regimens may also influence IFD risk and may affect the decision to administer antifungal prophylaxis.
# Recommendation 7
If systemic antifungal prophylaxis is warranted, administer a mold-active agent (Evidence quality: high; Strength of recommendation: strong).
Explanation. This strong recommendation was based on the comparison of different systemic antifungal prophylaxis agents (Table 4) where a mold-active agent versus fluconazole significantly reduced proven or probable IFD, mold infection, and IA, and reduced fungal infection-related mortality. Although a mold-active agent also increased adverse effects, the panel felt the benefits outweighed the negative aspects. Direct pediatric data were available, increasing quality of the evidence.
Trials comparing a mold-active agent versus fluconazole were presumably conducted in settings where there is an appreciable risk for mold infection. In settings where the risk for mold is sufficiently low, fluconazole may be an appropriate choice for prophylaxis.
# Recommendation 8
In choosing a mold-active agent, administer an echinocandin or a mold-active azole (Evidence quality: moderate; Strength of recommendation: strong).
Explanation. If systemic antifungal prophylaxis is warranted, the choice of which specific mold-active agent is influenced by multiple factors including local epidemiology, adverse effect profile, drug interaction potential, costs, and jurisdictional availability. All mold-active agents have disadvantages. For example, echinocandins must be administered intravenously daily, which may make this option less desirable for ambulatory populations. Use of moldactive azoles may be limited by drug interactions, hepatotoxicity, and adverse effects resulting in discontinuation of prophylaxis. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested based on efficacy, adverse effects, and availability of pediatric dosing information. In settings where all agents are available, either an echinocandin or voriconazole is favored based on toxicity profile. However, itraconazole may be used if other options are not available. Posaconazole may also be used in those 13 years of age and older. When using mold-active azoles, best practices with respect to therapeutic drug monitoring should be applied.
# Recommendation 9
Do not use amphotericin routinely as systemic antifungal prophylaxis (Evidence quality: low; Strength of recommendation: strong).
Explanation. This strong recommendation was based on the finding that amphotericin was not more effective than fluconazole in reducing proven or probable IFD but was associated with more adverse effects (Table 4). Stratified analysis did not reveal differential efficacy based on whether amphotericin was administered on a daily or nondaily schedule (Data Supplement).
# Recommendation 10
If systemic antifungal prophylaxis is warranted, consider administration during periods of observed or expected severe neutropenia. For allogeneic HSCT recipients, consider administration during systemic immunosuppression for GVHD treatment (Evidence quality: low; Strength of recommendation: weak).
Explanation. There are limited data that inform the decision of when to initiate and discontinue systemic antifungal prophylaxis. This recommendation was based both on criteria used in the included randomized trials and the anticipated highest risk periods.
# DISCUSSION
This CPG of systemic antifungal prophylaxis is important because of the impact of IFD in pediatric patients with cancer and HSCT recipients and uncertainty in the ideal approach. If systemic antifungal prophylaxis is warranted, the panel made a strong recommendation to administer a mold-active agent with an echinocandin or a mold-active azole. In choosing a specific agent, local epidemiology, adverse effect profile, potential for drug interactions, costs, and jurisdictional availability must be weighed against each other for specific settings. If all agents are available and appropriate from a microbiologic perspective, echinocandins may be favored when limiting adverse effects and hepatotoxicity are valued. Conversely, mold-active azoles may be favored when oral administration and convenience are favored.
It is possible that more broad-spectrum antifungal prophylaxis will change the choice of empirical antifungal therapy, and if the new choice has more adverse effects, the strategy could result in more toxicity overall. Future comparative effectiveness studies should evaluate the overall impact of antifungal prophylaxis selection on empirical antifungal choice and overall toxicities.
We found that fluconazole, when compared with no systemic antifungal prophylaxis, was associated with a reduction in fungal infection-related mortality but not overall mortality. It is possible that the reduction in fungal infection-related mortality occurred because these trials were conducted at a time when there were fewer IFD treatment options. It is also possible that this reduction is related to classification bias given the challenges in assigning cause of death. 5 As with all CPGs, a structured approach to local adaptation, implementation, and evaluation is a key consideration. Important factors in this process include a baseline understanding of local and disease-specific epidemiology, establishing a leadership team that will oversee the process, and appropriate engagement and education of key stakeholders. Pediatric acute lymphoblastic leukemia is a particularly challenging population in which to make universal recommendations regarding systemic antifungal prophylaxis because of the wide variability in treatment regimens, each with differing IFD risk patterns and limitations to specific antifungal agents. Implementation of this CPG will likely require protocol-specific recommendations for patients with acute lymphoblastic leukemia.
In summary, we created a CPG for systemic antifungal prophylaxis in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guidelineconcordant rates and impacts are important future steps.
# AFFILIATIONS
# ACKNOWLEDGMENT
We thank Elizabeth Uleryk for conducting the literature search, Chris Dvorak, MD, and Maria Santolaya, MD, for their input, and Sandra Cabral for her invaluable research assistance throughout the process. We also thank Ivy Zou and Yuko Shimamoto for help with the article translation.
# SUPPORT
# AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if applicable) are available with this article at DOI https://doi.org/10.1200/ JCO.20.00158. The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
# AUTHOR CONTRIBUTIONS
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
# Thomas Lehrnbecher
# Journal of Clinical Oncology
| None | None |
827b91dfcdeacfb7fb6c1d972be61b20bf59a19f | cma | None | The 2020 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for the Secondary Prevention of Stroke includes current evidence-based recommendations and expert opinions intended for use by clinicians across a broad range of settings. They provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations address triage, diagnostic testing, lifestyle behaviors, vaping, hypertension, hyperlipidemia, diabetes, atrial fibrillation, other cardiac conditions, antiplatelet and anticoagulant therapies, and carotid and vertebral artery disease. This update of the previous 2017 guideline contains several new or revised recommendations. Recommendations regarding triage and initial assessment of acute transient ischemic attack (TIA) and minor stroke have been simplified, and selected aspects of the etiological stroke workup are revised. Updated treatment recommendations based on new evidence have been made for dual antiplatelet therapy for TIA and minor stroke; anticoagulant therapy for atrial fibrillation; embolic strokes of undetermined source; low-density lipoprotein lowering; hypertriglyceridemia; diabetes treatment; and patent foramen ovale management. A new section has been added to provide practical guidance regarding temporary interruption of antithrombotic therapy for surgical procedures. Cancer-associated ischemic stroke is addressed. A section on virtual care delivery of secondary stroke prevention services in included to highlight a shifting paradigm of care delivery made more urgent by the global pandemic. In addition, where appropriate, sex differences as they pertain to treatments have been addressed. The CSBPR include supporting materials such as implementation resources to facilitate the adoption of evidence into practice and performance measures to enable monitoring of uptake and effectiveness of recommendations.# INTRODUCTION
Optimizing stroke prevention is a major public health priority. Stroke remains a leading cause of adult neurological disability (both physical and cognitive), dementia, and death globally. The seventh update of the Canadian Stroke Best Practice Recommendations (CSBPR) Secondary Prevention of Stroke guidelines includes a summary of current evidence-based recommendations for healthcare professionals. They focus on reducing the risk of recurrent stroke following an index ischemic stroke or transient ischemic attack (TIA) and are applicable to patients managed across a variety of care settings. They emphasize a coordinated and organized approach to assessment and aggressive risk factor management. The core elements of integrated and effective secondary stroke prevention services are included in the supplemental material, Appendix Four. Patient management aims to identify treatable risk factors, apply evidence-based treatment interventions to minimize risk, provide patient education and shared decision-making, and encourage patient adherence and persistence with treatment recommendations.
These recommendations have been developed in collaboration with the Canadian Stroke Consortium. We collaborate with the Canadian Cardiovascular Society, Thrombosis Canada, Diabetes Canada, and Hypertension Canada to ensure alignment of recommendations wherever possible. Those guidelines should be consulted for additional detail and information beyond the scope of the CSBPR. The Canadian Stroke Best Practice Recommendations (CSBPR) Secondary Prevention of Stroke 2020 Seventh Edition module supersedes all recommendations contained in the CSBPR Secondary Prevention of Stroke 2017 Sixth Edition module.
# GUIDELINE DEVELOPMENT METHODOLOGY
The CSBPR development and update process follows a rigorous framework 1,2 and addresses all criteria defined within the AGREE trust model. 3 The methodology for development and updates to the CSBPR has previously published 4,5 and detailed methodology can be found on our Canadian Stroke Best Practices website at www.strokebestpractices.ca. A broad interdisciplinary group of experts was convened and participated in reviewing, drafting, and revising all recommendation statements, and a panel of people with lived experience participated in a parallel review process. 6 Evidence levels were assigned based on the quality of available evidence and expert opinion. These guidelines have undergone extensive internal and objective external review and consensus was achieved for all content. For additional methodology and information on these recommendations, including rationale, system implications, performance measures, knowledge translation and implementation tools, and an extended summary of the evidence, please visit / recommendations/secondary-prevention-of-stroke.
# SECONDARY PREVENTION OF STROKE RECOMMENDATIONS Section 1: Triage and Initial Diagnostic Evaluation of Transient Ischemic Attack and Non-Disabling Stroke
An acute TIA or minor stroke is a medical emergency. Initial management aims to establish an accurate diagnosis, determine the likely etiology, and institute secondary prevention therapy as quickly as possible. Patients with acute TIA or minor stroke are at risk of recurrent stroke both in the short-term (particularly within the first week) 7 and long-term. 8 Our triage recommendations have been simplified to focus on patients presenting within the first 48 h of a suspected new acute TIA or stroke as they are at highest risk of early recurrent stroke. For such patients, immediate assessment is recommended, with imaging of both brain (head computerized tomography or magnetic resonance imaging ) and vessels (ideally with a CT angiogram from aortic arch to vertex) on an urgent basis. 9 An embolic stroke or TIA can be the first manifestation of previously unrecognized atrial fibrillation. We recommend a tiered approach to searching for atrial fibrillation in patients with a new acute embolic ischemic stroke or TIA. 10 The goal of post-stroke electrocardiogram (ECG) monitoring is to detect high-burden atrial fibrillation for which anticoagulation would likely be beneficial. However, ECG monitoring often reveals brief subclinical paroxysmal atrial fibrillation, and it remains unclear what amount of device-detected atrial fibrillation warrants anticoagulation. Trials underway are evaluating this question. The effect of post-stroke prolonged ECG monitoring on hard clinical outcomes (i.e., recurrent stroke) remains to be determined and is the subject of ongoing research (FIND-AF2 trial, NCT04371055).
Echocardiography can be a valuable tool in the etiological assessment and risk stratification of patients with stroke and TIA. However, it can be overutilized and we recommend responsible use of this resource. Thus, the recommendations emphasize that echocardiography is not required for all stroke patients but should be considered for those with an embolic ischemic stroke or TIA of undetermined source (ESUS) or when a cardioembolic etiology or paradoxical embolism is suspected.
We have recommended against extensive thrombophilia testing for hereditary hypercoagulable disorders in the routine investigation of adults with arterial ischemic stroke events. Such testing is often overused in practice and should be limited to selected patients such as those with unexplained cerebral venous thrombosis or patent foramen ovale-related (PFO) paradoxical embolism.
An important lesson of the COVID-19 pandemic has been how essential remote or virtual contact with patients and families is to providing safe and timely care for stroke patients. In particular, care for patients living in rural or remote communities or patients for whom mobility and transport to clinic or hospital are prohibitive, can be improved via virtual care. Home blood pressure monitoring is encouraged in accordance with Hypertension Canada guidelines. 11 Home delivery of ECG patch monitors that can be self-applied by patients is a welcome option in regions where it is available. Virtual care interventions can be effective for blood pressure lowering, improvements in diet, increased physical activity, drug adherence, and satisfaction with access to care, 12 reduced HgbA1c, smoking cessation, 13 and reduced risk of cardiovascular events. 14 Section 1 Recommendations 2020 1.0 Patients with acute stroke or transient ischemic attack (TIA) who present to an ambulatory setting (such as primary care) or a hospital should undergo clinical evaluation by a healthcare professional with expertise in stroke care to determine risk for recurrent stroke and initiate appropriate and timely investigations and management strategies. 1. Referral to a healthcare professional with expertise in stroke care should be considered for patients with a suspected uncommon cause of stroke, including for young stroke patients (e.g., <45 years); 15
# Section 2: Lifestyle Behaviors and Risk Factor Management
A healthy lifestyle, which includes a Mediterranean or Dietary Approaches to Stop Hypertension (DASH) diet, exercise, weight control, reduction, and avoidance of alcohol and tobacco, reduces the risk of an initial stroke and the risk of a subsequent stroke for patients with a prior history of stroke. Although individually, these habits can reduce the risk of stroke, their impact is greater when combined. Even greater impacts can be achieved with population level interventions for physical activity include investments in health promoting infrastructure (e.g., sidewalks, walking paths, bike lanes). At the core of these of interventions is a focus on making the healthy choice the easy choice.
# Section 2.8 Clinical Considerations
Use of E-Cigarettes 1. Although some individuals may find vape products helpful in smoking cessation, the evidence base around their population-based effectiveness is not clear. 2. There is some evidence that shows people who use vaping as a mechanism to quit cigarettes may continue to vape even after cessation of cigarette use, in contrast to use of nicotine replacement therapy which has not been found to be continued in an ongoing basis. 16
# Emerging evidence indicates an association between
vaping and elevated blood pressure; the strength of the association is not clear at this time. 4. The most common pattern of use in Canada is dual use of both vape and combustible tobacco products and therefore smoking cessation strategies should include consideration for both methods of nicotine consumption. 5. Education and counselling should be provided regarding the risks versus benefits of e-cigarettes in people with stroke, including in younger age groups who have experienced stroke. Hypertension is the major modifiable risk factor for stroke. In Canada, systolic hypertension is estimated to account for about 45% of the total stroke burden. 18 Although the optimal target blood pressure to prevent a first or recurrent stroke has not been formally established, the current treatment recommendation to attain a blood pressure of consistently lower than 140/90 mm Hg for people who have had an ischemic stroke or TIA, can help to reduce recurrent events. Using the results from a subset of 13 randomized controlled trials (RCTs) that included persons with a previous history of stroke, Law et al. 19 reported that blood pressure treatment resulting in a reduction of 10 mm Hg systolic and 5 mm Hg diastolic was associated with a 34% reduced risk of recurrent stroke (RR = 0.66, 95% CI 0.56-0.79). In the RE-SPECT trial, 20 persons with a history of stroke within the previous 30 d to three years who were randomized to a standard treatment group with a target of <140/90 mm Hg or an intensive treatment group with a target of <120/80 mm Hg, did not have a significantly reduced risk of recurrent stroke (HR = 0.73, 95% CI 0.49-1.11, p = 0.15); however, when these results were incorporated into an updated meta-analysis, the risk was reduced significantly with intensive therapy. The number needed to treat to prevent one recurrent stroke was 67, with an absolute risk reduction of 1.5%. Section 3 Clinical Considerations 1. (New for 2020) For patients with a non-revascularized critical intracranial or extracranial arterial stenosis who are experiencing neurological symptoms attributed to hemodynamic (low flow) cerebral or retinal ischemia (e.g., orthostatic TIAs), it is reasonable to aim for higher than usual blood pressure targets (i.e., permissive hypertension), and avoidance of hypotension, for prevention of hemodynamic stroke; if such patients are asymptomatic, then usual blood pressure targets should be followed in the post-acute phase of stroke.
# Section 4: Lipid Management
New evidence supports more aggressive lipid management for secondary stroke prevention. The recommended target low-density lipoprotein (LDL) cholesterol level has been lowered to <1.8 mmol/L, from previously recommended targets of LDL < 2.0 mmol/L or 50% LDL reduction. If this target cannot be achieved with maximum tolerated statin therapy, ezetimibe or a PCSK9 inhibitor may be added for ischemic stroke patients with atherosclerotic disease. Clinicians are reminded that lipid lowering therapies are not recommended for secondary prevention of intracerebral hemorrhage, or for patients with cardioembolic ischemic stroke (e.g., atrial fibrillation) in the absence of atherosclerotic disease.
The Treat Stroke to Target trial studied 2860 patients with atherosclerotic disease who had an ischemic stroke within the previous 3 months or a TIA within the previous 15 d. Treatment to an LDL cholesterol target <1.8 mmol/L, as compared to a target of 2.3-2.8 mmol/L, was associated with a lower risk of major cardiovascular events over a median of 3.5 years (8.5% vs. 10.9%, HR = 0.78, 95% CI 0.61-0.98; p = 0.04). 21 About a third of patients in this study required the addition of ezetimibe to their high-dose statin to achieve the more aggressive LDL target.
Treatment of hypertriglyceridemia with icosapent ethyl 2 g bid may be considered for patients with ischemic stroke who have established atherosclerotic cardiovascular disease, or diabetes plus additional vascular risk factors, and elevated serum triglycerides (≥1.5 mmol/L) despite statin therapy. In Canada, almost 2.5 million people have type 1 or 2 diabetes. 23 Diabetes is known to increase the risk of ischemic stroke by 227%. 24 Although tighter glycemic control along with other risk factor reduction strategies, can collectively help to reduce stroke risk, on its own, aggressive glycemic control does not reduce stroke risk. 25,26 However, trials of newer antihyperglycemic agents, including SGLT-2 and GLP-1 receptor agonists, have demonstrated benefit for major cardiovascular outcomes, including stroke. 1. The Pioglitazone after Ischemic Stroke or TIA trial 32 suggested that while there is a benefit of pioglitazone for stroke prevention in patients with positive insulin resistance, it is offset by the increased risk of fractures and bladder cancer. A post-hoc analysis of patients in the trial with prediabetes and good drug adherence suggested a benefit of pioglitazone over placebo with regards to stroke, acute coronary syndrome, stroke/myocardial infarction (MI)/hospitalization for heart failure, and progression to diabetes. The decision to use this agent could be considered based on the specific risk profile for each patient.
Section 6.0: Antiplatelet Therapy for Individuals with Ischemic Stroke or TIA Short-term administration of dual antiplatelet therapy with aspirin and clopidogrel is recommended for secondary stroke prevention, starting within 24 h for eligible patients with acute non-hemorrhagic high-risk TIA or minor ischemic stroke based on the POINT, 33 CHANCE, 34 and FASTER 35 trials. The optimal duration of dual antiplatelet therapy has been clarified by additional analyses 36,37 with net benefit of dual antiplatelet therapy over aspirin alone likely confined to the first 21 d post-TIA/stroke (maximal within the first 10 d). Compared with aspirin, the shortterm dual antiplatelet therapy protocol prevents 20 more strokes (and causes two major bleeds) for every 1000 patients treated. Pharmacogenetic testing can identify patients with clopidogrel resistance, however, its clinical implications for stroke prevention practice are unclear at this time. Another short-term dual antiplatelet treatment option is the combination of daily low-dose aspirin and ticagrelor, a P2Y12 antagonist most often used in coronary artery disease. The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial tested a 30-d course of the aspirin-ticagrelor combination starting within 24 h of a high-risk TIA or minor ischemic stroke. 41 Ticagrelor was administered as a 180 mg loading dose followed by 90 mg twice daily, along with aspirin 75-100 mg daily. This combination reduced the risk of recurrent stroke or death compared with aspirin alone, although the risk of severe bleeding, intracranial bleeding, and fatal bleeding was higher in the ticagrelor-aspirin group. Maximum benefit was observed in patients with ipsilateral large vessel atherosclerotic disease. 42 The defining features of ESUS are an acute brain infarct visualized on neuroimaging (not a subcortical lacune 50%; no atrial fibrillation or other major risk cardioembolic source; and no other likely cause for the stroke. 43 Patients with ESUS have an average annual stroke recurrence risk of approximately 5%. Two trials published since the last edition investigated whether patients with ESUS would benefit more from anticoagulation than aspirin. Neither trial showed found a significant reduction in recurrent stroke risk and therefore anticoagulation is not recommended for patients with ESUS. 44,60 The lack of an overall benefit of anticoagulation likely reflects that ESUS comprises a heterogeneous group of many etiologies, with atherosclerotic or other mechanisms likely predominating over occult atrial fibrillation in the patients enrolled in these trials. The ARCADIA trial (NCT03192215) is testing apixaban versus aspirin in a subset of ESUS patients who have markers of atrial myopathy.
# Section 7: Anticoagulant Therapy for Atrial Fibrillation
Oral anticoagulant therapy is strongly recommended for secondary stroke prevention in patients with atrial fibrillation. Anticoagulation for AF has been associated with a 66% relative risk reduction of recurrent stroke, with an absolute risk reduction of 7.3%. 45 Direct oral anticoagulants (DOACs) are generally preferred over warfarin for most patients with non-valvular atrial fibrillation (non-valvular is now defined as atrial fibrillation without moderate-severe mitral stenosis or mechanical heart valves). 46 A recent trial supports the use of rivaroxaban over warfarin for patients with atrial fibrillation and a bioprosthetic mitral valve. 47 Clinicians are reminded to avoid inappropriate underdosing of DOACs, a practice that is associated with increased stroke risk. For patients with atrial fibrillation and chronic stable coronary artery disease (or >1-year post-percutaneous coronary intervention or coronary artery bypass graft ), the addition of an antiplatelet agent to chronic DOAC therapy is not recommended as it increases bleeding risk without providing additional benefit in reducing ischemic events (cardiac or cerebral). The Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE) trial showed that rivaroxaban alone was as effective as the combination of rivaroxaban and aspirin in this patient population, with a lower incidence of bleeding. 48 1. The optimal timing to start anticoagulant therapy after an ischemic stroke has not yet been well defined by clinical trial evidence and should be based on individual benefit/risk assessment taking into account the clinical circumstances, stroke severity, infarct size, imaging appearances, risk of hemorrhagic transformation, age, comorbidities, and estimated stroke recurrence risk. 2. There is a lack of randomized evidence to guide specific timing. According to expert consensus, a general approach to the target timing of initiation of DOAC therapy post-stroke is as follows: a. For patients with a brief TIA and no visible infarct or hemorrhage on imaging, anticoagulation may be started within the first 24 h post-TIA. b. For patients with a minor clinical stroke/small nonhemorrhagic infarct on imaging, anticoagulation may be started 3 d post-stroke. c. For patients with a moderate clinical stroke/moderatesized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 6-7 d post-stroke. d. For patients with a severe clinical stroke/large-sized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 12-14 d post-stroke. 3. If anticoagulation is delayed beyond 24 h, it is recommended to obtain repeat brain imaging for reassessment prior to initiation of anticoagulation to exclude the presence of asymptomatic hemorrhagic transformation of the index infarct.
- It is reasonable to delay the initiation of anticoagulation for more than 2 weeks post-stroke if in the judgement of the clinician the risk of intracranial bleeding is felt to be high, for example, for some patients with large infarcts and those with hemorrhagic transformation.
Stroke while on DOAC Therapy 1. (New for 2020): For patients with atrial fibrillation who experience ischemic stroke or TIA despite anticoagulant therapy, either continuing the current agent or switching to a different anticoagulant agent are reasonable options. At the present time, evidence is lacking to make more specific recommendations. 2. The routine addition of acetylsalicylic acid to chronic anticoagulant therapy is not recommended because of increased bleeding risk without clear evidence of benefit and potential for harm unless there is a specific medical indication. months or more frequently) may be considered for patients with renal impairment or a dehydrating illness for medication adjustment if required, particularly for patients receiving dabigatran . iv. For patients taking chronic oral anticoagulant therapy for non-valvular atrial fibrillation, the addition of antiplatelet therapy is not recommended due to increased bleeding risk unless there is a specific medical indication for antiplatelet therapy (e.g., recent vascular stent; certain mechanical heart valves) . v. (New for 2020): For patients with atrial fibrillation and chronic stable coronary artery disease (and >1-year post-PCI or CABG), the addition of an antiplatelet agent to DOAC therapy is not recommended as it increases bleeding risk without providing any significant benefit in reducing ischemic events (cardiac or cerebral) .
Section 8: Perioperative Management of Anticoagulant and Antiplatelet Therapy (New for 2020)
This edition features a new section on perioperative antithrombotic managementa commonly encountered issue in the stroke population and one in which practice variations abound. Our recommendations are aligned with Thrombosis Canada. 49 For stroke or TIA patients who require temporary interruption of chronic antiplatelet or anticoagulant therapy for an upcoming elective surgery, decisions regarding the duration of therapy interruption depend on the agent and the estimated bleeding risk associated with the surgery or procedure. The goal is to minimize the risk of ischemic stroke while simultaneously minimizing the risk of clinically important (major) bleeding. Patients should avoid unnecessary or prolonged interruptions of their antithrombotic therapy. Clinicians should communicate clear instructions to patients regarding their perioperative management plan before an elective procedure.
Because DOACs have a rapid offset (average half-life of approximately 12 h) and a rapid onset of action, the duration of DOAC interruption can be kept short to minimize the risk of ischemic stroke. This approach of standardized DOAC interruption and resumption appeared safe in the Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study of 3007 DOACtreated patients; the 30-d post-operative rates of arterial thromboembolism and major bleeding were <1% and <2%, respectively. 50 For patients undergoing a minimal-bleed-risk procedure, anticoagulants can generally be continued without interruption, with some caveats; for DOACs, it is reasonable to omit the morning DOAC dose before the procedure to reduce bleeding risk.
# Descriptions of type of surgery or procedure and bleeding risk category:
- A high-bleed-risk surgery or procedure includes major abdominal surgery (e.g., cancer resection), major thoracic surgery, major orthopedic surgery, and any cardiac, spinal, or intracranial surgery. Any patient having neuraxial anesthesia is classified as high-bleed-risk because of the risk for spinal epidural hematomas which could cause limb paralysis.
- A low-to-moderate-bleed-risk surgery or procedure includes most surgeries that are <1-h duration and procedures that do not involve neuraxial anesthesia.
- A minimal-bleed-risk surgery or procedure includes tooth extractions, root canal, skin biopsies, cataract surgery, and selected colonoscopies, for which anticoagulants can be continued without interruption. Permanent pacemaker and internal cardiac defibrillator implantation, as well as cardiac catheterization, also can be done without stopping anticoagulants.
# Section 8 Recommendations 2020
i. Patients with atrial fibrillation or a mechanical heart valve who are receiving oral anticoagulant therapy and require a procedure associated with a minimal risk of bleeding (e.g., tooth extraction, skin biopsy, cataract removal, cardiac pacemaker) should not have anticoagulation interrupted around the time of the procedure . ii. For patients with atrial fibrillation receiving a DOAC for stroke prevention who require temporary DOAC interruption for an elective surgery or procedure, the following approach is recommended : a. For a low-to-moderate-bleed-risk surgery or procedure, stop the DOAC the day before the procedure and the day of the procedure (i.e., skip 2 d total), and restart the day after the procedure. b. For a high-bleed-risk surgery or procedure, stop the DOAC 2 d before the procedure, the day of the procedure, and one day after the procedure (i.e., skip 4 d total). Note: An exception involves patients on dabigatran with impaired renal function (CrCl <50 mL/min) in whom an additional 1-2 d of interruption is suggested before surgery or procedure. Refer to clinical considerations for additional information. iii. For patients with atrial fibrillation receiving warfarin for stroke prevention who require temporary warfarin interruption for an elective surgery or procedure: a. For patients at low-to-moderate stroke risk (e.g., CHADS2 score 0-4), warfarin should be stopped for 5 d pre-procedure, and resumed within 24 h post-procedure, without heparin bridging .
# Section 8 Clinical Considerations
Perioperative management of patients undergoing a minimal-bleed-risk procedure 1. For patients undergoing minor procedures that are considered minimal-bleed-risk (refer to definition above), it is not routinely necessary to stop anticoagulants. However, there are some caveats to the management of such patients: a. Any of the minimal-bleed-risk procedures could be considered as having a higher bleed risk warranting anticoagulant interruption (e.g., tooth extraction in a patient with poor dentition or cataract surgery with retrobulbar anesthesia) based on individual patient circumstances. b. In patients receiving a DOAC who are undergoing a minimal bleed-risk procedure, it is prudent to omit the morning DOAC dose just before the procedure because the peak anticoagulant effect, occurring 1-3 h after intake, may coincide with the timing of the procedure and may increase the risk for bleeding. c. For pacemaker or ICD implantation, patients can continue warfarin, but the INR should be <3.0 at the time of the procedure. d. For coronary angiography, continuing anticoagulants if a femoral artery approach is used may not be advisable as such patients are at increased risk for developing a hematoma or false aneurysm. e. For colonoscopy, anticoagulation can be continued in selected patients in which the likelihood of polypectomy or multiple biopsies is low.
f. For dental procedures, oral tranexamic acid mouthwash can be used before and 2-3 times daily after the procedure to reduce bleeding since such oral bleeding, although not clinically important, may cause distress to patients. Carotid endarterectomy (CEA) has been shown to prevent stroke recurrence in patients who have sustained a minor stroke or TIA with ipsilateral high-grade carotid stenosis. For those with 50%-99% stenosis, the number of persons needed to undergo surgery to prevent one ipsilateral stroke in five years was estimated to be 9 for men versus 36 for women. Women with symptomatic disease had significantly higher odds of 30-d mortality following CEA compared with men. (adjusted OR = 1.4, 95% CI 1.02-1.94). 51 The use of CEA for asymptomatic carotid artery disease is controversial. One-year results from the recent SPACE-2 trial, 52 indicated there were no significant differences between groups (CEA vs. best medical management) in the occurrences of any stroke after day 30, up to one-year, ipsilateral stroke, disabling stroke, any death, myocardial infarction, restenosis or TIA. The trial was terminated early due to low recruitment. In this same trial, there were no significant differences in the same outcomes for the comparison of best medical management versus carotid-artery angioplasty. 53 and additional meta-analyses and other reports further support PFO closure for secondary stroke prevention in selected patients. Given that TIA can be difficult to differentiate from mimics and the fact that only one of the PFO trials enrolled patients with TIA as an index event, clinicians should be cautious when contemplating PFO closure for TIA unless there is a high certainty of ischemia; accordingly, these 2021 recommendations no longer indicate TIA as an unqualified indication for closure. There is now moderatestrength evidence that PFO closure may be targeted to patient groups with higher risk echocardiographic features.
For patients with heart failure and without atrial fibrillation, the COMMANDER-HF trial, 57 which compared rivaroxaban to standard care, found no significant difference in the frequency of the primary outcome (a composite of death from any cause, MI, or stroke) between groups. The risks of the individual components of the primary outcome did not differ between groups with the exception of the risk of stroke, which was reduced significantly with rivaroxaban (1.08 vs. 1.63 events/100-person years; HR = 0.66, 95% CI 0.47-0.95). In the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, 58 which compared the effectiveness of anticoagulation compared with antiplatelet therapy for stroke prevention in patients with heart failure in sinus rhythm, warfarin was associated with a significantly reduced risk of ischemic stroke (HR = 0.52, 95% CI 0.33-0.82, p = 0.005); however, the risks of major and minor hemorrhages were significantly increased. 59 A diagnosis of cancer can increase the risk of stroke in the months or years following the diagnosis, particularly among persons with lung cancer or with more advanced cancers. 60,61 Thrombosis is a common complication of malignancy and represents a frequent cause of death in cancer patients with a history of stroke.
# CHALLENGES AND FUTURE DIRECTIONS
Advances in stroke prevention, driven by high-quality clinical studies, continue to inform each new edition of these guidelines.
However, we are still far from adequately addressing, at a global level, the 10 modifiable risk factors that account for 90% of the population attributable risk of stroke. 62 The largest impact on stroke prevention globally will likely be achieved by continued large-scale efforts to address hypertension, diabetes, diet, exercise, smoking, in addition to atrial fibrillation at both policy and individual levels.
A key tenet of secondary stroke prevention remains the importance of identifying the most likely stroke etiology and tailoring therapy accordingly. Although the completed ESUS trials found no overall benefit of anticoagulation, further research aims to identify whether specific subgroups may benefit. Dual pathway inhibition is a promising strategy. 63 Newer anticoagulants targeting factor XI represent promising future treatments for stroke prevention. Studies are ongoing (NCT02604667) and others are needed to better define when and how occult cancer should be investigated in cryptogenic stroke patients, and if found, what antithrombotic regimen best protects these patients from recurrent arterial strokes. 64 Immediate challenges to optimal secondary stroke prevention would therefore include the need to develop, grow, and maintain systems for virtual delivery of care to patients through telemedicine. 65,66 The SARS-CoV2 virus represents a well-documented challenge to acute stroke care 67 but its impact on the risk of stroke recurrence, either directly among patients having been infected with the virus, or on other patients who have suffered collateral damage from diminished access to stroke care, will be important to now study.
A challenge that concerns research in all fields of medicineincluding stroke 68 is the need to ensure adequate sex and gender representation in therapeutic trials to ensure generalizability of results to both men and women. This edition is the first of our guidelines to start incorporating a sex and gender descriptive analysis into the literature review for each recommendation, and future editions will strive to include gender and sex-based recommendations where appropriate.
# SUMMARY
The 2020 update of the Canadian Stroke Best Practice Secondary Prevention of Stroke Recommendations provide a common set of guiding principles for important aspects of secondary stroke prevention, emphasizing that individuals who have experienced a stroke or TIA require access expert prevention care in a timely way. In Canada, coordinated systems have evolved over time, growing the number of stroke prevention services and protocols to increase access in many under-serviced areas. In the age of Covid-19, there are new opportunities to provide prevention interventions remotely to narrow the inequities in access to care. | The 2020 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for the Secondary Prevention of Stroke includes current evidence-based recommendations and expert opinions intended for use by clinicians across a broad range of settings. They provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations address triage, diagnostic testing, lifestyle behaviors, vaping, hypertension, hyperlipidemia, diabetes, atrial fibrillation, other cardiac conditions, antiplatelet and anticoagulant therapies, and carotid and vertebral artery disease. This update of the previous 2017 guideline contains several new or revised recommendations. Recommendations regarding triage and initial assessment of acute transient ischemic attack (TIA) and minor stroke have been simplified, and selected aspects of the etiological stroke workup are revised. Updated treatment recommendations based on new evidence have been made for dual antiplatelet therapy for TIA and minor stroke; anticoagulant therapy for atrial fibrillation; embolic strokes of undetermined source; low-density lipoprotein lowering; hypertriglyceridemia; diabetes treatment; and patent foramen ovale management. A new section has been added to provide practical guidance regarding temporary interruption of antithrombotic therapy for surgical procedures. Cancer-associated ischemic stroke is addressed. A section on virtual care delivery of secondary stroke prevention services in included to highlight a shifting paradigm of care delivery made more urgent by the global pandemic. In addition, where appropriate, sex differences as they pertain to treatments have been addressed. The CSBPR include supporting materials such as implementation resources to facilitate the adoption of evidence into practice and performance measures to enable monitoring of uptake and effectiveness of recommendations.# INTRODUCTION
Optimizing stroke prevention is a major public health priority. Stroke remains a leading cause of adult neurological disability (both physical and cognitive), dementia, and death globally. The seventh update of the Canadian Stroke Best Practice Recommendations (CSBPR) Secondary Prevention of Stroke guidelines includes a summary of current evidence-based recommendations for healthcare professionals. They focus on reducing the risk of recurrent stroke following an index ischemic stroke or transient ischemic attack (TIA) and are applicable to patients managed across a variety of care settings. They emphasize a coordinated and organized approach to assessment and aggressive risk factor management. The core elements of integrated and effective secondary stroke prevention services are included in the supplemental material, Appendix Four. Patient management aims to identify treatable risk factors, apply evidence-based treatment interventions to minimize risk, provide patient education and shared decision-making, and encourage patient adherence and persistence with treatment recommendations.
These recommendations have been developed in collaboration with the Canadian Stroke Consortium. We collaborate with the Canadian Cardiovascular Society, Thrombosis Canada, Diabetes Canada, and Hypertension Canada to ensure alignment of recommendations wherever possible. Those guidelines should be consulted for additional detail and information beyond the scope of the CSBPR. The Canadian Stroke Best Practice Recommendations (CSBPR) Secondary Prevention of Stroke 2020 Seventh Edition module supersedes all recommendations contained in the CSBPR Secondary Prevention of Stroke 2017 Sixth Edition module.
# GUIDELINE DEVELOPMENT METHODOLOGY
The CSBPR development and update process follows a rigorous framework 1,2 and addresses all criteria defined within the AGREE trust model. 3 The methodology for development and updates to the CSBPR has previously published 4,5 and detailed methodology can be found on our Canadian Stroke Best Practices website at www.strokebestpractices.ca. A broad interdisciplinary group of experts was convened and participated in reviewing, drafting, and revising all recommendation statements, and a panel of people with lived experience participated in a parallel review process. 6 Evidence levels were assigned based on the quality of available evidence and expert opinion. These guidelines have undergone extensive internal and objective external review and consensus was achieved for all content. For additional methodology and information on these recommendations, including rationale, system implications, performance measures, knowledge translation and implementation tools, and an extended summary of the evidence, please visit https://www.strokebestpractices.ca/ recommendations/secondary-prevention-of-stroke.
# SECONDARY PREVENTION OF STROKE RECOMMENDATIONS Section 1: Triage and Initial Diagnostic Evaluation of Transient Ischemic Attack and Non-Disabling Stroke
An acute TIA or minor stroke is a medical emergency. Initial management aims to establish an accurate diagnosis, determine the likely etiology, and institute secondary prevention therapy as quickly as possible. Patients with acute TIA or minor stroke are at risk of recurrent stroke both in the short-term (particularly within the first week) 7 and long-term. 8 Our triage recommendations have been simplified to focus on patients presenting within the first 48 h of a suspected new acute TIA or stroke as they are at highest risk of early recurrent stroke. For such patients, immediate assessment is recommended, with imaging of both brain (head computerized tomography [CT] or magnetic resonance imaging [MRI]) and vessels (ideally with a CT angiogram from aortic arch to vertex) on an urgent basis. 9 An embolic stroke or TIA can be the first manifestation of previously unrecognized atrial fibrillation. We recommend a tiered approach to searching for atrial fibrillation in patients with a new acute embolic ischemic stroke or TIA. 10 The goal of post-stroke electrocardiogram (ECG) monitoring is to detect high-burden atrial fibrillation for which anticoagulation would likely be beneficial. However, ECG monitoring often reveals brief subclinical paroxysmal atrial fibrillation, and it remains unclear what amount of device-detected atrial fibrillation warrants anticoagulation. Trials underway are evaluating this question. The effect of post-stroke prolonged ECG monitoring on hard clinical outcomes (i.e., recurrent stroke) remains to be determined and is the subject of ongoing research (FIND-AF2 trial, NCT04371055).
Echocardiography can be a valuable tool in the etiological assessment and risk stratification of patients with stroke and TIA. However, it can be overutilized and we recommend responsible use of this resource. Thus, the recommendations emphasize that echocardiography is not required for all stroke patients but should be considered for those with an embolic ischemic stroke or TIA of undetermined source (ESUS) or when a cardioembolic etiology or paradoxical embolism is suspected.
We have recommended against extensive thrombophilia testing for hereditary hypercoagulable disorders in the routine investigation of adults with arterial ischemic stroke events. Such testing is often overused in practice and should be limited to selected patients such as those with unexplained cerebral venous thrombosis or patent foramen ovale-related (PFO) paradoxical embolism.
An important lesson of the COVID-19 pandemic has been how essential remote or virtual contact with patients and families is to providing safe and timely care for stroke patients. In particular, care for patients living in rural or remote communities or patients for whom mobility and transport to clinic or hospital are prohibitive, can be improved via virtual care. Home blood pressure monitoring is encouraged in accordance with Hypertension Canada guidelines. 11 Home delivery of ECG patch monitors that can be self-applied by patients is a welcome option in regions where it is available. Virtual care interventions can be effective for blood pressure lowering, improvements in diet, increased physical activity, drug adherence, and satisfaction with access to care, 12 reduced HgbA1c, smoking cessation, 13 and reduced risk of cardiovascular events. 14 Section 1 Recommendations 2020 1.0 Patients with acute stroke or transient ischemic attack (TIA) who present to an ambulatory setting (such as primary care) or a hospital should undergo clinical evaluation by a healthcare professional with expertise in stroke care to determine risk for recurrent stroke and initiate appropriate and timely investigations and management strategies. 1. Referral to a healthcare professional with expertise in stroke care should be considered for patients with a suspected uncommon cause of stroke, including for young stroke patients (e.g., <45 years); 15
# Section 2: Lifestyle Behaviors and Risk Factor Management
A healthy lifestyle, which includes a Mediterranean or Dietary Approaches to Stop Hypertension (DASH) diet, exercise, weight control, reduction, and avoidance of alcohol and tobacco, reduces the risk of an initial stroke and the risk of a subsequent stroke for patients with a prior history of stroke. Although individually, these habits can reduce the risk of stroke, their impact is greater when combined. Even greater impacts can be achieved with population level interventions for physical activity include investments in health promoting infrastructure (e.g., sidewalks, walking paths, bike lanes). At the core of these of interventions is a focus on making the healthy choice the easy choice.
# Section 2.8 Clinical Considerations
Use of E-Cigarettes 1. Although some individuals may find vape products helpful in smoking cessation, the evidence base around their population-based effectiveness is not clear. 2. There is some evidence that shows people who use vaping as a mechanism to quit cigarettes may continue to vape even after cessation of cigarette use, in contrast to use of nicotine replacement therapy which has not been found to be continued in an ongoing basis. 16
# Emerging evidence indicates an association between
vaping and elevated blood pressure; the strength of the association is not clear at this time. 4. The most common pattern of use in Canada is dual use of both vape and combustible tobacco products and therefore smoking cessation strategies should include consideration for both methods of nicotine consumption. 5. Education and counselling should be provided regarding the risks versus benefits of e-cigarettes in people with stroke, including in younger age groups who have experienced stroke. Hypertension is the major modifiable risk factor for stroke. In Canada, systolic hypertension is estimated to account for about 45% of the total stroke burden. 18 Although the optimal target blood pressure to prevent a first or recurrent stroke has not been formally established, the current treatment recommendation to attain a blood pressure of consistently lower than 140/90 mm Hg for people who have had an ischemic stroke or TIA, can help to reduce recurrent events. Using the results from a subset of 13 randomized controlled trials (RCTs) that included persons with a previous history of stroke, Law et al. 19 reported that blood pressure treatment resulting in a reduction of 10 mm Hg systolic and 5 mm Hg diastolic was associated with a 34% reduced risk of recurrent stroke (RR = 0.66, 95% CI 0.56-0.79). In the RE-SPECT trial, 20 persons with a history of stroke within the previous 30 d to three years who were randomized to a standard treatment group with a target of <140/90 mm Hg or an intensive treatment group with a target of <120/80 mm Hg, did not have a significantly reduced risk of recurrent stroke (HR = 0.73, 95% CI 0.49-1.11, p = 0.15); however, when these results were incorporated into an updated meta-analysis, the risk was reduced significantly with intensive therapy. The number needed to treat to prevent one recurrent stroke was 67, with an absolute risk reduction of 1.5%. Section 3 Clinical Considerations 1. (New for 2020) For patients with a non-revascularized critical intracranial or extracranial arterial stenosis who are experiencing neurological symptoms attributed to hemodynamic (low flow) cerebral or retinal ischemia (e.g., orthostatic TIAs), it is reasonable to aim for higher than usual blood pressure targets (i.e., permissive hypertension), and avoidance of hypotension, for prevention of hemodynamic stroke; if such patients are asymptomatic, then usual blood pressure targets should be followed in the post-acute phase of stroke.
# Section 4: Lipid Management
New evidence supports more aggressive lipid management for secondary stroke prevention. The recommended target low-density lipoprotein (LDL) cholesterol level has been lowered to <1.8 mmol/L, from previously recommended targets of LDL < 2.0 mmol/L or 50% LDL reduction. If this target cannot be achieved with maximum tolerated statin therapy, ezetimibe or a PCSK9 inhibitor may be added for ischemic stroke patients with atherosclerotic disease. Clinicians are reminded that lipid lowering therapies are not recommended for secondary prevention of intracerebral hemorrhage, or for patients with cardioembolic ischemic stroke (e.g., atrial fibrillation) in the absence of atherosclerotic disease.
The Treat Stroke to Target trial studied 2860 patients with atherosclerotic disease who had an ischemic stroke within the previous 3 months or a TIA within the previous 15 d. Treatment to an LDL cholesterol target <1.8 mmol/L, as compared to a target of 2.3-2.8 mmol/L, was associated with a lower risk of major cardiovascular events over a median of 3.5 years (8.5% vs. 10.9%, HR = 0.78, 95% CI 0.61-0.98; p = 0.04). 21 About a third of patients in this study required the addition of ezetimibe to their high-dose statin to achieve the more aggressive LDL target.
Treatment of hypertriglyceridemia with icosapent ethyl 2 g bid may be considered for patients with ischemic stroke who have established atherosclerotic cardiovascular disease, or diabetes plus additional vascular risk factors, and elevated serum triglycerides (≥1.5 mmol/L) despite statin therapy. In Canada, almost 2.5 million people have type 1 or 2 diabetes. 23 Diabetes is known to increase the risk of ischemic stroke by 227%. 24 Although tighter glycemic control along with other risk factor reduction strategies, can collectively help to reduce stroke risk, on its own, aggressive glycemic control does not reduce stroke risk. 25,26 However, trials of newer antihyperglycemic agents, including SGLT-2 and GLP-1 receptor agonists, have demonstrated benefit for major cardiovascular outcomes, including stroke. [27][28][29][30][31] 1. The Pioglitazone after Ischemic Stroke or TIA trial 32 suggested that while there is a benefit of pioglitazone for stroke prevention in patients with positive insulin resistance, it is offset by the increased risk of fractures and bladder cancer. A post-hoc analysis of patients in the trial with prediabetes and good drug adherence suggested a benefit of pioglitazone over placebo with regards to stroke, acute coronary syndrome, stroke/myocardial infarction (MI)/hospitalization for heart failure, and progression to diabetes. The decision to use this agent could be considered based on the specific risk profile for each patient.
Section 6.0: Antiplatelet Therapy for Individuals with Ischemic Stroke or TIA Short-term administration of dual antiplatelet therapy with aspirin and clopidogrel is recommended for secondary stroke prevention, starting within 24 h for eligible patients with acute non-hemorrhagic high-risk TIA or minor ischemic stroke based on the POINT, 33 CHANCE, 34 and FASTER 35 trials. The optimal duration of dual antiplatelet therapy has been clarified by additional analyses 36,37 with net benefit of dual antiplatelet therapy over aspirin alone likely confined to the first 21 d post-TIA/stroke (maximal within the first 10 d). Compared with aspirin, the shortterm dual antiplatelet therapy protocol prevents 20 more strokes (and causes two major bleeds) for every 1000 patients treated. Pharmacogenetic testing can identify patients with clopidogrel resistance, however, its clinical implications for stroke prevention practice are unclear at this time. [38][39][40] Another short-term dual antiplatelet treatment option is the combination of daily low-dose aspirin and ticagrelor, a P2Y12 antagonist most often used in coronary artery disease. The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial tested a 30-d course of the aspirin-ticagrelor combination starting within 24 h of a high-risk TIA or minor ischemic stroke. 41 Ticagrelor was administered as a 180 mg loading dose followed by 90 mg twice daily, along with aspirin 75-100 mg daily. This combination reduced the risk of recurrent stroke or death compared with aspirin alone, although the risk of severe bleeding, intracranial bleeding, and fatal bleeding was higher in the ticagrelor-aspirin group. Maximum benefit was observed in patients with ipsilateral large vessel atherosclerotic disease. 42 The defining features of ESUS are an acute brain infarct visualized on neuroimaging (not a subcortical lacune <1.5 cm); absence of proximal atherosclerotic vessel stenosis >50%; no atrial fibrillation or other major risk cardioembolic source; and no other likely cause for the stroke. 43 Patients with ESUS have an average annual stroke recurrence risk of approximately 5%. Two trials published since the last edition investigated whether patients with ESUS would benefit more from anticoagulation than aspirin. Neither trial showed found a significant reduction in recurrent stroke risk and therefore anticoagulation is not recommended for patients with ESUS. 44,60 The lack of an overall benefit of anticoagulation likely reflects that ESUS comprises a heterogeneous group of many etiologies, with atherosclerotic or other mechanisms likely predominating over occult atrial fibrillation in the patients enrolled in these trials. The ARCADIA trial (NCT03192215) is testing apixaban versus aspirin in a subset of ESUS patients who have markers of atrial myopathy.
# Section 7: Anticoagulant Therapy for Atrial Fibrillation
Oral anticoagulant therapy is strongly recommended for secondary stroke prevention in patients with atrial fibrillation. Anticoagulation for AF has been associated with a 66% relative risk reduction of recurrent stroke, with an absolute risk reduction of 7.3%. 45 Direct oral anticoagulants (DOACs) are generally preferred over warfarin for most patients with non-valvular atrial fibrillation (non-valvular is now defined as atrial fibrillation without moderate-severe mitral stenosis or mechanical heart valves). 46 A recent trial supports the use of rivaroxaban over warfarin for patients with atrial fibrillation and a bioprosthetic mitral valve. 47 Clinicians are reminded to avoid inappropriate underdosing of DOACs, a practice that is associated with increased stroke risk. For patients with atrial fibrillation and chronic stable coronary artery disease (or >1-year post-percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]), the addition of an antiplatelet agent to chronic DOAC therapy is not recommended as it increases bleeding risk without providing additional benefit in reducing ischemic events (cardiac or cerebral). The Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE) trial showed that rivaroxaban alone was as effective as the combination of rivaroxaban and aspirin in this patient population, with a lower incidence of bleeding. 48 1. The optimal timing to start anticoagulant therapy after an ischemic stroke has not yet been well defined by clinical trial evidence and should be based on individual benefit/risk assessment taking into account the clinical circumstances, stroke severity, infarct size, imaging appearances, risk of hemorrhagic transformation, age, comorbidities, and estimated stroke recurrence risk. 2. There is a lack of randomized evidence to guide specific timing. According to expert consensus, a general approach to the target timing of initiation of DOAC therapy post-stroke is as follows: a. For patients with a brief TIA and no visible infarct or hemorrhage on imaging, anticoagulation may be started within the first 24 h post-TIA. b. For patients with a minor clinical stroke/small nonhemorrhagic infarct on imaging, anticoagulation may be started 3 d post-stroke. c. For patients with a moderate clinical stroke/moderatesized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 6-7 d post-stroke. d. For patients with a severe clinical stroke/large-sized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 12-14 d post-stroke. 3. If anticoagulation is delayed beyond 24 h, it is recommended to obtain repeat brain imaging for reassessment prior to initiation of anticoagulation to exclude the presence of asymptomatic hemorrhagic transformation of the index infarct.
4. It is reasonable to delay the initiation of anticoagulation for more than 2 weeks post-stroke if in the judgement of the clinician the risk of intracranial bleeding is felt to be high, for example, for some patients with large infarcts and those with hemorrhagic transformation.
Stroke while on DOAC Therapy 1. (New for 2020): For patients with atrial fibrillation who experience ischemic stroke or TIA despite anticoagulant therapy, either continuing the current agent or switching to a different anticoagulant agent are reasonable options. At the present time, evidence is lacking to make more specific recommendations. 2. The routine addition of acetylsalicylic acid to chronic anticoagulant therapy is not recommended because of increased bleeding risk without clear evidence of benefit and potential for harm unless there is a specific medical indication. months or more frequently) may be considered for patients with renal impairment or a dehydrating illness for medication adjustment if required, particularly for patients receiving dabigatran [Evidence Level C]. iv. For patients taking chronic oral anticoagulant therapy for non-valvular atrial fibrillation, the addition of antiplatelet therapy is not recommended due to increased bleeding risk unless there is a specific medical indication for antiplatelet therapy (e.g., recent vascular stent; certain mechanical heart valves) [Evidence Level B]. v. (New for 2020): For patients with atrial fibrillation and chronic stable coronary artery disease (and >1-year post-PCI or CABG), the addition of an antiplatelet agent to DOAC therapy is not recommended as it increases bleeding risk without providing any significant benefit in reducing ischemic events (cardiac or cerebral) [Evidence Level B].
Section 8: Perioperative Management of Anticoagulant and Antiplatelet Therapy (New for 2020)
This edition features a new section on perioperative antithrombotic managementa commonly encountered issue in the stroke population and one in which practice variations abound. Our recommendations are aligned with Thrombosis Canada. 49 For stroke or TIA patients who require temporary interruption of chronic antiplatelet or anticoagulant therapy for an upcoming elective surgery, decisions regarding the duration of therapy interruption depend on the agent and the estimated bleeding risk associated with the surgery or procedure. The goal is to minimize the risk of ischemic stroke while simultaneously minimizing the risk of clinically important (major) bleeding. Patients should avoid unnecessary or prolonged interruptions of their antithrombotic therapy. Clinicians should communicate clear instructions to patients regarding their perioperative management plan before an elective procedure.
Because DOACs have a rapid offset (average half-life of approximately 12 h) and a rapid onset of action, the duration of DOAC interruption can be kept short to minimize the risk of ischemic stroke. This approach of standardized DOAC interruption and resumption appeared safe in the Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study of 3007 DOACtreated patients; the 30-d post-operative rates of arterial thromboembolism and major bleeding were <1% and <2%, respectively. 50 For patients undergoing a minimal-bleed-risk procedure, anticoagulants can generally be continued without interruption, with some caveats; for DOACs, it is reasonable to omit the morning DOAC dose before the procedure to reduce bleeding risk.
# Descriptions of type of surgery or procedure and bleeding risk category:
• A high-bleed-risk surgery or procedure includes major abdominal surgery (e.g., cancer resection), major thoracic surgery, major orthopedic surgery, and any cardiac, spinal, or intracranial surgery. Any patient having neuraxial anesthesia is classified as high-bleed-risk because of the risk for spinal epidural hematomas which could cause limb paralysis.
• A low-to-moderate-bleed-risk surgery or procedure includes most surgeries that are <1-h duration and procedures that do not involve neuraxial anesthesia.
• A minimal-bleed-risk surgery or procedure includes tooth extractions, root canal, skin biopsies, cataract surgery, and selected colonoscopies, for which anticoagulants can be continued without interruption. Permanent pacemaker and internal cardiac defibrillator implantation, as well as cardiac catheterization, also can be done without stopping anticoagulants.
# Section 8 Recommendations 2020
i. Patients with atrial fibrillation or a mechanical heart valve who are receiving oral anticoagulant therapy and require a procedure associated with a minimal risk of bleeding (e.g., tooth extraction, skin biopsy, cataract removal, cardiac pacemaker) should not have anticoagulation interrupted around the time of the procedure [Evidence Level B]. ii. For patients with atrial fibrillation receiving a DOAC for stroke prevention who require temporary DOAC interruption for an elective surgery or procedure, the following approach is recommended [Evidence Level B]: a. For a low-to-moderate-bleed-risk surgery or procedure, stop the DOAC the day before the procedure and the day of the procedure (i.e., skip 2 d total), and restart the day after the procedure. b. For a high-bleed-risk surgery or procedure, stop the DOAC 2 d before the procedure, the day of the procedure, and one day after the procedure (i.e., skip 4 d total). Note: An exception involves patients on dabigatran with impaired renal function (CrCl <50 mL/min) in whom an additional 1-2 d of interruption is suggested before surgery or procedure. Refer to clinical considerations for additional information. iii. For patients with atrial fibrillation receiving warfarin for stroke prevention who require temporary warfarin interruption for an elective surgery or procedure: a. For patients at low-to-moderate stroke risk (e.g., CHADS2 score 0-4), warfarin should be stopped for 5 d pre-procedure, and resumed within 24 h post-procedure, without heparin bridging [Evidence • Heparin bridging is recommended for selected patients with a mitral valve prosthesis and for high-risk patients with an aortic valve prosthesis (e.g., with additional risk factors for stroke) [Evidence Level B].
# Section 8 Clinical Considerations
Perioperative management of patients undergoing a minimal-bleed-risk procedure 1. For patients undergoing minor procedures that are considered minimal-bleed-risk (refer to definition above), it is not routinely necessary to stop anticoagulants. However, there are some caveats to the management of such patients: a. Any of the minimal-bleed-risk procedures could be considered as having a higher bleed risk warranting anticoagulant interruption (e.g., tooth extraction in a patient with poor dentition or cataract surgery with retrobulbar anesthesia) based on individual patient circumstances. b. In patients receiving a DOAC who are undergoing a minimal bleed-risk procedure, it is prudent to omit the morning DOAC dose just before the procedure because the peak anticoagulant effect, occurring 1-3 h after intake, may coincide with the timing of the procedure and may increase the risk for bleeding. c. For pacemaker or ICD implantation, patients can continue warfarin, but the INR should be <3.0 at the time of the procedure. d. For coronary angiography, continuing anticoagulants if a femoral artery approach is used may not be advisable as such patients are at increased risk for developing a hematoma or false aneurysm. e. For colonoscopy, anticoagulation can be continued in selected patients in which the likelihood of polypectomy or multiple biopsies is low.
f. For dental procedures, oral tranexamic acid mouthwash can be used before and 2-3 times daily after the procedure to reduce bleeding since such oral bleeding, although not clinically important, may cause distress to patients. Carotid endarterectomy (CEA) has been shown to prevent stroke recurrence in patients who have sustained a minor stroke or TIA with ipsilateral high-grade carotid stenosis. For those with 50%-99% stenosis, the number of persons needed to undergo surgery to prevent one ipsilateral stroke in five years was estimated to be 9 for men versus 36 for women. Women with symptomatic disease had significantly higher odds of 30-d mortality following CEA compared with men. (adjusted OR = 1.4, 95% CI 1.02-1.94). 51 The use of CEA for asymptomatic carotid artery disease is controversial. One-year results from the recent SPACE-2 trial, 52 indicated there were no significant differences between groups (CEA vs. best medical management) in the occurrences of any stroke after day 30, up to one-year, ipsilateral stroke, disabling stroke, any death, myocardial infarction, restenosis or TIA. The trial was terminated early due to low recruitment. In this same trial, there were no significant differences in the same outcomes for the comparison of best medical management versus carotid-artery angioplasty. 53 and additional meta-analyses and other reports further support PFO closure for secondary stroke prevention in selected patients. [54][55][56] Given that TIA can be difficult to differentiate from mimics and the fact that only one of the PFO trials enrolled patients with TIA as an index event, clinicians should be cautious when contemplating PFO closure for TIA unless there is a high certainty of ischemia; accordingly, these 2021 recommendations no longer indicate TIA as an unqualified indication for closure. There is now moderatestrength evidence that PFO closure may be targeted to patient groups with higher risk echocardiographic features.
For patients with heart failure and without atrial fibrillation, the COMMANDER-HF trial, 57 which compared rivaroxaban to standard care, found no significant difference in the frequency of the primary outcome (a composite of death from any cause, MI, or stroke) between groups. The risks of the individual components of the primary outcome did not differ between groups with the exception of the risk of stroke, which was reduced significantly with rivaroxaban (1.08 vs. 1.63 events/100-person years; HR = 0.66, 95% CI 0.47-0.95). In the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, 58 which compared the effectiveness of anticoagulation compared with antiplatelet therapy for stroke prevention in patients with heart failure in sinus rhythm, warfarin was associated with a significantly reduced risk of ischemic stroke (HR = 0.52, 95% CI 0.33-0.82, p = 0.005); however, the risks of major and minor hemorrhages were significantly increased. 59 A diagnosis of cancer can increase the risk of stroke in the months or years following the diagnosis, particularly among persons with lung cancer or with more advanced cancers. 60,61 Thrombosis is a common complication of malignancy and represents a frequent cause of death in cancer patients with a history of stroke.
# CHALLENGES AND FUTURE DIRECTIONS
Advances in stroke prevention, driven by high-quality clinical studies, continue to inform each new edition of these guidelines.
However, we are still far from adequately addressing, at a global level, the 10 modifiable risk factors that account for 90% of the population attributable risk of stroke. 62 The largest impact on stroke prevention globally will likely be achieved by continued large-scale efforts to address hypertension, diabetes, diet, exercise, smoking, in addition to atrial fibrillation at both policy and individual levels.
A key tenet of secondary stroke prevention remains the importance of identifying the most likely stroke etiology and tailoring therapy accordingly. Although the completed ESUS trials found no overall benefit of anticoagulation, further research aims to identify whether specific subgroups may benefit. Dual pathway inhibition is a promising strategy. 63 Newer anticoagulants targeting factor XI represent promising future treatments for stroke prevention. Studies are ongoing (NCT02604667) and others are needed to better define when and how occult cancer should be investigated in cryptogenic stroke patients, and if found, what antithrombotic regimen best protects these patients from recurrent arterial strokes. 64 Immediate challenges to optimal secondary stroke prevention would therefore include the need to develop, grow, and maintain systems for virtual delivery of care to patients through telemedicine. 65,66 The SARS-CoV2 virus represents a well-documented challenge to acute stroke care 67 but its impact on the risk of stroke recurrence, either directly among patients having been infected with the virus, or on other patients who have suffered collateral damage from diminished access to stroke care, will be important to now study.
A challenge that concerns research in all fields of medicineincluding stroke 68 is the need to ensure adequate sex and gender representation in therapeutic trials to ensure generalizability of results to both men and women. This edition is the first of our guidelines to start incorporating a sex and gender descriptive analysis into the literature review for each recommendation, and future editions will strive to include gender and sex-based recommendations where appropriate.
# SUMMARY
The 2020 update of the Canadian Stroke Best Practice Secondary Prevention of Stroke Recommendations provide a common set of guiding principles for important aspects of secondary stroke prevention, emphasizing that individuals who have experienced a stroke or TIA require access expert prevention care in a timely way. In Canada, coordinated systems have evolved over time, growing the number of stroke prevention services and protocols to increase access in many under-serviced areas. In the age of Covid-19, there are new opportunities to provide prevention interventions remotely to narrow the inequities in access to care.
# ACKNOWLEDGEMENTS
Heart &Stroke gratefully acknowledges the Secondary Prevention of Stroke writing group leaders and members all of whom have volunteered their time and expertise to the update of these recommendations. Members of the Canadian Stroke Consortium were involved in all aspects of the development of these recommendations. These recommendations (in whole or specific parts) underwent external review by: Jason Andrade, Rohit Bhatia, Margie Burns, Elena Adela Cora, Roxanne Cournoyer, Laurent Derex, Paul Dorian, Charles Duffy, Eric Ehrensperger, Yuriy Flomin, Kirsten George-Phillips, Sarah Grant, Milan Gupta, Rahul Jain, Shirin Jalani, Glen Jickling, Hooman Kamel, Hong Kao, Puneet Kapur, Lisa Keon, Lisa Korec, Catherine Legault, Gerald MacDonald, GB John Mancini, Michael MacDonald, Kaylee Murphy, Kelvin Kuan Huei Ng, Darlene Peacock, Andre Roussin, Joanna D Schaafsma, Peter Senior, Aleksander Tkach, Sean Virani, Elissa Weinberg, Heather Williams, and Janice Williams. We thank the Canadian Stroke Best Practices and Quality Advisory Committee members, including Eric Smith
# SUPPLEMENTARY MATERIAL
To view supplementary material for this article, please visit https://doi.org/10.1017/cjn.2021.127.
# FUNDING
The development of the CSBPR is funded in its entirety by Heart & Stroke. No funds for the development of these guidelines come from commercial interests, including pharmaceutical and device companies. All members of the recommendation writing groups, and external reviewers are volunteers and do not receive any remuneration for participation in guideline development, updates, and reviews. All participants complete a conflict of interest declaration prior to participation.
# CONFLICTS OF INTEREST
The following authors have identified actual or potential conflicts of interest which have been mitigated through the design of a multidisciplinary writing group model and additional measures by the advisory committee as required. David J. Gladstone received a Mid-Career Investigator Award from the Heart and Stroke Foundation, a peer-reviewed provincial operating grant from Ontario Genomics; all funds paid to his institution to support the project (no personal fees); Independent Medical Safety Monitor for the NINDS-sponsored ARCADIA trial (uncompensated), and local site PI for the NASPAF-ICH and
# STATEMENT OF AUTHORSHIP
David J Gladstone (First author) and Alexandre Y. Poppe (Senior Author) are co-chairs of the Secondary Prevention of Stroke expert writing group and lead authors contributing to all aspects of the development, evidence and data analysis, writing, editing, and final approval of this manuscript; M. Patrice Lindsay is corresponding author, senior editor of the Canadian Stroke Best Practice Recommendations (CSBPR) and of this manuscript, involved in all aspects of scientific literature review, writing group deliberations, external review process, manuscript preparation, and a writer of supplementary documentation. Aline Bourgoin, Jafna | None | None |
e6b6c736ffa744d6fbcd9eade27b66ae65cd2d8a | cma | None | Background & Aims: We aim to provide guidance for medical treatment of luminal Crohn's disease in children. Methods: We performed a systematic search of publication databases to identify studies of medical management of pediatric Crohn's disease. Quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. We developed statements through an iterative online platform and then finalized and voted on them. Results: The consensus includes 25 statements focused on medical treatment options. Consensus was not reached, and no recommendations were made, for 14 additional statements, largely due to lack of evidence. The group suggested corticosteroid therapies (including budesonide for mild to moderate disease). The group suggested exclusive enteral nutrition for induction therapy and biologic tumor necrosis factor antagonists for induction and maintenance therapy at diagnosis or at early stages of severe disease, and for patients failed by steroid and immunosuppressant induction therapies. The group recommended against the use of oral 5-aminosalicylate for induction or maintenance therapy in patients with moderate disease, and recommended against thiopurines for induction therapy, corticosteroids for maintenance therapy, and cannabis in any role. The group was unable to clearly define the role of concomitant immunosuppressants during initiation therapy with a biologic agent, although thiopurine combinations are not recommended for male patients. No consensus was reached on the#
While inflammatory bowel disease (IBD) has become a global disease, the incidence and prevalence of both pediatric-and adult-onset IBD in Canada remain among the highest worldwide. 1,2 Canadian data suggest that the incidence may have stabilized among adults, but continues to increase in children, reaching 9.68 (95% confidence interval , 9.11-10.25) per 100,000 children under age 16 years for the period 1999-2010. 2 Although the highest percentage increases in incidence were among children aged younger than 5 years at time of diagnosis, pediatric-onset IBD still develops most commonly in adolescence. 2 Crohn's disease (CD) predominates over ulcerative colitis, accounting for 65.6% of pediatric IBD based on national administrative data up until 2010, 2 and occurring in 62% of 1146 children in the Canadian Children IBD Network inception cohort study. 3 Pediatric CD encompasses a heterogeneous spectrum of phenotypic features (as recognized by the Paris modification of the Montreal classification 4 ), disease severity, and treatment responsiveness. Intestinal healing, rather than symptom control alone, has become an important therapeutic goal. 5 This may be especially important in young patients, given the potential for growth impairment as a direct effect of persistent chronic inflammation 6,7 and their long lives ahead, during which disease complications may occur. Mucosal healing became a realistic goal for patients with the advent of monoclonal antibodies directed against tumor necrosis factor (TNF)-α. As alternate pathway biologic agents and new small molecule therapies emerge, it behooves clinicians to recommend treatment of pediatric CD based on critical evaluation of efficacy and safety.
Choice of treatment for active pediatric CD must always be made with a maintenance strategy in mind.
When the pediatric consensus group met in October 2017, the most recent consensus guidelines for the treatment of CD in pediatric patients were those from the European Society of Pediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organization published in April 2014, which incorporated data published until June 2013. 8 The Canadian Association of Gastroenterology (CAG) has established infrastructure for the development of consensus clinical practice guidelines, 9 but to date has focused on adult patients, including consensus guidelines for both luminal and fistulizing CD. Given the increasing prevalence of pediatric CD, the challenges specific to young patients, and the uncertainties around treatment choices, the Canadian Children IBD Network partnered with CAG to systematically review the literature relating to the medical management of luminal CD and to develop specific recommendations for pediatric patients.
# Methods
# Scope and Purpose
This guideline focuses on the medical management of luminal CD in pediatric patients, and does not specifically address the diagnostic evaluation of luminal CD, the role of surgical management, growth monitoring, social and psychological interventions, and preventative health measures, such as vaccinations. Specific questions pertaining to the medical management of luminal CD in pediatric patients Abbreviations used in this paper: were developed by the steering committee (DM, AG, EIB, JC, JD, and JM) and GRADE (Grading of Recommendation Assessment, Development, and Evaluation) experts (PM, FT).
Recommendations were developed by all members of the group at a face-to-face meeting in October 2017.
# Definitions Used in Framing Questions
# Disease activity
The categories of disease activity discussed in this guideline (mild to moderate and moderate to severe active CD) were defined in many clinical trials according to the Crohn's Disease Activity Index in studies involving adult patients or the Pediatric Crohn's Disease Activity Index in studies involving children. Therefore, in general, descriptions of activity in this document reflect Crohn's Disease Activity Index or Pediatric Crohn's Disease Activity Index scores, as described in the evidence.
# Outcomes
Clinical remission was consistently chosen as the primary outcome in the statements because of knowledge that until recently "clinical remission" (usually defined by a multi-item measure of disease activity) has been the primary end point in clinical trials assessing treatment efficacy. Evidence of efficacy of specific treatments in achieving mucosal healing is limited, therefore, "complete" or "deep" remission (clinical remission plus mucosal healing) was not the chosen primary outcome in this guideline. Mucosal healing, however, is increasingly replacing "clinical remission" as a treatment target for adults and children with IBD. 5 Such healing has been associated with sustained clinical remission and a reduced need for hospitalization and surgery. Statements regarding the importance of evaluating mucosal healing in pediatric patients achieving clinical remission were therefore discussed, despite the limitations of existing data precluding its choice as a primary outcome.
Clinical response was defined as reduction in symptoms determined by clinically meaningful changes in a multi-item measure of disease activity, in the absence of complete resolution of symptoms.
# Sources and Searches
A systematic search of the literature relevant to the selected questions from January 2000 to June 2017 was conducted by the Editorial Office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University using MEDLINE, EMBASE, Cochrane Central, and Cochrane database of systematic reviews. Key search terms included pediatric, Crohn's, antibiotic, 5-aminosalicylate, corticosteroid, anti-tumour necrosis factor, thiopurine, methotrexate, vedolizumab, ustekinumab, and enteral nutrition. The search was limited to human studies and English publications; additional details of the search strategies utilized are provided in the Supplementary Material Appendix 1.
The consensus process was facilitated by the CAG via a web-based consensus platform (ECD Solutions, Atlanta, GA). Using this platform, the steering committee reviewed the results of initial literature searches and identified relevant references that were then "tagged" (selected and linked) to each statement. Copies of the tagged references were available to all members of the consensus group. The full consensus group voted anonymously on their level of agreement with the individual statements, using a modified Delphi process. 13,14 Participants suggested revisions and commented on the statements, after which, the specific statements were revised through 2 iterations.
# Assessment of the Quality of Evidence
Two non-voting methodologists (PM, FT) used the GRADE approach 15 to assess the strength of the evidence for each statement. The quality of evidence for each consensus statement was classified as high, moderate, low, or very low, as described in GRADE 15,16 and used in previous CAG consensus guidelines. Randomized controlled trials (RCTs) began as high-quality evidence but could be downgraded because of heterogeneity or inconsistency of results, imprecision, indirect study findings, reporting bias, or if it was determined that a high risk of bias existed across studies supporting the statement. Data from observational studies began as low-quality evidence, but could be lowered because of the same factors, or raised if a very large treatment effect or a dose-response relationship was identified, or if all plausible biases would change the magnitude of effect toward the opposite direction. 15,16 Using the GRADE approach, it is rare to have high-quality evidence unless it fulfills all domains in terms of risk of bias, inconsistency, imprecision, indirectness, and no other bias (eg, publication bias). The evidence is always reviewed in relation to the PICO (patient population, intervention, comparator, and outcome) question. So, the trials may be high methodological quality, but if they do not address the PICO question directly in terms of populations, interventions, and outcomes, the evidence will be downgraded. In addition to an updated review of the literature, new meta-analyses were performed for this consensus.
Much of the evidence for the efficacy and safety of CD treatments was available from RCTs conducted in adult populations. In some cases, the quality of evidence was downgraded for indirectness with respect to the populations when no studies were found that evaluated the drug in children, and as such both safety and effectiveness data had to be extrapolated from adult studies. Considering the course of disease, responses to treatments and dose-response relationships may differ between pediatric and adult populations with CD and, as such, the evidence was less certain in children than in adults when only adult data were available. However, if there were studies done in children (even observational in nature) that supported the findings in adults, the evidence was not downgraded for indirectness. In some cases, when confronted by very-low-quality evidence in the absence of a compelling benefit to risk ratio, the consensus group agreed not to make a recommendation for or against a particular strategy.
Approved product labeling from government regulatory agencies varies from country to country, and although it was not ignored, recommendations were based on evidence from the literature and consensus discussion, and may not fully reflect the product labeling for a given country.
# Consensus Process
The 2-day, face-to-face consensus meeting was held in Toronto, Ontario, Canada, in October 2017. The consensus group was composed of 15 voting pediatric gastroenterologists, from Canada and the United States with expertise in multiple areas, including nutrition (SL, WE, HH, AO), growth impairment in IBD (TW, AG), microbiome (DM), clinical epidemiology, health services research and quality improvement (EB, PJ, AO, MS, MDK, WE), and patient-reported measures or patient engagement (AO, MDK). Non-voting participants included the co-chairs (AG, DM), GRADE experts (PM, FT), a representative from the adult CD CAG consensus group ( JM), nonvoting observers, and the co-moderators (PM, DS). At the consensus conference, data and the GRADE evaluations of the evidence were presented, and each individual statement was discussed and the wording finalized. Participants voted on their level of agreement for each statement. If ≥75% of participants voted 4 (agree) or 5 (strongly agree) on a 1-5 scale (1, 2, and 3 being disagree strongly, disagree, and uncertain, respectively), then the statement was accepted. If a statement was accepted, a second vote on the strength of the recommendation was conducted. A level of agreement of ≥75% of participants was needed to classify a statement as "strong" (we recommend); if this threshold was not met, the statement defaulted to "conditional" (we suggest). The strength of a recommendation considers the benefit-to-risk balance, patients' values and preferences, cost and resource allocation, and the quality of the evidence. Consequently, a recommendation could be classified as strong despite low-quality evidence, or conditional despite high-quality evidence. 22 As per the GRADE method, a strong recommendation is indicative of a more broadly applicable statement ("most patients should receive the recommended course of action"), whereas a conditional recommendation suggests clinicians should ". . . recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences. " 22 During the consensus meeting, voting members were unable to reach consensus on 14 statements (No recommendation A-N) and these statements were rejected. The evidence that was reviewed for these statements and the discussion has been summarized in the text, but the consensus group did not make a recommendation for or against these treatment strategies.
The manuscript was initially drafted by the co-chairs (DM, AG), and then reviewed and revised by the GRADE experts and members of the steering committee before being sent to the full consensus group for review. Upon approval from the group, the manuscript was made available to all CAG members for comment during a 2-week period before submission for publication.
In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months preceding the consensus meeting were provided by all participants, and made available to all group members, and CAG members reviewing the manuscript.
# Role of the Funding Sources | Background & Aims: We aim to provide guidance for medical treatment of luminal Crohn's disease in children. Methods: We performed a systematic search of publication databases to identify studies of medical management of pediatric Crohn's disease. Quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. We developed statements through an iterative online platform and then finalized and voted on them. Results: The consensus includes 25 statements focused on medical treatment options. Consensus was not reached, and no recommendations were made, for 14 additional statements, largely due to lack of evidence. The group suggested corticosteroid therapies (including budesonide for mild to moderate disease). The group suggested exclusive enteral nutrition for induction therapy and biologic tumor necrosis factor antagonists for induction and maintenance therapy at diagnosis or at early stages of severe disease, and for patients failed by steroid and immunosuppressant induction therapies. The group recommended against the use of oral 5-aminosalicylate for induction or maintenance therapy in patients with moderate disease, and recommended against thiopurines for induction therapy, corticosteroids for maintenance therapy, and cannabis in any role. The group was unable to clearly define the role of concomitant immunosuppressants during initiation therapy with a biologic agent, although thiopurine combinations are not recommended for male patients. No consensus was reached on the#
While inflammatory bowel disease (IBD) has become a global disease, the incidence and prevalence of both pediatric-and adult-onset IBD in Canada remain among the highest worldwide. 1,2 Canadian data suggest that the incidence may have stabilized among adults, but continues to increase in children, reaching 9.68 (95% confidence interval [CI], 9.11-10.25) per 100,000 children under age 16 years for the period 1999-2010. 2 Although the highest percentage increases in incidence were among children aged younger than 5 years at time of diagnosis, pediatric-onset IBD still develops most commonly in adolescence. 2 Crohn's disease (CD) predominates over ulcerative colitis, accounting for 65.6% of pediatric IBD based on national administrative data up until 2010, 2 and occurring in 62% of 1146 children in the Canadian Children IBD Network inception cohort study. 3 Pediatric CD encompasses a heterogeneous spectrum of phenotypic features (as recognized by the Paris modification of the Montreal classification 4 ), disease severity, and treatment responsiveness. Intestinal healing, rather than symptom control alone, has become an important therapeutic goal. 5 This may be especially important in young patients, given the potential for growth impairment as a direct effect of persistent chronic inflammation 6,7 and their long lives ahead, during which disease complications may occur. Mucosal healing became a realistic goal for patients with the advent of monoclonal antibodies directed against tumor necrosis factor (TNF)-α. As alternate pathway biologic agents and new small molecule therapies emerge, it behooves clinicians to recommend treatment of pediatric CD based on critical evaluation of efficacy and safety.
Choice of treatment for active pediatric CD must always be made with a maintenance strategy in mind.
When the pediatric consensus group met in October 2017, the most recent consensus guidelines for the treatment of CD in pediatric patients were those from the European Society of Pediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organization published in April 2014, which incorporated data published until June 2013. 8 The Canadian Association of Gastroenterology (CAG) has established infrastructure for the development of consensus clinical practice guidelines, 9 but to date has focused on adult patients, including consensus guidelines for both luminal and fistulizing CD. Given the increasing prevalence of pediatric CD, the challenges specific to young patients, and the uncertainties around treatment choices, the Canadian Children IBD Network partnered with CAG to systematically review the literature relating to the medical management of luminal CD and to develop specific recommendations for pediatric patients.
# Methods
# Scope and Purpose
This guideline focuses on the medical management of luminal CD in pediatric patients, and does not specifically address the diagnostic evaluation of luminal CD, the role of surgical management, growth monitoring, social and psychological interventions, and preventative health measures, such as vaccinations. Specific questions pertaining to the medical management of luminal CD in pediatric patients Abbreviations used in this paper: were developed by the steering committee (DM, AG, EIB, JC, JD, and JM) and GRADE (Grading of Recommendation Assessment, Development, and Evaluation) experts (PM, FT).
Recommendations were developed by all members of the group at a face-to-face meeting in October 2017.
# Definitions Used in Framing Questions
# Disease activity
The categories of disease activity discussed in this guideline (mild to moderate and moderate to severe active CD) were defined in many clinical trials according to the Crohn's Disease Activity Index in studies involving adult patients or the Pediatric Crohn's Disease Activity Index in studies involving children. Therefore, in general, descriptions of activity in this document reflect Crohn's Disease Activity Index or Pediatric Crohn's Disease Activity Index scores, as described in the evidence.
# Outcomes
Clinical remission was consistently chosen as the primary outcome in the statements because of knowledge that until recently "clinical remission" (usually defined by a multi-item measure of disease activity) has been the primary end point in clinical trials assessing treatment efficacy. Evidence of efficacy of specific treatments in achieving mucosal healing is limited, therefore, "complete" or "deep" remission (clinical remission plus mucosal healing) was not the chosen primary outcome in this guideline. Mucosal healing, however, is increasingly replacing "clinical remission" as a treatment target for adults and children with IBD. 5 Such healing has been associated with sustained clinical remission and a reduced need for hospitalization and surgery. [10][11][12] Statements regarding the importance of evaluating mucosal healing in pediatric patients achieving clinical remission were therefore discussed, despite the limitations of existing data precluding its choice as a primary outcome.
Clinical response was defined as reduction in symptoms determined by clinically meaningful changes in a multi-item measure of disease activity, in the absence of complete resolution of symptoms.
# Sources and Searches
A systematic search of the literature relevant to the selected questions from January 2000 to June 2017 was conducted by the Editorial Office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University using MEDLINE, EMBASE, Cochrane Central, and Cochrane database of systematic reviews. Key search terms included pediatric, Crohn's, antibiotic, 5-aminosalicylate, corticosteroid, anti-tumour necrosis factor, thiopurine, methotrexate, vedolizumab, ustekinumab, and enteral nutrition. The search was limited to human studies and English publications; additional details of the search strategies utilized are provided in the Supplementary Material Appendix 1.
The consensus process was facilitated by the CAG via a web-based consensus platform (ECD Solutions, Atlanta, GA). Using this platform, the steering committee reviewed the results of initial literature searches and identified relevant references that were then "tagged" (selected and linked) to each statement. Copies of the tagged references were available to all members of the consensus group. The full consensus group voted anonymously on their level of agreement with the individual statements, using a modified Delphi process. 13,14 Participants suggested revisions and commented on the statements, after which, the specific statements were revised through 2 iterations.
# Assessment of the Quality of Evidence
Two non-voting methodologists (PM, FT) used the GRADE approach 15 to assess the strength of the evidence for each statement. The quality of evidence for each consensus statement was classified as high, moderate, low, or very low, as described in GRADE 15,16 and used in previous CAG consensus guidelines. [17][18][19][20][21] Randomized controlled trials (RCTs) began as high-quality evidence but could be downgraded because of heterogeneity or inconsistency of results, imprecision, indirect study findings, reporting bias, or if it was determined that a high risk of bias existed across studies supporting the statement. Data from observational studies began as low-quality evidence, but could be lowered because of the same factors, or raised if a very large treatment effect or a dose-response relationship was identified, or if all plausible biases would change the magnitude of effect toward the opposite direction. 15,16 Using the GRADE approach, it is rare to have high-quality evidence unless it fulfills all domains in terms of risk of bias, inconsistency, imprecision, indirectness, and no other bias (eg, publication bias). The evidence is always reviewed in relation to the PICO (patient population, intervention, comparator, and outcome) question. So, the trials may be high methodological quality, but if they do not address the PICO question directly in terms of populations, interventions, and outcomes, the evidence will be downgraded. In addition to an updated review of the literature, new meta-analyses were performed for this consensus.
Much of the evidence for the efficacy and safety of CD treatments was available from RCTs conducted in adult populations. In some cases, the quality of evidence was downgraded for indirectness with respect to the populations when no studies were found that evaluated the drug in children, and as such both safety and effectiveness data had to be extrapolated from adult studies. Considering the course of disease, responses to treatments and dose-response relationships may differ between pediatric and adult populations with CD and, as such, the evidence was less certain in children than in adults when only adult data were available. However, if there were studies done in children (even observational in nature) that supported the findings in adults, the evidence was not downgraded for indirectness. In some cases, when confronted by very-low-quality evidence in the absence of a compelling benefit to risk ratio, the consensus group agreed not to make a recommendation for or against a particular strategy.
Approved product labeling from government regulatory agencies varies from country to country, and although it was not ignored, recommendations were based on evidence from the literature and consensus discussion, and may not fully reflect the product labeling for a given country.
# Consensus Process
The 2-day, face-to-face consensus meeting was held in Toronto, Ontario, Canada, in October 2017. The consensus group was composed of 15 voting pediatric gastroenterologists, from Canada and the United States with expertise in multiple areas, including nutrition (SL, WE, HH, AO), growth impairment in IBD (TW, AG), microbiome (DM), clinical epidemiology, health services research and quality improvement (EB, PJ, AO, MS, MDK, WE), and patient-reported measures or patient engagement (AO, MDK). Non-voting participants included the co-chairs (AG, DM), GRADE experts (PM, FT), a representative from the adult CD CAG consensus group ( JM), nonvoting observers, and the co-moderators (PM, DS). At the consensus conference, data and the GRADE evaluations of the evidence were presented, and each individual statement was discussed and the wording finalized. Participants voted on their level of agreement for each statement. If ≥75% of participants voted 4 (agree) or 5 (strongly agree) on a 1-5 scale (1, 2, and 3 being disagree strongly, disagree, and uncertain, respectively), then the statement was accepted. If a statement was accepted, a second vote on the strength of the recommendation was conducted. A level of agreement of ≥75% of participants was needed to classify a statement as "strong" (we recommend); if this threshold was not met, the statement defaulted to "conditional" (we suggest). The strength of a recommendation considers the benefit-to-risk balance, patients' values and preferences, cost and resource allocation, and the quality of the evidence. Consequently, a recommendation could be classified as strong despite low-quality evidence, or conditional despite high-quality evidence. 22 As per the GRADE method, a strong recommendation is indicative of a more broadly applicable statement ("most patients should receive the recommended course of action"), whereas a conditional recommendation suggests clinicians should ". . . recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences. " 22 During the consensus meeting, voting members were unable to reach consensus on 14 statements (No recommendation A-N) and these statements were rejected. The evidence that was reviewed for these statements and the discussion has been summarized in the text, but the consensus group did not make a recommendation for or against these treatment strategies.
The manuscript was initially drafted by the co-chairs (DM, AG), and then reviewed and revised by the GRADE experts and members of the steering committee before being sent to the full consensus group for review. Upon approval from the group, the manuscript was made available to all CAG members for comment during a 2-week period before submission for publication.
In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months preceding the consensus meeting were provided by all participants, and made available to all group members, and CAG members reviewing the manuscript.
# Role of the Funding Sources
Funding for the consensus meeting was provided by unrestricted, arms-length grants to the CAG by AbbVie and Takeda Canada, and a Planning and Dissemination Grant from the Canadian Institutes of Health Research. The CAG administered all aspects of the meeting, and the funding sources had no involvement in the process at any point, nor were they made aware of any part of the process from development of search strings and statements to drafting and approval of these guidelines.
# Recommendation Statements
The individual recommendation statements are provided and include the strength of recommendation and quality of supporting evidence (according to the GRADE approach), and the voting result. This is followed by a discussion of the evidence considered for the specific statement. A summary of the recommendation statements is provided in Table 1. See Supplementary Material Appendix 2 for more detailed quality of evidence summaries.
The majority of RCTs in patients with CD are conducted in adults, and therefore much of the evidence has been downgraded for indirectness and is of very low quality. As a result of the very low quality of evidence, there were insufficient data for the consensus group to make recommendations for or against many treatments (14 statements); however, the available evidence and ensuing discussion relevant to these treatments is presented.
# Statements with no recommendations
No consensus A: In patients with mild CD, the consensus group does not make a recommendation (for or against) regarding the use of 5-ASAs to induce clinical remission.
# No consensus B:
In patients with mild CD limited to the colon, the consensus group does not make a recommendation (for or against) regarding the use sulfasalazine to induce clinical remission. No consensus C: In patients with mild CD who have achieved clinical remission with sulfasalazine or 5-ASA, the consensus group does not make a recommendation (for or against) regarding continuing sulfasalazine or 5-ASA to maintain clinical remission. No consensus D: In patients with mild to moderate CD, the consensus group does not make a recommendation (for or against) regarding the use of antibiotics to induce clinical remission. No consensus E: In patients with mild to moderate CD, the consensus group does not make a recommendation (for or against) regarding the use of antibiotics to maintain clinical remission. No consensus F: In male patients with CD the consensus group does not make a recommendation (for or against) regarding a thiopurine to maintain remission. No consensus G: In patients with mild to moderate CD, the consensus group does not make a recommendation (for or against) regarding methotrexate monotherapy to induce clinical remission. (5-ASA) in mild to moderate active CD. 25 These analyses included studies using various formulations and doses of nonsulfasalazine 5-ASAs (ie, mesalamine and olsalazine), and generally reported no benefit with these agents over placebo for induction of remission. In 1 analysis of 4 trials (n = 647), the relative risk (RR) of failure to induce remission with mesalamine compared with placebo was 0.91 (95% CI, 0.77-1.06). 23 One SR&MA reported no significant benefits with either low-dose or high-dose 5-ASA, 24 while the NMA showed that high-dose mesalamine was superior to placebo in inducing remission (odds ratio [OR], 1.87; 95% credible interval, 1.14-3.15), but low-dose was not. 25 In the induction studies, there was no significant difference noted in adverse events between mesalamine and placebo (RR, 0.99; 95% CI, 0.84-1.15). 23 The data did not assess mild and moderate disease separately, and no RCTs in pediatric patients were found.
The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness with respect to populations (lack of pediatric data and inability to separate mild from moderate disease), and very serious imprecision.
Discussion: The SR&MAs generally do not report a statistically significant efficacy with 5-ASA for induction therapy in patients with mild to moderate disease activity, but also do not convincingly demonstrate that 5-ASAs are without benefits (eg, potential benefits with high-dose therapy 25 ). The data cannot be separated into mild and moderate patients, however, the group strongly recommended against this option in patients with moderate (or greater) disease activity, because of the potential negative consequences of delaying the use of other therapies with more definitively demonstrated efficacy.
Data specifically in patients with mild disease were lacking, and the consensus group concluded that the evidence was not sufficiently convincing to recommend for or against 5-ASA for mild CD. The potential negative consequences of delaying use of more effective treatments would be of less concern than in the case of moderate CD. An additional concern was the rare cases of pancreatitis and interstitial nephritis that have been reported with mesalamine. 26 In summary, because 5-ASAs have not demonstrated a consistent, significant benefit, the consensus group made a strong recommendation against their use in patients with moderate CD. However, because ineffectiveness in mild disease was not demonstrated in the literature, no recommendation was made for or against its use to induce clinical remission in patients with mild disease. a The strength of each recommendation was assigned by the consensus group, per the GRADE system, as strong ("we recommend... ") or conditional ("we suggest... "). A recommendation could be classified as strong despite low-quality evidence to support it, or conditional despite the existence of high-quality evidence due to the 4 components considered in each recommendation (risk to benefit balance, patients' values and preferences, cost and resource allocation, and quality of evidence).
# Statement 2: In patients with moderate Crohn's disease limited to the colon, we suggest against the use of sulfasalazine to induce clinical remission.
Journal of the Canadian Association of Gastroenterology, 2019, Vol. 2, No. 3 e41
No consensus B: In patients with mild Crohn's disease limited to the colon, the consensus group does not make a recommendation (for or against) regarding the use sulfasalazine to induce clinical remission.
# Key evidence:
There was very limited evidence on the efficacy of sulfasalazine in CD. The 2 SR&MAs, 23,24 and the NMA, 25 all included the same 2 small, older RCTs in adults with active CD. 27,28 Meta-analyses of these 2 trials (n = 263), yielded a marginal benefit over placebo: RR for failure to achieve remission, 0.83 (95% CI, 0.69-1.00), 23 and RR for induction of remission, 1.38 (95% CI, 1.00-1.89). 24 The NMA, also reported that sulfasalazine was not superior to placebo (OR, 1.50; 95% credible interval, 0.71-3.12). 25 Both of the original RCTs reported significant benefits with sulfasalazine only in the subgroup of patients with disease confined to the colon, however, the sample sizes were very small. 27,28 No RCTs were found in pediatric patients, and while mild disease was analyzed separately, the subgroup of patients was very small.
The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness with respect to populations (lack of pediatric data and inability to separate mild from moderate disease), and very serious imprecision.
Discussion: As was the case in Statement 1, the consensus group concluded that there was insufficient evidence to warrant routine use of sulfasalazine in pediatric patients with moderate disease. Although the statement suggested against sulfasalazine, it was conditional because of the trend toward efficacy in colonic disease, which is the location targeted by sulfasalazine. Similar to 5-ASA, given the potential efficacy of sulfasalazine in mild disease and the fact that treatment delays may be of less concern in such patients, the consensus group did not make a recommendation for or against its use in patients with mild colonic disease. Some participants argued that it is one of the few products that are available in a suspension, and recommending against a potentially effective treatment would limit the options available for some children who are unable to swallow capsules or tablets. However, others argued that the adverse events, albeit rare, may not be benign, and can include allergic reactions, agranulocytosis, and hepatitis. 29
# Statement 3: In patients with Crohn's disease in clinical remission, we recommend against sulfasalazine or 5-aminosalicylic acid to maintain clinical remission.
of which 30 included 1 RCT in pediatric patients. 31 Using different eligibility criteria, 1 meta-analysis included 16 RCTs (n = 2496) 23 and the other 12 RCTs (n = 2146). 30 Sulfasalazine was not effective in preventing relapse of CD (n = 4 studies; RR, 0.98; 95% CI, 0.82-1.17), but there was a non-significant trend toward improvement over placebo with mesalamine (n = 11 studies; RR, 0.94; 95% CI, 0.87-1.01). 23 A meta-analysis of data from 12 maintenance trials showed no significant difference in the RR of adverse events between mesalamine and placebo (RR, 1.08; 95% CI, 0.87-1.34). 23 A pediatric RCT in 132 patients reported no statistically significant difference in relapse rates at 12 months 31 with mesalamine compared to placebo (74% vs 69%; RR, 1.07; 95% CI, 0.86-1.33 30 ).
The reviewed studies did not include analyses assessing efficacy according to baseline disease severity or treatment used for induction.
The quality of evidence was downgraded to very low due to serious risk of bias and very serious imprecision.
Discussion: Evidence suggests that 5-ASA and sulfasalazine are generally not effective for maintenance therapy, therefore, the consensus group made a strong recommendation against their use for most patients who have achieved remission.
However, a per-protocol analysis found a significant benefit of mesalamine for the reduction of risk of relapse (RR, 0.79; 95% CI, 0.66-0.95). 23 Therefore, the consensus group questioned whether these agents would be useful as maintenance therapy in patients whose remission had been induced with 5-ASA or sulfasalazine. There are few data to inform a maintenance strategy in such patients; it is unknown whether the best strategy would be to continue these agents, provide no maintenance therapy, or switch to a more effective medication. In most of the trials, the agents used to achieve remission were not specified, but in 1 RCT that used 5-ASA for induction, there was no significant benefit with continued 5-ASA maintenance therapy. 32 The consensus group did not make a recommendation for or against this strategy. largely due to positive studies with rifaximin (n = 2 studies; RR for failure to achieve remission, 0.81; 95% CI, 0.68-0.97). 33 The RCTs in these meta-analyses used a variety of antibiotics and doses, therefore no conclusions could be drawn for specific antibiotic regimens, with the exception of rifaximin. There were no serious adverse events, and no significant differences in adverse events between rifaximin and placebo. 35,36 The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness with respect to populations (lack of pediatric data) and interventions (diverse regimens), and serious imprecision.
Two SR&MAs assessed the efficacy of antibiotics for the maintenance of remission in patients with quiescent CD. 33,37 All of the RCTs included in these analyses assessed the efficacy of anti-mycobacterial therapies either alone or in combination. The most recent SR&MA including 4 RCTs (n = 206) found that antibiotics significantly reduced the risk of relapse compared to placebo in patients with quiescent CD (RR, 0.58; 95% CI, 0.45-0.75). 37 The anti-mycobacterial therapies were associated with a greater risk of adverse events compared to placebo (RR, 2.57; 95% CI, 1.45-4.55). 37 The most common adverse events included increased skin pigmentation and rashes. One additional RCT, which did not include an anti-mycobacterial agent, reported a statistically greater rate of maintenance of clinical remission at 48 weeks with rifaximin compared to placebo (71% vs 53%; P < .05). 38 The majority of both induction and maintenance RCTs had small sample sizes, and no RCTs were found that included pediatric patients.
The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness with respect to populations (lack of pediatric data), interventions (variability in antibiotic regimens), and outcomes (definitions of relapse), and serious imprecision.
Discussion: A variety of antibiotic regimens were used in the trials, which makes interpretation difficult. 33,34 This is further complicated by the fact that, with the exception of rifaximin, the majority of patients were also receiving corticosteroids and other medications. While the data supported the efficacy of antibiotics overall for induction of remission in meta-analyses, this result was mainly driven by rifaximin. 33,34 In addition, antimycobacterial therapies have demonstrated efficacy as maintenance therapy. 33,37 However, group members expressed substantial concern about the potential development of antibiotic resistance as well as cost, particularly when used for maintenance therapy. No serious adverse events were reported in the trials, but long-term complications were not reported. 37 In addition, there were no pediatric studies, and no safety data in children.
Although antibiotics play a role in the management of perianal and postoperative CD, their role in luminal disease remains poorly defined. The consensus group concluded that there are insufficient data to fully evaluate whether the potential benefit (very low quality of evidence suggesting efficacy) outweighs the potential risk (adverse effects and antimicrobial resistance) and therefore, did not make a recommendation for or against the use of antibiotics for induction or maintenance therapy.
# Budesonide
# Statement 4: In patients with mild to moderate ileal and/ or right colonic Crohn's disease, we suggest oral controlled ileal release budesonide to induce clinical remission.
Key evidence: Evidence for the efficacy of budesonide compared to placebo in inducing clinical remission in patients with mild to moderate ileal and/or right colonic CD was available from 3 SR&MAs. [39][40][41] and an NMA. 25 In a meta-analysis of 3 RCTs in adults, budesonide ≥9 mg/d was twice as likely to induce remission vs placebo (RR, 1.93; 95% CI, 1.37-2.73; 3 RCTs). 41 A lower dose of budesonide (3 mg/d) was not superior to placebo. 40,41 Budesonide was significantly less effective than conventional corticosteroids for induction of remission (RR, 0.85; 95% CI, 0.75-0.97; 8 RCTs), but was associated with fewer adverse events (RR, 0.64; 95% CI, 0.54-0.76). 41 There was no significant difference between budesonide and mesalamine (2 RCTs). 41 The NMA reported similar results. 25 Three small RCTs were conducted in pediatric patients; 2 reported comparable clinical remission rates between budesonide and prednisone, 42,43 while the other found no significant difference in remission rates between high-dose and standarddose budesonide. 44 Adverse events, such as Cushingoid facies, acne, and myopathy, were more common with conventional corticosteroids compared to budesonide. 42,43 Overall, the quality of evidence was downgraded to low due to serious risk of bias and serious imprecision.
These RCTs used the oral controlled ileal release preparation or the pH-dependent release formulation, and no studies that used budesonide MMX for the treatment of CD were found.
Discussion: A meta-analysis of RCT data in adult and pediatric patients has shown that budesonide is more effective than placebo, but less effective than conventional corticosteroids. 41 The more limited pediatric-specific data are underpowered to identify this treatment inferiority of budesonide compared with conventional corticosteroids. 42,43 In both adult and pediatric patients, budesonide was associated with fewer adverse events, and suppression of adrenal function was also less frequent, but was still reported with budesonide. 42,45 In an RCT in pediatric patients, mean morning plasma cortisol concentration was significantly higher with budesonide compared to prednisolone after 8 weeks. 42 However, in non-IBD studies of budesonide, morning cortisol concentration was demonstrated to be less sensitive in identifying adrenocortical suppression compared with ACTH-stimulation test. 46 The consensus group suggested the use of budesonide based on clinical remission rates in comparative clinical trials of budesonide vs conventional oral corticosteroids in adults and children, and in trials of budesonide vs placebo in adults, as well as in light of the superior safety and tolerability profile of budesonide compared to conventional corticosteroids. However, this was a conditional suggestion because budesonide was less effective and more costly than conventional corticosteroids.
# Statement 5: In patients with Crohn's disease, we recommend against oral controlled ileal release budesonide to maintain clinical remission.
GRADE: Strong recommendation, very low-quality evidence.
Vote: strongly agree, 87%; agree, 13%.
Key evidence: Two SR&MAs found no significant difference between budesonide and placebo for prevention of relapse or maintenance of remission in patients with quiescent CD. 39,47 In a meta-analysis of 5 RCTs, budesonide 6 mg/d was no more effective than placebo for maintenance of remission at 6 months (RR, 1.15; 95% CI, 0.95-1.39) or 12 months (RR, 1.13; 95% CI, 0.94-1.35). 47 However, an NMA showed that budesonide 6 mg/d was superior to placebo (OR, 1.69; 95% CI, 1.05-2.75). 40 For maintenance of remission there was no statistically significant difference between budesonide and azathioprine, but budesonide 6 mg was superior to mesalamine 3 g/d. 47 The risk of corticosteroid-related adverse events was significantly higher with budesonide compared to placebo (RR, 2.19; 95% CI, 1.08-4.46). 39 A meta-analysis of maintenance RCTs found significantly higher rates of adrenal suppression with budesonide compared to placebo. 47 In addition, a higher incidence of endocrine disorders, mainly due to a higher rate of Cushingoid symptoms, has been reported with budesonide. 48 A small, non-comparative, pediatric, cohort study also reported a high incidence of adverse events (74.0%) with budesonide. 45 The RCTs included in these analyses pooled studies using oral controlled ileal release preparation and the pH-dependent release formulation. RCTs had small sample sizes, low event rates, and no maintenance RCTs in pediatric patients were found.
Discussion: The majority of the evidence from RCTs in adults fails to show benefit of budesonide over placebo for maintenance therapy. RCTs in pediatric patients were not found. In an observational pediatric study, maintenance therapy with budesonide was associated with a significant worsening of disease activity over 12 weeks of treatment. 45 As discussed in Statement 4, adrenal suppression in children is of concern. 42,45 In addition, in a cohort study, subnormal growth velocity was reported during up to 1 year of treatment. 49 Based on the lack of demonstrated efficacy and the potential for negative long-term effects, including adrenal suppression and impaired linear growth, the consensus group strongly recommended against the use of budesonide for maintenance therapy in pediatric patients.
# Corticosteroids
# Statement 6: In patients with moderate to severe Crohn's disease, we suggest conventional corticosteroids (eg, prednisone) to induce clinical remission.
GRADE: Conditional recommendation, very-low-quality evidence.
Vote: strongly agree, 47%; agree, 53%.
Key evidence: Evidence for the efficacy of oral corticosteroids over placebo was derived from 2 positive RCTs in adults, 27,28 which have been included in 2 SR&MAs 39,50 and an NMA. 25 In the meta-analysis, which used failure to achieve remission as the primary outcome, there was no significant benefit of corticosteroids over placebo (RR, 0.46; 95 % CI, 0.17-1.28). 39 However, the SR&MA and the NMA both found that corticosteroids were significantly more effective than placebo for induction of symptomatic remission (SR&MA: RR, 1.99; 95% CI, 1.51-2.64; 50 NMA: OR, 3.64; 95% credible interval, 2.16-6.19, 25 respectively). Corticosteroids were associated with higher rates of adverse events than placebo (RR, 4.89; 95% CI, 1.98-12.07). 50 One small RCT assessed corticosteroids vs exclusive enteral nutrition (EEN) therapy in pediatric patients and found no difference in clinical remission rates between the 2 active treatments. 51 The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness with respect to comparisons (lack of placebo controlled pediatric data), and serious imprecision.
Discussion: Although the data are very low quality, corticosteroids appear to be more effective than placebo for induction of remission in adults with CD. In pediatric patients, there were no placebo-controlled RCTs, however, conventional corticosteroids appeared to be as effective as budesonide and EEN in several small RCTs. 42,43,51 Based on evidence suggesting efficacy, and the fact that this is an inexpensive treatment option, the consensus group suggested conventional corticosteroids for short-term use for induction of remission. However, this statement was a conditional recommendation because of the potential negative consequences of delaying the use of other options with greater efficacy, as well as the adverse event profile of corticosteroids,
# Key evidence:
The evidence for the efficacy of systemic corticosteroids compared to placebo was discussed in Statement 6. In addition, RCTs comparing conventional corticosteroids and budesonide were considered. As described in Statement 4, conventional corticosteroids were significantly more effective than budesonide for induction of remission in a meta-analysis of 8 trials. 41 The 2 small RCTs that compared prednisolone with budesonide in pediatric patients were inadequately powered to demonstrate a treatment benefit. 42,43 The quality of evidence was downgraded to moderate due to serious risk of bias. However, it was not downgraded for imprecision, inconsistency, or indirectness in relation to populations due to the availability of limited data from pediatric populations. Discussion: Although less adequately examined in children, conventional corticosteroids have been shown to be more effective than budesonide and 5-ASA in adults. 25,41 In an SR&MA conducted for this consensus, conventional corticosteroids were more effective than EEN in adults, whereas both treatments were equally effective in pediatric patients with comparatively shorter duration of CD (frequently new onset) (see Statement 9). The data supporting superior efficacy of conventional corticosteroids in head-to-head trials suggest that patients have a greater likelihood of responding, and thus may benefit from these agents after failure of budesonide, 5-ASA, or EEN. Efficacy directly after other treatment failures, however, has not been assessed specifically. Therefore, the consensus group made a conditional suggestion in favor of the use of conventional corticosteroids as a second-line treatment option for induction of remission.
# Statement 8: In patients with Crohn's disease of any severity, we recommend against oral corticosteroids to maintain clinical remission.
GRADE: Strong recommendation, low-quality evidence. Vote: strongly agree, 100%.
# Key evidence:
A meta-analysis including 3 RCTs found no significant reduction in the odds of relapse with ongoing corticosteroid therapy compared to placebo (12-month OR, 0.82; 95% CI, 0.47-1.44). 52 In addition, attrition was high, with only about 36% of patients available for the 12-month analysis, primarily due to adverse events. The quality of evidence was downgraded to low due to serious risk of bias and serious imprecision. However, it was not downgraded for indirectness with respect to populations due to the availability of limited data from pediatric populations.
Discussion: The consensus group made a strong recommendation against the use of corticosteroids for maintenance therapy because of the lack of demonstrated efficacy in preventing relapse and concerns around the adverse events associated with long-term use, particularly in children.
# Exclusive enteral nutrition
# Statement 9: In patients with Crohn's disease, we suggest exclusive enteral nutrition to induce clinical remission.
GRADE: Conditional recommendation, very low-quality evidence.
Vote: strongly agree, 33%; agree, 67%.
Key evidence: Seven SR&MAs have been published that evaluated studies comparing EEN to corticosteroids for induction of clinical remission in adult, [53][54][55] pediatric, [56][57][58] or a mixed population of patients with CD. 59 Due to limitations of these previous SR&MAs, an updated SR&MA was conducted to inform the development of this guideline. The SR&MA conducted for this meeting included only RCTs published in full that compared EEN with placebo or other active treatments in patients with active CD. No placebocontrolled trials were identified. The MA included 9 RCTs (2 pediatric 51,60 and 7 adult trials [61][62][63][64][65][66][67] ) comparing EEN with corticosteroids in 435 patients (57 pediatric and 378 adult patients). EEN was inferior to corticosteroids for induction of remission in the combined (OR, 0.43; 95% CI, 0.22-0.87) and adult patient populations (OR, 0.27; 95% CI, 0.17-0.43). In the 57 pediatric patients randomized, there was no significant difference in clinical remission rates between EEN and corticosteroids (83% vs 61%; OR, 3.04, 95% CI, 0.73-12.65). There was no significant difference in the incidence of adverse events between EEN and corticosteroids (21% vs 30%; OR, 0.41; 95% CI, 0.15-1.09). All adverse events were minor and included nausea, vomiting, abdominal pain, and diarrhea with EEN, and Cushingoid facies and acne with corticosteroids. However, the more serious adverse effects of steroids (eg, osteoporosis, growth failure, adrenal suppression) were not evaluated in these trials. EEN was associated with significantly higher withdrawal rates than corticosteroids in the adult RCTs (OR, 6.57; 95% CI, 2.24-19.24), but not in the pediatric RCTs (OR, 0.59; 95% CI, 0.09-4.01).
There was wide variation in disease activity, onset of disease, disease location, study designs, methods used to define disease activity and remission, duration of interventions, length of follow-up, and use of concomitant medication. In addition, due to the nature of the intervention, blinding was not possible.
In the combined population, the overall quality of evidence for the outcome of clinical remission was very low against the use of EEN, however, in the pediatric population, the evidence was very low in support of the use of EEN. The quality of evidence was downgraded to very low due to serious risk of bias, serious inconsistency, serious indirectness with respect to disease activity, onset of disease, and disease location, as well as variations in the types of enteral formula used and the use of concomitant medications, and serious imprecision.
Discussion: There were very-low-quality data showing that EEN was less effective than corticosteroids in a combined population of adults and pediatric patients. However, in 2 very small trials of pediatric patients alone, no difference in clinical remission rates with EEN vs corticosteroids was demonstrated. Most pediatric studies included newly diagnosed patients, whereas adult clinical trials have been conducted among patients with a much longer time since diagnosis. No placebo-controlled RCTs were found, and the available data suggested that at least in pediatric patients, EEN was as effective as an active therapy (corticosteroids) for the induction of remission (see Statement 6). In the pediatric trials, mucosal healing rates with EEN were significantly greater than those with corticosteroids, however, there were limitations, such as small numbers of participants and lack of blinding or allocation concealment. 51,60 Withdrawal rates were high in the adult studies, but not in the pediatric trials. Adverse events with EEN were generally minor, and mainly gastrointestinal in nature.
Under-nutrition in children with CD, although less important than direct effects of pro-inflammatory cytokines released from inflamed intestine, can contribute to impairment of growth and pubertal development. 7,68 Use of EEN restores a normal nutritional status and avoids corticosteroid use, which may also impede linear growth. 69 Growth data reported in one of the pediatric EEN RCTs showed a significant improvement in weight gain with EEN compared to corticosteroids, but no difference in height gain. 51 Protocols for EEN therapy varied with respect to specific formula used (although usually polymeric), mode of administration (nocturnally via nasogastric tube or via oral drinking), allowance of clear fluids other than water during treatment, and duration of therapy. 70 One RCT 71 and 1 prospective study 72 found EEN (defined as 100% EN) to be more effective than partial EN (PEN; defined as 50% of calories via EN while eating an unrestricted diet).
Shorter duration of CD among children vs adults included in clinical trials, as well as better adherence, may explain the better results in the SR&MA of pediatric RCTs compared to RCTs in adults. In clinical practice, EEN is generally attempted early as first-line therapy in patients with new-onset CD. 8 Nutrition is important in children with CD, and, based on similar efficacy and better safety compared to corticosteroids in the pediatric RCTs, the consensus group suggested a course of EEN for induction of remission was a reasonable first-line treatment strategy in pediatric patients, although the group concluded that there was not enough evidence to define the required duration of therapy. However, this statement was a conditional suggestion due to the conflicting evidence in adults, and the very small number of children included in individual pediatric RCTs, most of which had a high risk of bias. Moreover, reimbursement of formula in many Canadian jurisdictions has, until recently, required that the formula be administered via nasogastric tube. The inconvenience of such enteral feeding has been a major barrier to acceptance.
# Statement 10: In patients with Crohn's disease, we recommend against partial enteral nutrition to induce clinical remission.
corticosteroid and thiopurine therapy. 77,83 A meta-analysis of 6 studies found that azathioprine was significantly superior to placebo in maintaining remission over 6-18 months (RR, 1.19; 95% CI, 1.05-1.34). 83 One additional small RCT withdrawal trial, published after the meta-analyses, also reported a reduction in risk of relapse with ongoing thiopurine therapy, which was significant at 1 year, but not at 2 years. 84 Because most of the patients in these studies had achieved remission while on a thiopurine, they may have been more likely to show a positive effect with thiopurine maintenance therapy. Thiopurine use was associated with a 40% (hazard ratio [HR], 0.59; 95% CI, 0.48-0.73) reduction in the risk of first surgical resection in patients with CD in a meta-analysis of retrospective observational studies. 85 One RCT 86 and 1 observational study 87 assessed thiopurine maintenance therapy in pediatric patients. The small RCT found that, in children receiving corticosteroid therapy, the addition of 6-mercaptopurine was associated with a lower rate of relapse compared to adjunctive placebo at 18 months (9% vs 47%; P = .007). 86 Thiopurine use was also associated with decreased use of corticosteroids. In the observational study, 47% and 23% of pediatric patients remained in remission with thiopurine therapy at 6 and 12 months, respectively. 87 Compared to placebo, azathioprine demonstrated a significantly greater risk of adverse events (RR, 1.29; 95% CI, 1.02-1.64) and serious adverse events (RR, 2.45; 95% CI, 1.22-4.90). Common events included pancreatitis, leukopenia, nausea, allergic reaction, and infection. 83 The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness with respect to the populations, and serious imprecision.
Discussion: Evidence from adult and pediatric RCTs supports the efficacy of thiopurines for maintenance therapy. However, thiopurines are associated with tolerability issues, 83 and a risk of rare, but serious adverse outcomes, including lymphoma (eg, HSTCL), 78,79 non-melanoma skin cancers, 80 and cervical cancer. 88 During longitudinal surveillance of more than 189,000 IBD patients for a median of almost 7 years, the risk of lymphoma among those exposed to thiopurine monotherapy was increased (adjusted HR, 2.60; 95% CI, 1.96-3.44; P < .001). However, the absolute incidence rate of 0.54 (95% CI, 0.41-0.67) per 1000 person-years was low among patients exposed to thiopurines. The risk with exposure to thiopurines and/or anti-TNFs was higher in males than females (adjusted HR, 1.56; 95% CI, 1.25-1.94), but was elevated in both groups compared to those without thiopurine exposure. 79 In 2014, Health Canada issued an alert warning of the risk of HSTCL with thiopurines. 89 This warning led to a position statement from the CAG recommending that continuation of thiopurine therapy consider the benefits and risks for an individual patient. 90 In pediatric patients, the DEVELOP Registry (An Inflammatory Bowel Disease Multicenter, Prospective, Long-Term Registry of Pediatric Patients) has been established to provide post-marketing data on infliximab safety in pediatric patients with CD or ulcerative colitis. 91 The registry identified exposure to thiopurines as increasing the risks of malignancy compared to Surveillance, Epidemiology, and End Results Program database age-and sex-matched healthy peers, and of hemophagocytic lymphohistiocytosis occurrences in the setting of first exposure to Epstein-Barr virus.
The consensus group concluded that the evidence for efficacy suggested that thiopurines were a viable option for maintenance of remission, but there were safety concerns. In balancing the concern of teratogenicity with methotrexate, the consensus group made a suggestion in favor of their use in female patients, but this was conditional because although the risk of lymphoma is higher in males, it remains elevated in both sexes. Although a vote was conducted, both safety concerns and lack of consensus prevented the group from making a recommendation regarding the use of thiopurine maintenance therapy in male patients. Some participants argued that the benefits outweighed the risks, while others argued that the potential for life-threatening adverse events was not acceptable given the availability of alternate therapies.
# Statement 14: In patients with Crohn's disease, we suggest that testing for thiopurine methyltransferase by genotype or enzymatic activity be done prior to initiating thiopurine therapy to guide dosing.
GRADE: Conditional recommendation, very low-quality evidence.
Vote: strongly agree, 27%; agree, 67%; neutral, 7%.
Key evidence: Three RCTs assessed the benefits of thiopurine methyltransferase (TPMT) testing compared to no testing before initiating thiopurine therapy to individualize dosing and thereby minimize the risk of early profound neutropenia in those with low TPMT activity. [92][93][94] Genotyping was used in 2 studies 92,93 and enzymatic activity in 1 study. 94 Although specific studies on the role of TPMT testing (genotype or enzymatic activity) in pediatric patients were not found, studies suggest that pediatric and adult patients have similar TPMT activity and similar adverse event frequencies. 96,97 The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness (with respect to the populations), and serious imprecision.
Discussion. Although the incidence of patients with low or absent levels of TPMT (the enzyme needed to metabolize thiopurines) is low, these patients can be at risk of early severe myelosuppression if treated with standard thiopurine doses. 81,82 Of note, data suggest that thiopurines may be more likely to affect myelosuppression in East Asian populations than in Caucasian populations regardless of TPMT expression due to other genetic factors. 98 In a meta-analysis of 7 studies of patients with IBD treated with thiopurines, 3.2% developed leukopenia, and 0.09% of patients died. 81 Although rare, leukopenia can result in infectious or bleeding complications 99 and can be rapidly fatal. 81,100 Thus, there can be considerable harm associated with using thiopurines in patients with low or absent TPMT levels.
The risks of myelosuppression are reportedly highest in first 8 weeks of treatment, 99 but can occur at any time. [92][93][94] In patients with subnormal TMPT activity, clinical trials have suggested dose adjustments, such as a 50% dose in patients with intermediate enzymatic activity and even lower doses or not using thiopurines at all in patients with low/absent enzyme activity. [92][93][94] TMPT levels in pediatric patients appear to be similar to those in adults.
In light of the potential life-threatening consequences, the consensus group suggested TPMT testing (genotype or enzymatic activity) before initiating thiopurine therapy. This was a conditional suggestion because of concerns that TPMT testing may yield a false sense of security, as the majority of cases of leukopenia are unpredictable and independent of TPMT enzyme activity. TPMT testing results also do not correlate with the development of other adverse events, such as hepatotoxicity or pancreatitis.
Testing can be costly; however, 2 cost-effectiveness analyses in patients with IBD and rheumatoid arthritis, 81,101 and a prospective economic evaluation of the TARGET study, 93,102 suggested that TPMT testing (genotype) was a cost-effective strategy compared to no testing for patients initiating thiopurine therapy.
# No consensus G:
In patients with mild to moderate Crohn's disease, the consensus group does not make a recommendation (for or against) regarding methotrexate monotherapy to induce clinical remission.
# Statement 15: In patients with Crohn's disease, we suggest parenteral methotrexate to maintain clinical remission.
# GRADE: Conditional recommendation, low-quality evidence.
Vote: strongly agree, 40%; agree, 60%. No consensus H: In patients with Crohn's disease, the consensus group does not make a recommendation (for or against) regarding oral methotrexate to maintain clinical remission. Key evidence: Methotrexate induction therapy. Evidence for the efficacy of methotrexate for the induction of symptomatic remission comes from 1 SR&MA, 77 which included 2 RCTs conducted in adult patients with steroid-dependent CD. There was no statistically significant benefit on the outcome of failure to achieve remission (RR, 0.82; 95% CI, 0.65-1.03). 77 Although 1 of the RCTs found no benefit with oral methotrexate, 103 the other demonstrated a significant improvement in remission rates at 16 weeks, with an intramuscular methotrexate vs placebo (RR, 1.95; 95% CI, 1.09-3.48; P = .025). 104 Another SR without meta-analysis included 4 trials assessing methotrexate vs active comparators. 105 Methotrexate appeared to be as effective as thiopurines, and more effective than 5-ASA.
Very-low-quality pediatric data were available from an SR of 10, predominantly retrospective, case series. Short-term remission rates (≤3 months) were only reported for parenteral methotrexate therapy. The remission rate in 1 study was 57% at 1 month and 29% to 70% at 3 months. 106 The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness with respect to the populations and interventions, and serious imprecision.
# Parenteral methotrexate maintenance therapy
Evidence for the efficacy of methotrexate for maintenance therapy in adults with CD in clinical remission was available from 2 SR&MAs. 77,107 Only 1 trial assessed intramuscular methotrexate as maintenance therapy. 108 In this trial, there was a significant reduction in the risk of relapse with methotrexate compared to placebo (RR, 0.57; 95% CI, 0.35-0.94) in adult patients who had achieved remission with a combination of steroid and methotrexate therapy. Two other small trials included in the SR&MAs showed no significant benefit of oral methotrexate on the risk of relapse. 103,109 In the SR of pediatric observational studies, long-term remission rates were 37% to 62% at 6 months, and 25% to 53% at 12 months, primarily with parenteral methotrexate, although this was switched to oral in some case series. 106 The lack of a comparator group, varying patient populations, interventions, concomitant therapy, and definitions of remission, make these data difficult to interpret.
# Oral methotrexate maintenance therapy
There were 2 RCTs using oral methotrexate for maintenance therapy, both of which demonstrated no significant benefit 103,109 ; however, there was some question as to whether methotrexate was used to induce remission in these trials Journal of the Canadian Association of Gastroenterology, 2019, Vol. 2, No. 3 e49 because patients had chronic steroid-dependent CD, and may not have been in remission. 77,107 The only positive maintenance RCT was the intramuscular trial. 108 If this is extrapolated to support the use of the oral form, the evidence would be further downgraded to very low quality. In the SR of pediatric data, some patients were switched to oral methotrexate, and the case series comparing oral and subcutaneous methotrexate reported similar remission rates. 106 However, these data are likely confounded by preferential use of oral therapy in patients with milder disease.
# Safety
In the intramuscular study, withdrawals due to adverse events were significantly more common with methotrexate vs placebo (RR, 8.00; 95% CI, 1.09-59.51). 104 No serious adverse events were reported in the clinical trials.
In the SR of pediatric data, adverse events were similar to those seen in adults, with the most common adverse events being nausea and vomiting. 106 In a retrospective study, 31% of 102 pediatric patients with IBD experienced methotrexate intolerance (gastrointestinal or behavioral symptoms). 110 Strategies to reduce these effects in children have been reported. 111 Other adverse events included elevated liver function tests, headache, and hematologic toxicity. 106 Infectious adverse events were also reported (upper respiratory tract infection, varicella zoster reactivation). 106 An SR&MA of 12 cohort studies assessed the incidence of hepatotoxicity among children with IBD taking methotrexate. Overall, 10.2% (95% CI, 5.4%-18.5%) of patients had abnormal liver biochemistry and 4.5% (95%, CI, 2.8%-7.2%) of patients required discontinuation of the drug. 112 As the drug has the potential for teratogenic effects, embryotoxicity, abortion, and fetal defects in humans it cannot be used in pregnant females, raising significant concerns in those who provide care when pregnancy is possible.
The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness (with respect to the populations), and serious imprecision.
Discussion. Significant benefits with methotrexate for the management of CD are seen only in the 1 RCT, which used the intramuscular formulation for induction and maintenance therapy. 108 RCTs using oral methotrexate for induction or maintenance therapy have not shown significant benefit. There were no RCTs in pediatric patients, but the observational data suggested that about 25% to 50% of patients can achieve longterm remission with subcutaneous and/or oral methotrexate. 106 Pharmacokinetic data show differences between oral and parenteral methotrexate, 113 and common practice in rheumatology has included switching from oral to parenteral in cases where oral methotrexate was not effective. In clinical practice, subcutaneous methotrexate is used more often than intramuscular delivery. The pharmacokinetics of the subcutaneously administered drug have been shown to be similar to intramuscular injection. 114,115 In addition, subcutaneous administration minimizes local reactions at the injection site, and may be more convenient and less painful. 113,114 The RCTs using methotrexate as induction therapy provided conflicting results; the oral trials were negative, while the intramuscular trial was positive. Short-term results from the observational data in pediatric patients were only available for parenteral methotrexate. Based on these conflicting data, the consensus group did not make a recommendation for or against the use of methotrexate for induction therapy. Participants in support of this strategy cited the potential efficacy as demonstrated in the intramuscular trial, and the observational studies. Because there are very few treatments for CD, which is a lifelong disease, methotrexate is a potentially useful treatment that should not be discarded. Methotrexate has a slow onset of action, therefore, for patients who are not acutely symptomatic and in whom a delayed response would be acceptable, it may be an option to start it in the induction phase in order to use it as maintenance therapy. Participants who were against recommending methotrexate for induction therapy argued that the trials were not monotherapy trials; most patients were on other therapies (particularly corticosteroids), and the contribution of methotrexate is uncertain.
Based on evidence supporting beneficial effects of intramuscular methotrexate, the consensus group suggested parenteral methotrexate for use as maintenance therapy. However, there was insufficient evidence to make a recommendation regarding the use of oral methotrexate in this setting. While the RCTs using oral methotrexate were negative, these trials were very small, and the doses used may have been inadequate. The data from the intramuscular trial suggest the potential for efficacy with this medication. Some consensus participants argued that some patients in stable remission may continue to benefit when switched from parenteral to lower cost, more convenient, oral methotrexate. This is supported by observational data reported in the SR of pediatric studies. 106 10,11 The SR&MA of prospective cohort data, including 12 studies found that patients who had achieved mucosal healing had significantly increased rates of long-term clinical remission (OR, 2.80; 95% CI, 1.91-4.10) and mucosal healing (OR, 14.30; 95% CI, 5.57-36.74). 11 There was a trend to a greater CD-related surgery-free rate (OR, 2.22; 95% CI, 0.86-5.69), but this was not significant.
# Statement 16: In patients with Crohn's disease who are in clinical remission with a thiopurine or methotrexate as maintenance therapy, we suggest assessment for mucosal healing within the first year to determine the need to modify therapy if significant ulcerations persist.
In pediatric patients, complete mucosal healing was associated with significantly higher rates of long-term remission for up to 3 years compared to ongoing active endoscopic disease. 12 Rates of mucosal healing with anti-TNF therapy (27%-31%) were higher than those seen with immunosuppressants (16.5%) or placebo (0-13%). [116][117][118] Combination anti-TNF and immunosuppressant therapy (43.9%) provided even higher rates compared to anti-TNF (30.1%; P = .06) or immunosuppressant therapy (16.5%; P < .001) alone. 118 In addition, a higher rate of mucosal healing with combination therapy compared to conventional therapy at 2 years (73% vs 30%; P = .0028) 119 was a significant predictor of remaining in remission at 3 and 4 years (OR, 4.35; 95% CI, 1.10-17.22). 120 Several case series in pediatric patients have reported rates of mucosal healing associated with anti-TNF therapy. Complete mucosal healing was seen in 22%-25% of patients, and endoscopic improvement in 44%-67%. [121][122][123] The evidence was downgraded to very low due to serious risk of bias, serious indirectness with respect to the use of surrogate outcomes (mucosal healing) and serious imprecision.
Discussion. There are long-term benefits associated with mucosal healing. Assessment for mucosal healing generally requires endoscopy, which is both costly and invasive. Imaging (eg, magnetic resonance enterography) and biomarker levels (eg, C-reactive protein and fecal calprotectin) have been shown to correlate with endoscopy, 124 and changes in these parameters were recently shown to correlate with mucosal healing. The open-label, RCT CALM (published outside the search window) compared treatment escalation with an anti-TNF therapy based on both clinical symptoms and biomarkers (tight control) to symptom-driven decisions alone (clinical management) in 244 adult patients. At week 48, significantly more patients in the tight control group achieved mucosal healing (46%) than in the clinical management group (30%, risk difference, 16.1%; 95% CI, 3.9-28.3; P = .010). 125 Based on the potential benefits associated with mucosal healing, the consensus group suggested that assessing this outcome was a useful management strategy in patients receiving immunosuppressant therapy. Data suggest higher mucosal healing rates with anti-TNF therapies and better long-term outcomes when healing is achieved. The consensus group, nevertheless, did not make a universal recommendation regarding switching to or adding an anti-TNF to therapy in all patients who have achieved clinical remission but not mucosal healing with immunosuppressant therapy. This was largely related to the fact that the degree of mucosal healing required to achieve clinically relevant benefits needs to be more clearly defined. The REACT-2 trial is underway in adults to assess whether early treatment intensification based on mucosal healing will reduce the risk of hospitalization, surgery, and CD complications compared to conventional step-up therapy.
# Anti-Tumor Necrosis Factor Biologic Therapy
# Statement 17: In patients with moderate to severe inflammatory Crohn's disease who have failed to achieve clinical remission with corticosteroids, we recommend anti-TNF therapy (adalimumab, infliximab) to induce and maintain clinical remission.
(RR, 0.99; 95% CI, 0.90-1.08) or maintenance of remission (RR, 0.93; 95% CI, 0.84-1.03) compared with placebo. 126 The quality of evidence was rated as high with no concerns for risk of bias, inconsistency, indirectness, or imprecision.
Discussion. There is high-quality evidence for the efficacy of anti-TNF therapy for patients who have failed corticosteroids, or immunosuppressant therapies. These subgroups are not clearly differentiated in most trials, and most of the RCTs included both populations. Adalimumab and infliximab have demonstrated efficacy in adults in RCTs and in children in trials with open-label induction and randomized dose-ranging maintenance therapy. Results from studies assessing certolizumab for induction of remission did not demonstrate significant benefit, but benefit was demonstrated for maintenance of remission. 126 However, there were no controlled trials in pediatric patients, and generally maintenance therapy is continued with the agent used for induction, making certolizumab less appropriate.
In pediatric patients, anti-TNF induction therapy has been reported only in open-label trials. [130][131][132][133] For maintenance, 1 double-blind RCT 132 and 2 open-label RCTs (REACH-1 131 and a French trial 133 ) were found. None of these trials was placebo-controlled, but rather compared different doses, different dosing intervals, or scheduled vs on-demand therapy. The majority of patients were receiving concomitant immunosuppressant therapy. The 1 double-blind RCT (IMAgINE-1) assessed adalimumab dose-ranging maintenance therapy after open-label weight-adjusted induction therapy, and reported a remission rate of 33.5% at week 26, with no significant difference between high-and low-dose adalimumab. 132 In the openlabel RCT (REACH) of infliximab every 8 weeks vs every 12 weeks after open-label induction, the clinical remission rate was 56% after 1 year. 131 Impaired growth, particularly if defined by the most sensitive parameter of reduced height velocity, has historically been a frequent complication of pediatric CD developing before puberty. Risk factors include prolonged disease before diagnosis and the inter-related factors of chronically, uncontrolled, intestinal inflammation, under-nutrition, and chronic corticosteroid use. 6,69 Anti-TNF therapies have been associated with improved growth in IMAgINE-2, 134,135 REACH-1, 131 the French trial, 133 the RISK study, 136 and a prospective cohort study. 137 Anti-TNFs are generally well tolerated; however, increased risk of infections and reactivation of tuberculosis have been reported in adults. 79,138,139 In pediatric patients, upper respiratory tract infections and nasopharyngitis were frequent, being reported in about 37%-43% of children in open-label extension trials. 134,140 During almost 5 years of follow-up of 100 pediatric patients who entered the IMAgINE-2, open-label, extension study, the incidence of opportunistic infections was 5.7% (2.2/100 patient-years), with all but 1 being considered non-serious adverse events. 134 Only one opportunistic infection was reported in the open-label extension of the REACH trial (n = 60, up to 3-year follow-up), also considered non-serious. 140 In adults, the risks of lymphoma were highest in those exposed to combination therapy, but were also elevated in patients exposed to anti-TNF monotherapy compared to no exposure (adjusted HR, 2.41; 95% CI, 1.60-3.64; P < .001). 79 Based on the efficacy demonstrated in RCTs in adults and children, the consensus group strongly recommended anti-TNF therapy for patients with moderate to severe CD who have failed corticosteroid or immunosuppressant therapy.
Only 2 members of the consensus group reported no conflict of interest regarding anti-TNF therapies. Two separate votes were conducted for statement 17, one for these 2 members, and another for the consensus group as a whole, in both cases the vote was unanimously "strongly agree. "
# Statement 19: In patients with severe inflammatory Crohn's disease judged at risk for progressive, disabling disease, we suggest anti-TNF therapy as first-line therapy to induce and maintain clinical remission.
GRADE: Conditional recommendation, very low-quality evidence.
Vote: strongly agree, 47%; agree, 53%.
Key evidence. The efficacy of anti-TNF therapy in adults with CD is described under Statements 17 and 18. The majority of RCTs were conducted in patients who had received previous non-biologic therapies. These data were extrapolated to the use of these agents as first-line treatments, and therefore downgraded in assessment of quality to very-low-quality evidence.
Additional support for the early use of anti-TNF therapy comes from open-label, prospective trials using combined anti-TNF and immunosuppressive therapy in newly diagnosed, treatment naïve patients. 119,141 In these studies, "top-down" treatment was associated with significantly higher rates of symptomatic remission at earlier time points compared to not using early anti-TNF therapy. Post-hoc analyses of several other adult RCTs have suggested that rates of deep remission (clinical remission plus mucosal healing) may be highest in patients with early CD (<18-24 months duration) with anti-TNFcontaining regimens. 142,143 Discussion. Some evidence has demonstrated the benefits of using early anti-TNF therapy in adults who are treatment naïve 119,141 and those who are naïve to anti-TNF and immunosuppressant therapy. 119,142 Secondary analysis of data from the RISK observational study using propensity scores compared the early introduction of anti-TNF therapy, immunosuppressant therapy, and no immunotherapy, within 3 months of diagnosis in pediatric patients in a real-world clinical setting. 136 Early anti-TNF therapy was superior to early treatment with an immunosuppressant (85.3% e52 vs 60.3%; RR, 1.41; 95% CI, 1.14-1.75; P = .0017), or no early immunotherapy (54.4%; RR, 1.57; 95% CI, 1.23-1.99; P = .0002) in achieving corticosteroid-free remission at 1 year after diagnosis. In addition, the mean height z-scores increased compared with baseline only in the early anti-TNF group.
The consensus group suggested the use of anti-TNF agents as a first-line treatment based on the demonstrated efficacy as induction therapy, and supportive data suggesting benefits in newly diagnosed patients. This was a conditional suggestion because of the same concerns discussed under Statements 17 and 18.
The group discussed that early anti-TNF may be warranted in pediatric patients with extensive disease or deep colonic ulcerations, or in those in whom corticosteroids could be expected to provide no benefit or could have the potential to exacerbate underlying conditions, such as complex perianal disease, severe bone disease, mental health disorders, or linear growth delay. The group also emphasized that there is an urgent need for better predictors of chronically active, severe inflammatory disease, and disease that will result in progressive intestinal damage that would necessitate intestinal resection.
# Statement 20: When starting infliximab in males, we suggest against using it in combination with a thiopurine.
GRADE: Conditional recommendation, low-quality evidence. Vote: strongly agree, 40%; agree, 47%; neutral, 13%. No consensus J: When starting infliximab in females, the consensus group does not make a recommendation (for or against) regarding combining it with a thiopurine to maintain a durable clinical remission. Key evidence. Evidence of a treatment benefit for infliximab in combination with a thiopurine comes from the prospective randomized SONIC trial in adults, which demonstrated higher rates of clinical remission and endoscopic healing at week 26 with combination vs infliximab monotherapy (57% vs 44%; P = .02). 118 In an SR&MA, this yielded an RR of failure to achieve remission with combination vs infliximab monotherapy of 0.78 (95% CI, 0.62-0.97). 144 An SR&MA of cohort data from RCTs of anti-TNF therapy (adalimumab, certolizumab, or infliximab), found no significant differences in the rates of clinical remission with the combination of an anti-TNF plus an immunosuppressant (thiopurine or methotrexate) compared to an anti-TNF alone for induction (OR, 1.28; 95% CI, 0.77-2.16) or maintenance therapy (OR, 1.02; 95% CI, 0.80-1.31). 145 There were no significant differences in rates of clinical remission between monotherapy and combination therapy for maintenance treatment when the 3 anti-TNF agents were pooled, or when they were analyzed separately.
In the SONIC trial, the incidence of adverse events was generally similar in the combination and monotherapy groups, and there were no significant differences in the RR of serious infection. 118,144 Evidence on rare, but important adverse events was very low quality. Observational data suggest a higher risk of lymphoma 79 and activation of tuberculosis 138 in patients exposed to combination vs anti-TNF monotherapy.
One open-label, pediatric RCT randomized patients after 10 weeks of combination induction therapy to maintenance with either 54 weeks of combination therapy or 26 weeks of combination therapy, followed by 26 weeks of anti-TNF monotherapy. 146 At the end of the 10-week open induction phase, 65.5% of patients were in clinical remission. At the end of the 54-week maintenance phase, there was no significant benefit of combination therapy with <5% of patients in either group experiencing a loss of response. The incidence of serious adverse events was 9%, of which the most common was primary Epstein-Barr virus infection.
The evidence was downgraded to low due to serious inconsistency and serious imprecision.
Discussion. In the REACH pediatric study of infliximab, all patients were required to be administered immunosuppressants, and 10-week remission rates were 59%. However, there was no monotherapy comparison group. 131 One RCT in adults (downgraded to low-quality evidence for indirectness [extrapolated to pediatric] and imprecision [low number of events]) suggested a potential efficacy benefit with combination therapy over anti-TNF monotherapy. However, administration of infliximab monotherapy in the SONIC study was strictly according to standard protocol (precisely 5 mg/kg every 8 weeks) without any attention to optimizing drug exposure via therapeutic drug monitoring. There is also an important benefit of concomitant immunomodulators in prolonging clearance of infliximab and reducing rates of anti-infliximab antibody development, as demonstrated in SONIC and in pediatric cohort studies. 137,147 Avoiding secondary loss of response related to anti-drug antibody development is extremely important in young patients, given the long lives ahead, during which treatment will be needed. The modest increment in efficacy of combination therapy might be overcome via individualized dosing regimens of infliximab monotherapy to avoid low or absent trough titers to help avoid development of anti-drug antibodies.
The consensus group recognized the improved durability of infliximab response with combination therapy, but suggested against selection of thiopurines as the concomitant drug for males based on safety concerns, as described in Statements 12 and 13. Specifically, the risk of the extremely rare but almost uniformly fatal HSTCL, is attributable to thiopurine use, both alone and in combination with anti-TNF. The highest risk has been reported among males aged <35 years receiving combination thiopurine and anti-TNF therapy. 148 Post-marketing surveillance of infliximab continues to identify at least 2 occurrences Journal of the Canadian Association of Gastroenterology, 2019, Vol. 2, No. 3 e53 worldwide annually and always in patients receiving anti-TNF in combination with a thiopurine. Two such occurrences were reported in the DEVELOP pediatric IBD registry. 91 In adults, the risk of other lymphomas (usually Epstein-Barr virus-driven), which is age-related and of lesser concern for pediatric patients, was increased in patients exposed to combination thiopurine plus anti-TNF therapy compared to no exposure, thiopurine monotherapy, or anti-TNF monotherapy. 79 In the open-label, RCT in 84 pediatric patients, there were 4 occurrences of primary EBV infection, 1 of herpes simplex virus, and 1 of chickenpox infection, throughout the study. 146 The group concluded that the benefits of thiopurine in combination with infliximab did not outweigh the risk of HSTCL in males. However, the consensus group did not make a recommendation regarding the use of combination therapy for females. The risk of HSTCL, although lower in females, remains elevated compared to no exposure, therefore, some participants argued that the risks outweighed the benefits, while others disagreed and noted that combination therapy with thiopurines remains a potentially useful strategy for some patients.
# Statement 21: When starting adalimumab in males, we suggest against using it in combination with a thiopurine.
GRADE: Conditional recommendation, very-low-quality evidence. Vote: strongly agree, 40%; agree, 53%; neutral, 7%. No consensus K: When starting adalimumab in females, the consensus group does not make a recommendation (for or against) regarding combining it with a thiopurine to maintain a durable clinical remission.
# Key evidence.
An open-label, RCT (DIAMOND), in adults who were immunosuppressant-and biologic-naïve found no difference in 26-week clinical remission rates between the combination of adalimumab plus azathioprine (68.1%) and adalimumab monotherapy (71.8%; P = .63). The rate of endoscopic improvement was significantly higher with combination therapy at 6 months but not 12 months. 149 Similarly, post-hoc analyses of cohort data from RCTs in adults did not show a significant benefit with combination adalimumab and immunosuppressant therapy (thiopurine or methotrexate) over adalimumab alone for induction (OR, 0.88; 95% CI, 0.60-1.27) or maintenance of remission (OR, 0.88; 95% CI, 0.58-1.35). 145 Additional very low quality of evidence data in pediatric patients also reported no benefit with the combination of adalimumab plus an immunosuppressant. In a post-hoc analysis of the IMAgINE-1 RCT, there was no difference in remission rates between those who received concomitant immunosuppressants and those who did not (35.9% vs 29.6%). 132,150 The evidence was downgraded to very low due to serious risk of bias and very serious imprecision.
Discussion. There were very few data to suggest a benefit of adding a thiopurine when starting adalimumab therapy. In the DIAMOND trial, the primary end point was negative, but there was evidence of more rapid mucosal healing in the combination group. 149 Although not statistically significant, there were trends toward higher adalimumab trough levels and lower rates of anti-adalimumab antibodies in the combination group compared to the monotherapy group. Although overall there were not significant differences in the rates of adverse events or study discontinuations between the combination and monotherapy groups, withdrawals specifically for side effects were significantly more frequent in the combination group.
For the same reasons as described in Statement 20 for infliximab/thiopurine combination therapy regarding safety concerns and less evidence of benefit, the consensus group suggested against the combination in males and did not make a recommendation regarding the use of combination therapy in females.
# Statement 22: In male patients with Crohn's disease receiving immunomodulator therapy in combination with an anti-TNF therapy, we suggest methotrexate in
preference to thiopurines.
concomitant immunosuppressants, but only 10% specifically received methotrexate. 131 The quality of evidence was downgraded to very low due to serious risk of bias and very serious imprecision.
Discussion. Although the double-blind, placebo-controlled RCT failed to show a benefit with combination anti-TNF and methotrexate therapy, the evidence was assessed as very low quality. 151 The trial demonstrated that combination infliximab plus methotrexate was associated with a lower likelihood of developing antibodies to infliximab (4% vs 20%; P = .01), and there was a trend to higher median serum trough infliximab concentrations (6.35 μg/mL vs 3.75 μg/mL; P = .08). However, there was no significant clinical benefit. Of note, there were very high success rates among the patients in this trial, potentially due to the use of systemic corticosteroids to induce remission in all patients. The high success rate in both arms of the trial may have resulted in a lack of power to demonstrate clinical benefit of concomitant methotrexate. 151 The most frequent adverse event with methotrexate therapy is nausea (up to 25% of patients), however, there is a risk of rare, but serious adverse events, including hepatotoxicity, bone marrow suppression, hypersensitivity pneumonitis, gastrointestinal toxicity, teratogenicity, and infections. 153 In contrast to thiopurines (see Statement 20), methotrexate has not been associated with an increased incidence of lymphoma, however, historic rates of use in CD are low. 153 Although a vote was conducted, both insufficient evidence and lack of consensus prevented the group from making a recommendation regarding combining infliximab or adalimumab with methotrexate to maintain a durable clinical remission in all patients or males alone. However, if a clinician judges a patient to require the combination of an anti-TNF and an immunosuppressant, the consensus group suggested that methotrexate should be used over thiopurines in males. This was a conditional suggestion, as, despite the lower risk of lymphoma, there are other safety concerns in addition to a lack of evidence demonstrating the efficacy of combination therapy with methotrexate in CD.
# Statement 23: In patients with Crohn's disease who have a suboptimal clinical response to anti-TNF induction therapy or loss of response to maintenance therapy, we suggest regimen intensification informed by therapeutic drug monitoring.
GRADE: Conditional recommendation, very-low-quality evidence. Vote: strongly agree, 53%; agree, 47%.
Key evidence. One RCT (TAXIT) evaluated the efficacy of regular therapeutic drug monitoring (TDM) in adults with IBD, who were stable on infliximab maintenance therapy, and had their dose proactively optimized before study entry to achieve an infliximab trough concentration between 3-7 μg/mL. 154 Among CD patients, there was no significant difference in clinical remission rates between those who were randomized to dosing guided by TDM and those randomized to standard clinically-based dosing (62.6% vs 54.9%; P = .353). Relapse rates were significantly lower in patients who received TDM-based dosing compared to those who received clinically based dosing (17% vs 7%; P = .018); however, this was in the combined IBD population.
The majority of data related to TDM come from observational studies, which have been assessed in SR&MAs of studies in adults using infliximab 155,156 or adalimumab. 157 These analyses showed that antibodies to anti-TNFs were associated with greater likelihood of loss of response, 156,157 and higher serum anti-TNF levels were associated with a greater probability of clinical remission and mucosal healing. 155,157 However, these studies do not assess whether using TDM proactively will have an impact on patient outcomes, as opposed to reactive TDM when patients are symptomatic.
In the IMAgINE-1 study in pediatric patients, higher trough levels were associated with greater rates of remission, but there was no correlation between antibodies to anti-TNF therapy and remission/response (n = 6 patients with antibodies). 158 In a retrospective case series of pediatric patients with IBD, those with very low infliximab drug levels had high rates of infliximab antibodies, non-response, or loss of response. 159 The quality of evidence was downgraded to very low due to serious risk of bias and very serious imprecision.
Discussion. Evidence suggests that regimen intensification (increasing the dose or shortening the dosing interval) may help increase remission rates. In TAXIT, dose optimization before randomization resulted in significant improvements in remission rates (88% vs 65%; P = .02) and median C-reactive protein concentrations (3.2 mg/L vs 4.3 mg/L; P < .001) compared to before dose escalation. 154 Two SRs of case series have shown response rates of about 54%-90%, and remission rates of about 31%-40% among patients who underwent dose intensification. 160,161 In addition, among pediatric patients losing response in the REACH trial, planned dose intensification resulted in 75% of patients (n = 24/32) regaining response. 131 Observational data suggest that antibodies to anti-TNFs are associated with greater likelihood of loss of response, and higher serum anti-TNF levels are associated with a greater likelihood of maintained remission. However, the only RCT that prospectively assessed the impact of proactive TDM to guide dosing during infliximab maintenance therapy demonstrated no significant benefit in its primary outcome of higher clinical remission rate at 1 year. 154 In a small, single-blind RCT, treatment of secondary anti-TNF failure using an algorithm based on combined drug serum levels and antibody measurements significantly reduced average treatment costs per patient compared with routine dose escalation. 162 The TDM-guided approach did not Journal of the Canadian Association of Gastroenterology, 2019, Vol. 2, No. 3 e55 have a negative effect on clinical efficacy, and was cost-effective during longer-term follow-up. 163 Based on the evidence that regimen intensification can improve outcomes, the consensus group suggested this strategy before considering a change in therapy. The statement was a conditional suggestion because of uncertainties of TDM, not uncertainty pertaining to the value of dose intensification.
# No consensus L:
In patients with Crohn's disease who have achieved a clinical remission with anti-TNF therapy, the consensus group does not make a recommendation (for or against) regarding assessment for mucosal healing within the first year to determine the need to modify therapy. Key evidence. Evidence for the potential benefits of mucosal healing and the rates of mucosal healing with anti-TNF therapy were discussed under Statement 16.
Discussion. The discussion around the utility of assessing for mucosal healing was discussed under Statement 16.
In the context of anti-TNF therapy, the consensus group did not make a recommendation regarding endoscopic assessment of mucosal healing among patients in clinical remission. Data concerning endoscopic healing achieved with other agents, including alternate pathway biologic therapies, are very sparse. In addition, the degree of mucosal healing warranting a change in therapy has not been defined, nor has the ideal duration of therapy before assessing for endoscopic healing.
# Non-Anti-Tumor Necrosis Factor Biologic Therapy
# Statement 24: In patients with moderate to severe Crohn's disease who fail to achieve or maintain clinical remission with anti-TNF-based therapy, we suggest ustekinumab to induce and maintain clinical remission.
GRADE: Conditional recommendation, moderate-quality evidence for induction, moderate-quality evidence for maintenance. Vote: strongly agree, 47%; agree, 53% Key evidence. Evidence for the efficacy of ustekinumab for induction of remission was available from 4 RCTs in adult patients, including both patients who had and those who had not failed anti-TNF therapy. [164][165][166] In an SR&MA of these 4 trials (n = 1947), ustekinumab was significantly better than placebo for the outcome of failure to achieve remission (RR, 0.91; 95% CI, 0.86-0.95). 167 Two RCTs were conducted in patients who had previously failed anti-TNF therapy. 164,165 In CERTIFI, there were no significant differences in remission rates at week 6, despite ustekinumab being associated with a higher response rate compared to placebo. 165 However, in the UNITI-1 trial, 1 intravenous infusion of ustekinumab at 6 mg/kg resulted in improved rates of both response (34%) and remission (21%) at week 8, compared to placebo (22% and 7%, respectively). 164 Two RCTs assessed the use of ustekinumab as maintenance therapy in patients who previously failed anti-TNF therapy. 164,165 In the CERTIFI trial, ustekinumab resulted in significantly increased rates of clinical remission at 22 weeks compared with placebo (41.7% vs 27.4%; P = .03). 165 In the combined population in the UNITI-IM trial, which included responding patients who had previously failed either anti-TNF or were biologicnaïve but had failed conventional therapy, significantly more patients were in remission with maintenance ustekinumab after 1 year of treatment compared to placebo (49%-53% vs 36%). In the UNITI-1 subgroup of patients with prior anti-TNF failure, there were no significant differences in clinical remission rates between ustekinumab and placebo at 1 year. 164 In the SR&MA, there were no significant differences in the rates of adverse events, serious adverse events, or withdrawals due to adverse events. 167 No RCTs assessing ustekinumab in pediatric patients with CD were found.
The quality of evidence was downgraded to moderate due to indirectness with respect to populations (lack of pediatric data).
Discussion. Ustekinumab has demonstrated efficacy for induction and maintenance of remission in the overall patient population, as well as patients who have previously failed or were unable to tolerate anti-TNF therapy.
No RCTs in pediatric patients with CD were found; specific, pediatric case-series and experience among participants are still limited. [168][169][170] Among the 6 cases reported, all had previous primary or secondary failure, or intolerance to, anti-TNF therapy, and 3 of the 6 successfully achieved clinical remission.
Ustekinumab has been studied in a RCT in adolescent patients from 12 to 17 years of age with plaque psoriasis. 171 There were no significant differences in the rates of adverse events between ustekinumab and placebo at 12 weeks. 171 Infections were the most common adverse events, primarily nasopharyngitis, upper respiratory tract infections, and pharyngitis. During the 60-week follow-up, there were no reported malignancies, tuberculosis, opportunistic infections, anaphylactic reactions, or serum sickness-like reactions.
Based on the evidence for efficacy in adults and the reported safety in pediatric patients with plaque psoriasis, the consensus group made a conditional suggestion in favor of ustekinumab therapy in patients who have failed anti-TNF therapy. This was a conditional suggestion because of the lack of RCTs in pediatric patients with CD and the modest effect sizes in the adult trials.
# No consensus M:
In patients with moderate to severe Crohn's disease who fail to achieve or maintain clinical remission with an anti-TNF-based therapy, the consensus group does not make a recommendation (for or against) regarding the use vedolizumab to induce and maintain clinical remission.
# e56
Journal of the Canadian Association of Gastroenterology, 2019, Vol. 2, No. 3 Key evidence. Evidence for the efficacy of vedolizumab for induction therapy was available from 3 RCTs in adults with CD who had previously failed anti-TNF therapy. 172,173 or had no prior anti-TNF exposure, 174 which have been analyzed in several SR&MAs. 129,175 For the outcome of failure to induce symptomatic remission, vedolizumab was superior to placebo in the combined patient group (RR, 0.87; 95% CI, 0.79-0.95), and trended to benefit in the subgroup of patients who had previously failed anti-TNF therapy (RR, 0.89; 95% CI, 0.78-1.01). 175 In the RCT that assessed the efficacy of vedolizumab maintenance therapy among responders to induction therapy, vedolizumab resulted in significantly higher 1-year remission rates compared to placebo (36%-39% vs 22%; OR, 2.20; 95% CI, 1.40-3.44). 129,172 Among those who had previously failed anti-TNF therapy, but who achieved clinical "response" at week 6 and were then re-randomized to vedolizumab vs placebo maintenance therapy, continuation of vedolizumab was significantly more effective than placebo. 172 There were no significant differences in the rates of serious adverse events, infections, or malignant neoplasms between vedolizumab and placebo. 129 The evidence was assessed as very low quality due to the significant heterogeneity among the induction studies, as well as imprecision and indirectness. No RCTs assessing vedolizumab in pediatric patients with CD were found.
The evidence was downgraded to very low due to serious inconsistency, indirectness with respect to populations (paucity of pediatric data), and serious imprecision.
Discussion. No RCTs in pediatric patients with CD were found, but a small, prospective observational study 176 and case reports 177,178 suggest it may be beneficial in some children who have previously failed anti-TNF therapy. In the prospective study, 25% of patients with CD achieved remission at week 14 and 31% at week 22. 176 The retrospective case reports of pediatric patients with IBD found that vedolizumab tended to be slower acting and have lower remission rates in patients with CD compared to those with ulcerative colitis. 177,178 Long-term, open-label follow-up data report low rates of infusion reactions, serious infections, and malignancy. 179,180 The consensus group did not make a recommendation for or against the use of vedolizumab in patients who had failed prior anti-TNF therapy. Vedolizumab did not show a significant benefit over placebo for induction of remission in prior treatment failures in the SR&MA. 175 One RCT in the setting of maintenance of remission suggested benefit in patients who had responded to vedolizumab induction therapy compared to placebo, but anticipated efficacy is overall very low in this anti-TNF failure population. 172 Finally, there were no RCTs in pediatric patients in any disease state, and very limited safety data in the pediatric population. It is anticipated that experience will gradually accrue in pediatric patients with less treatmentrefractory disease. In the current era of access only for patients having failed anti-TNF, the consensus group concluded that evidence of efficacy in CD was less convincing than that for ustekinumab, the other non-anti-TNF biologic. Key evidence. Cannabis or derivatives has been assessed in 2 small RCTs in adults with CD inadequately controlled on steroids, immunomodulators, or anti-TNF therapy. 181,182 Both trials reported no significant differences in remission rates with either medical cannabis cigarettes or oral cannabidiol compared to placebo. 181,182 These studies included a total of 40 patients. No side effects and no withdrawal symptoms on discontinuation were reported. A patient survey reported higher rates of surgical intervention among patients with IBD who smoked cannabis to relieve their symptoms, compared to those who did not. 183 However, because of the cross-sectional design, this could represent reverse causation. The quality of evidence was downgraded to very low due to serious risk of bias, serious indirectness with respect to populations (no pediatric data), and very serious imprecision.
# Alternative Therapies
Discussion. There is increasing interest in medical marijuana; however, there is currently no support for the use of cannabis for the treatment of CD. Although one RCT showed improvement in quality of life with cannabis cigarettes, 181 both RCTs demonstrated no significant benefit of cannabis for clinical remission, or an objective measure of disease activity (C-reactive protein). 181,182 A review of the literature by the Canadian Paediatric Society concluded that cannabis use during adolescence can cause changes to the developing brain, and has been linked to substance use disorders, tobacco smoking, increased rates of psychiatric illnesses, cognitive decline, and diminished school performance and lifetime achievement. 184,185 They recommended that sales of all cannabis products to children and adolescents be prohibited in order to protect these individuals from the potential harms associated with cannabis use. 184,185 Based on the lack of evidence for efficacy in the treatment of CD, and the potential harms associated with long-term use, the consensus group made a strong recommendation against the use of cannabis products in pediatric patients with CD.
# Future Research Directions
The management of CD in pediatric patients has been inadequately studied, with most data being extrapolated from studies Journal of the Canadian Association of Gastroenterology, 2019, Vol. 2, No. 3 e57 in adult patients. Overall, there is a need for more RCTs of CD management strategies in pediatric populations, including positioning of biologic therapies relative to immunomodulators. The identification of molecular markers predictive of disease course would constitute a significant advance, allowing early selection of the most appropriate treatment plan for individual patients. More data are needed to define the efficacy and optimal protocol for EEN in pediatric patients, especially as a firstline treatment.
There is an absence of RCT data on the use of non-anti-TNF biologic therapies in pediatric patients, for both induction and maintenance therapy. The role of switching out of class in pediatric patients who have achieved clinical remission with anti-TNF therapy should be assessed. All trials in pediatric CD should include outcomes of mucosal healing and, importantly, should strive to determine the degree of healing required to meaningfully modify the long-term course of the disease beginning in childhood.
# Summary
Previous guidelines on the medical management of pediatric Crohn's disease were developed through traditional expert consensus-based methodology without formal assessment of the quality of evidence. 8 The current guidelines present recommendations for pediatric patients with CD based on the GRADE framework with systematic review of the literature and rigorous assessment of the quality of evidence. Consensus was reached for or against 25 statements relating to main treatment options: aminosalicylates, budesonide, systemic corticosteroids, exclusive enteral nutrition, thiopurines, methotrexate, anti-TNF biologics, non-anti-TNF biologics, and cannabis (Table 1). When consensus was not reached for a particular statement even after a thorough systematic review of the quality of evidence, balance of harms and benefits, values and preferences, as well as resource use, no recommendation was made. Instead, we presented the evidence and discussed the reasons we were not able to make a judgment. It is hoped that the available information will enhance the discussion between the clinician and the patient and enable the patient to make an evidence-based informed decision that is consistent with his or her own values and preferences.
It is important to note that there is discordance in the strength of recommendation and quality of evidence in 7 statements where strong recommendations were made against certain treatments based on low-or very-low-quality evidence of no benefit, but of potential harms due to side effects of medications. A judgment was made by the consensus group that there was also harm in not providing more effective treatment options in children. The implications of inadequately treated CD are of particular importance in children because of the potentially serious and irreversible consequences of growth impairment, delayed sexual maturation, as well as psychosocial, mental, and emotional maldevelopment. These effects may be long-lasting, persisting even after recovery from the disease. Undoubtedly, there is subjectivity in making this judgment regarding the strong desirability of avoiding irreparable harms to a child. However, GRADE does not seek to eliminate subjective judgments (appropriate or inappropriate). Such judgments are an inevitable part of rating evidence and making recommendations, but one merit of the GRADE system is that judgments are made in a systematic, explicit, and transparent manner.
While the goal of therapy is typically deep remission (clinical remission and mucosal healing), this could not be selected as the primary outcome for this guideline because, until recently, only clinical remission and response (not mucosal healing) have been assessed in the majority of RCTs. However, the consensus group endorsed the importance of achieving endoscopic mucosal healing, while acknowledging that more research is required to fully understand other aspects of intestinal healing, including the transmural nature of the disease and submucosal inflammatory histology.
These guidelines should help to optimize the use and proper positioning of existing medical therapies and improve outcomes in pediatric patients with CD. However, substantial unanswered questions remain. Studies in pediatric patients are needed to define optimal use of exclusive EN, positioning of biologic therapies vs immunomodulators, and of established anti-TNF agents vs emerging alternate pathway biologic therapies. As well, with the rapid advent of new treatments and therapies for CD, the term conventional therapy may become obsolete, as many of today's novel therapies will become tomorrow's standard treatments. These guidelines will be reconsidered and updated as appropriate when important new evidence emerges.
# Canadian Association of Gastroenterology Statement
This clinical practice guideline (CPG) on the management of pediatric CD was developed under the direction of Drs David Mack and Anne Griffiths, in accordance with the policies and procedures of the CAG and under the direction of CAG Clinical Affairs. It has been reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors. The CPG was developed following a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian and International panel composed of experts on this topic. The CPG aims to provide a reasonable and practical approach to care for specialists and allied health professionals are charged with the duty of providing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve.
# e58
Journal of the Canadian Association of Gastroenterology, 2019, Vol. 2, No. 3
# Acknowledgments
The consensus group would like to thank Paul Sinclair and Karen Sparkes (Canadian Association of Gastroenterology representatives) for administrative and technical support and logistical assistance, and Pauline Lavigne and Steven Portelance (unaffiliated) for medical writing services, supported by funds from the Canadian Association of Gastroenterology. Author contributions: All authors contributed to the developing the recommendations, and crafting the manuscript.
#
therapy with infliximab plus methotrexate to infliximab alone, and found no difference in rates of symptomatic remission between the 2 treatment groups (HR, 1.16; 95% CI, 0.62-2.17; P = .63). 151 A very, small, open, pilot study reported an early benefit of combination therapy that was not sustained. 152 The open-label, RCT in pediatric patients, described under Statement 20, included patients on either azathioprine or methotrexate in the combination treatment group, but did not specify the proportion receiving each drug. Overall combination therapy with infliximab plus an immunosuppressant was not associated with a benefit over infliximab alone in preventing loss of response over the 1-year follow-up. 146 Similarly, in the RCT assessing adalimumab in pediatric patients (IMAgINE-1), >60% of patients received immunosuppressants; however, the proportion receiving methotrexate was not reported, and a post-hoc analysis did not demonstrate a difference in remission rates between those who received concomitant immunosuppressants and those who did not. 132,150 All pediatric patients in the REACH study received e54
The CPG is not intended to be a substitute for physicians using their individual judgment in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available, and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.
# Supplementary Material
Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at https://doi.org/10.1053/j. gastro.2019.03.022.
# Reprint requests
# Conflicts of interest
These authors disclose the following: EIB participated in an advisory board for AbbVie but did not receive compensation for participation, financial or otherwise. JC has served on advisory boards for Janssen, and consulted for Nestle Health Sciences. JD has served on advisory boards for AbbVie and Janssen, received research support from Janssen, and participated in speaker's bureaus for AbbVie and Janssen. PM has served on advisory boards for Allergan and Shire, received research support from Takeda, and participated in speaker's bureaus for AbbVie and Allergan. PC has served on advisory boards for Janssen, and participated in speaker's bureaus for AbbVie and Janssen. CD has served on advisory boards for AbbVie and Janssen and has participated as a speaker/moderator for both companies, though not part of a speaker's bureau. WE has served on advisory boards for AbbVie and Janssen, and received research support from Janssen. HH has served on advisory boards for AbbVie and Janssen, and received research support from AbbVie, Allergan, and Janssen. PJ has served on advisory boards for Ferring. AO has served on advisory boards for AbbVie and Janssen, and received research support from AbbVie, Astellas, Janssen, and Shire. MS has served on advisory boards for AbbVie and Janssen. TW has served on advisory boards for AbbVie and Janssen, received research support from AbbVie, and participated in speaker's bureaus for AbbVie, Janssen, and Nestle Health Sciences. MK has consulted for AbbVie, GlaxoSmithKline, and Janssen, received research support from AbbVie and Janssen, participated in speaker's bureaus for AbbVie, and has owned stock in GlaxoSmithKline and Janssen. JM has served on advisory boards for AbbVie, Allergan, AstraZeneca, Boehringer-Ingelheim, Celgene, Celltrion, Ferring, Hospira, Janssen, Merck, Proctor & Gamble, Pfizer, Pharmascience, Shire, and Takeda, and participated in speaker's bureaus for AbbVie, Allergan, Ferring, Janssen, Proctor & Gamble, Shire, and Takeda. AG has served on advisory boards for AbbVie, Janssen, Celgene, Ferring, Pfizer, Gilead, and Lilly, received research support from AbbVie, and participated in speaker's bureaus for AbbVie and Janssen. The remaining authors disclose no conflicts.
# Funding
This guideline was supported through unrestricted grants to the Canadian Association of Gastroenterology by AbbVie and Takeda Canada, which had no involvement in any aspect of the guideline development or manuscript preparation. In addition, | None | None |
703c43477a7ff26311bb62d4ae24f4cb1cc2ac9e | cma | None | This document provides COVID-19 vaccine guidance for adults and children with metabolically unstable inborn errors of metabolism (IEM) including: urea cycle defects, methylmalonic aciduria, propionic acidemia, glutaric aciduria, and maple syrup urine disease. Patients with other rare IEM may also be determined to be metabolically unstable by British Columbia adult and pediatric experts.#
Is COVID-19 immunization recommended for people with metabolically unstable inborn errors of metabolism?
COVID-19 vaccines should be encouraged for patients with IEM and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
- IEM may place a patient at increased risk of complications if they develop intercurrent illness including COVID-19. No data have been published addressing the impact of COVID-19 on most of these disorders; however, a single case report 1 documents that COVID-19 can be a trigger for metabolic decompensation as other viral and bacterial infections. - Infection may lead to severe complications including metabolic stroke and this phenomenon is well-documented in other viruses including influenza. 2 - Although data are sparse on immune function in these rare conditions, one study did suggest that some patients with IEM are more prone to unusual infections, which suggests a suppressive effect of the condition on global immune function. 3 - Metabolic decompensation is very rapid and patients can progress from being well to critical state in a matter of hours. The consequences of metabolic decompensation in these disorders are severe and include cerebral edema, coma and death. - Also, some of the disorders may be associated with chronic kidney disease which puts the patients at higher risk of severe disease and mortality from COVID-19. 4 - The European Reference Network recommends that patients with IEM should be immunized against COVID-19. 5 While data specific to the safety and efficacy of COVID-19 vaccines for people with inborn errors of metabolism is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 6 The authors of this guidance agree that the benefits of vaccine induced immunity against COVID-19 for this population outweigh any theoretical risks of immunization.
Is COVID-19 immunization efficacious and safe for people with metabolically unstable inborn errors of metabolism?
As IEM are considered to be severe underlying medical diseases, people with these conditions were excluded from the COVID-19 vaccine clinical trials. Therefore, it is unknown if the currently available COVID-19 vaccines are as efficacious for patients with IEM as they were found to be for the clinical trial participants. There is nothing from a disease or treatment perspective pertinent to IEM to suggest that the vaccines would be less efficacious or safe for people with IEM than they are for the general population.
The COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna) vaccines are not live vaccines, and the VAXZEVRIA (AstraZeneca) vaccine is a replication-defective adenovirus vaccine and does not pose a risk of precipitating metabolic decompensation. Given that intercurrent systemic infections are a known precipitant of decompensation in patients with IEM, an event with life threatening consequences, the benefits of immunization are expected to be similar to the general population.
# Are there any specific contraindications or exceptions for patients with metabolically unstable inborn errors of metabolism?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 7 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Other than allergy, there are no specific contraindications or exceptions for people with IEM. COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. Are there specific recommendations or considerations for safe and/or most effective administration?
Patients who are experiencing a disease flare-up on the day of their vaccine appointment should cancel the appointment and re-book when their condition has stabilized. No additional precautions are required for safe or effective administration in this population.
# Authors
Dr. Sandra Sirrs, Clinical Professor, Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver General Hospital | This document provides COVID-19 vaccine guidance for adults and children with metabolically unstable inborn errors of metabolism (IEM) including: urea cycle defects, methylmalonic aciduria, propionic acidemia, glutaric aciduria, and maple syrup urine disease. Patients with other rare IEM may also be determined to be metabolically unstable by British Columbia adult and pediatric experts.#
Is COVID-19 immunization recommended for people with metabolically unstable inborn errors of metabolism?
COVID-19 vaccines should be encouraged for patients with IEM and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
• IEM may place a patient at increased risk of complications if they develop intercurrent illness including COVID-19. No data have been published addressing the impact of COVID-19 on most of these disorders; however, a single case report 1 documents that COVID-19 can be a trigger for metabolic decompensation as other viral and bacterial infections. • Infection may lead to severe complications including metabolic stroke and this phenomenon is well-documented in other viruses including influenza. 2 • Although data are sparse on immune function in these rare conditions, one study did suggest that some patients with IEM are more prone to unusual infections, which suggests a suppressive effect of the condition on global immune function. 3 • Metabolic decompensation is very rapid and patients can progress from being well to critical state in a matter of hours. The consequences of metabolic decompensation in these disorders are severe and include cerebral edema, coma and death. • Also, some of the disorders may be associated with chronic kidney disease which puts the patients at higher risk of severe disease and mortality from COVID-19. 4 • The European Reference Network recommends that patients with IEM should be immunized against COVID-19. 5 While data specific to the safety and efficacy of COVID-19 vaccines for people with inborn errors of metabolism is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 6 The authors of this guidance agree that the benefits of vaccine induced immunity against COVID-19 for this population outweigh any theoretical risks of immunization.
Is COVID-19 immunization efficacious and safe for people with metabolically unstable inborn errors of metabolism?
As IEM are considered to be severe underlying medical diseases, people with these conditions were excluded from the COVID-19 vaccine clinical trials. Therefore, it is unknown if the currently available COVID-19 vaccines are as efficacious for patients with IEM as they were found to be for the clinical trial participants. There is nothing from a disease or treatment perspective pertinent to IEM to suggest that the vaccines would be less efficacious or safe for people with IEM than they are for the general population.
The COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna) vaccines are not live vaccines, and the VAXZEVRIA (AstraZeneca) vaccine is a replication-defective adenovirus vaccine and does not pose a risk of precipitating metabolic decompensation. Given that intercurrent systemic infections are a known precipitant of decompensation in patients with IEM, an event with life threatening consequences, the benefits of immunization are expected to be similar to the general population.
# Are there any specific contraindications or exceptions for patients with metabolically unstable inborn errors of metabolism?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 7 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Other than allergy, there are no specific contraindications or exceptions for people with IEM. COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. [8][9][10][11] Are there specific recommendations or considerations for safe and/or most effective administration?
Patients who are experiencing a disease flare-up on the day of their vaccine appointment should cancel the appointment and re-book when their condition has stabilized. No additional precautions are required for safe or effective administration in this population.
# Authors
Dr. Sandra Sirrs, Clinical Professor, Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver General Hospital | None | None |
f56aba9cd35cc4d479f8a059ce38e652a354bdf1 | cma | None | # Imvamune® Vaccine
Imvamune® is a live attenuated, non-replicating vaccine that is approved in Canada for protection against smallpox, mpox, and other orthopoxvirus related illness; it is 3rd generation smallpox vaccine. It is produced from the Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) strain of orthopoxvirus and was developed to provide an alternative for the vaccination of immunocompromised individuals and those with atopic dermatitis, who could not safely receive earlier generation (replicating) smallpox vaccines.
Health Canada first approved the use of this vaccine for active immunization against smallpox in a public health emergency in 2013. In 2020, Health Canada expanded approval of Imvamune® to include additional indications, specifically for mpox and related orthopoxvirus infections in adults 18 years of age and older at high risk of exposure. The use of Imvamune® has not been studied in individuals less than 18 years of age or in those who are pregnant or breastfeeding.
Imvamune® can be used as post exposure prophylaxis (PEP) in individuals with a recent high-risk mpox exposure. This is based on evidence extrapolated from animal studies and historical experience with smallpox vaccine in humans which suggest that vaccination after an exposure to mpox infection may prevent infection or lessen disease severity in those who become infected.
Individuals with signs or symptoms of mpox infection should not receive the vaccine as the vaccine is not indicated in the treatment of mpox infection.
# Use of Imvamune® in Ontario
Given the current epidemiology in Ontario, Imvamune® should be offered as a two-dose primary series, with at least 28 days between first and second doses for individuals currently eligible for pre-exposure or post-exposure vaccination.
A full dose, 0.5ml of Imvamune®, should be given via the subcutaneous (SC) route for each dose. This approach will continue to be evaluated with any changes in the epidemiology and evidence surrounding the vaccine.
Imvamune® should be considered for the following:
- Pre-exposure vaccination -when Imvamune® is administered before known exposure to the virus
- Post-exposure vaccination -when Imvamune® is administered for individuals who have had a high-risk exposure to a probable or confirmed case of mpox, or within a setting where transmission is happening.
1) For the Purposes of Pre-Exposure Vaccination a) Two-spirit, non-binary, transgender cisgender, intersex, or gender-queer individuals who self-identify or have sexual partners who self-identify as belonging to the gay, bisexual, pansexual and other men who have sex with men (gbMSM) community AND at least one of the following:
- Had a confirmed sexually transmitted infection within the last year
- Have or are planning to have two or more sexual partners or are in a relationship where at least one of the partners may have other sexual partners,
- Have attended venues for sexual contact (i.e., bath houses, sex clubs) recently or may be planning to, or who work/volunteer in these settings; or
- Have had anonymous sex (e.g., using hookup apps) recently or may be planning to; and/or
- Are a sexual contact of an individual who engages in sex work.
b) Individuals who self-identify as engaging in sex work or are planning to, regardless of self-identified sex or gender.
Household and/or sexual contacts of those identified for pre-exposure vaccination eligibility in parts (a) and (b) above AND who are moderately to severely immunocompromised (see Appendix A) or pregnant may be at higher risk for severe illness from a mpox infection may be considered for pre-exposure vaccine and should contact their healthcare provider (or their local public health unit) for more information. Also see relevant sections under "Special Populations" for additional considerations.
# 2) For the Purposes of Post-Exposure Vaccination throughout Ontario
The provision of Imvamune® for post-exposure vaccination requires an assessment of the risk of exposure by the public health unit. If the identified person has a risk of potential exposure that is expected to continue beyond 28 days following the first 0.5mL SC dose, a second dose , 0.5mL SC, should be offered.
The first dose should be offered ideally within 4 days (up to 14 days) from the date of the last exposure to individuals who are a high risk contact of a confirmed or probable case of mpox. The second dose should be offered at least 28 days after the first dose.
Anyone who self-identifies as a high risk contact of a confirmed or probable case of mpox should contact their local public health unit for further assessment to see if post-exposure vaccination would be recommended.
Intermediate risk contacts may also be offered post-exposure vaccination, following the public health unit's assessment of individual risks and benefits (i.e., to balance the risks from exposure, protection from vaccination and potential side effects from the vaccine).
Post-exposure vaccination is not recommended for low-risk contacts including health care workers (see Table 1).
# Special Populations
# Individuals with History of Previous Smallpox Vaccine
Individuals eligible for Imvamune® as pre-exposure vaccination or post-exposure vaccination who previously received either an older generation replicating (live) smallpox vaccine or Imvamune® can be re-vaccinated:
- For individuals with a history of receiving 1 dose of a live smallpox vaccine, a single dose of Imvamune® is recommended.
- For individuals who completed a 2-dose series of Imvamune® more than 2 years ago, a single booster dose of Imvamune® is recommended.
- For individuals who completed a 2-dose series of Imvamune® within the last 2 years, no further doses are recommended.
# Individuals Who have had Previous Mpox Infection
At this time, individuals who have been diagnosed as a confirmed case of mpox in the current outbreak are NOT recommended to receive the mpox vaccine; this is based on the limited utility of the vaccine given that these persons are expected to have infection-mediated immunity due to recent infection. This recommendation is based on current evidence and may change as more information becomes available.
# Research Laboratory Employees
Research laboratory employees working directly with replicating orthopoxviruses, are eligible to receive two doses of Imvamune® at least 28 days apart as postexposure vaccination or pre-exposure vaccination if there is an ongoing risk of exposure.
# Moderately to Severely Immunocompromised
Individuals who are moderately to severely immunocompromised and are currently eligible for pre-exposure vaccination should receive two doses of the Imvamune® vaccine administered at the recommended interval. Please refer to:
- Appendix A for the definition of moderate to severe immunocompromise; and
- Appendix B for guidance on how to verify eligibility in this population.
Clinical trials of Imvamune® have included people living with human immunodeficiency virus (HIV) with a CD4 count of equal or greater than 100. There is less experience in individuals with severe immunosuppression. Additional risk/benefit discussion is indicated for those with severe immunosuppression prior to receiving vaccine as post-exposure vaccination.
# Allergy/Hypersensitivity
- Individuals who are hypersensitive to this vaccine or to any ingredient in the formulation or component of the container should not receive the vaccine. A list of ingredients can be found in the product monograph.
- Note: Imvamune® may contain trace amounts of antibiotics (gentamicin and ciprofloxacin) and egg products (egg cell DNA and protein) which are used during the vaccine production process. Individuals with known hypersensitivity to these products are still able to safely receive Imvamune® but should be monitored for an additional 15 minutes (30 minutes total) after vaccine administration.
# Pregnancy and Breastfeeding
- There are very limited data on the use of Imvamune® in pregnancy. No clinical trials have been conducted in pregnant individuals, although approximately 300 pregnancies have been reported to the manufacturer with no safety issues identified.
- There are no data on whether the vaccine is excreted in breastmilk, although this is unlikely as the vaccine is non-replicating.
- Additional risk/benefit discussion is indicated for those who are pregnant or breastfeeding prior to receiving vaccine as post-exposure vaccination.
# Children and Youth
- Imvamune® vaccine is not authorized for use in persons under 18 years of age, and has not been studied in this age group, although it has been offered
to children as PEP in previous United Kingdom mpox incidents as cited in UK PEP guidance. Clinical trials have studied other vaccines (TB and malaria)
using Modified Vaccinia Ankara (MVA) as a vector in children with a reassuring safety profile.
- Additional risk/benefit discussion is indicated for persons under 18 years of age prior to receiving vaccine as post-exposure vaccination. For the process of setting up infectious disease consults for mpox post-exposure vaccination in pediatric populations, please refer to Appendix C.
# Persons with Atopic Dermatitis
- Persons with atopic dermatitis may have more frequent and more intense reactions after vaccination. This population was specifically studied in clinical trials as those with a history or presence of atopic dermatitis are contraindicated to receive the previous generation of smallpox vaccine (ACAM2000).
# Potential Side Effects of Imvamune®
The most common side effects include reactions at the injection site like pain, erythema, induration and swelling. The most common systemic reactions observed after vaccination are fatigue, headache, myalgia, and nausea. Most of the reported adverse drug reactions observed in clinical trials were of mild to moderate intensity and resolved within the first seven days following vaccination.
Older generation (i.e., replicating) smallpox vaccines have been associated with myocarditis. No case of myocarditis or pericarditis was identified in clinical trials of Imvamune®, however post market surveillance of vaccine recipients identified cardiac adverse events of special interest (AESIs) including asymptomatic troponin elevation, abnormal ECG findings, tachycardia, and palpitations. Cardiac AESIs were reported to occur in 1.4% (91/6,640) of Imvamune® recipients and 0.2% (3/1,206) of placebo recipients who were smallpox vaccine-naïve. Individuals should be counselled to seek medical attention if cardiac symptoms (i.e., chest pain, shortness of breath, palpitations) develop following vaccination with Imvamune®.
# Informed Consent
The Health Care Consent Act, 1996 provides specific information as to the consent required for treatment. According to the HCCA, and the College of Nurses of Ontario (CNO) and College of Physicians and Surgeons of Ontario (CPSO) standards, nurses and physicians are accountable for obtaining consent when providing treatment. It is therefore the responsibility of the health practitioner who is proposing the treatment to take reasonable steps to ensure that informed consent for that treatment is obtained.
According to the HCCA, consent to treatment for a capable person is informed if, before giving the consent:
a. the person received the information about the treatment that a reasonable person in the same circumstances would require to make a decision; and b. the person received responses to his/her requests for additional information about the treatment.
# This information must include:
- The nature of the treatment
- The expected benefits of the treatment
- The material risks of the treatment
- The material side effects of the treatment
- Alternative courses of action
- The likely consequences of not having the treatment.
The elements required for consent to treatment include:
- The client must have the capacity to consent
- The consent must relate to the treatment
- The consent must be informed
- The consent must be given voluntarily
- The consent must not be obtained through misrepresentation or fraud.
# Evidence of Consent:
Although the HCCA states that consent to treatment may be expressed or implied (i.e., written or verbal), the CNO and CPSO strongly advise nurses and physicians to document that consent was obtained from the client. Examples include: 1) a signed consent form and/or 2) documented consent in the client's health records.
# How to order Imvamune®
To order the vaccine, the local public health unit must complete this electronic form. Please contact the Vaccine Policy & Programs Branch at [email protected] for any questions.
Clinicians who think they have a patient (i.e., a contact of a case) who might be recommended to receive post-exposure vaccination using the criteria above should contact their local public health unit.
# Co-Administration of Imvamune®
Interactions with Imvamune® and other vaccines have not been established. If vaccine timing can be planned, it is recommended to wait at least 4 weeks for live vaccines (or COVID-19 vaccines) or 2 weeks for inactive vaccines before or after administration of Imvamune®. These suggested waiting periods are precautionary but may help prevent erronerous attribution of an AEFI to one particular vaccine or the other.
However, the administration of Imvamune® as pre-or post-exposure vaccination should not be delayed in an individual who has recently received another vaccine. If vaccines must be co-administered, immunization on separate limbs is recommended to minimize the risk of interaction.
# Storage Conditions
Please see mpox Virus (gov.on.ca) for information on storing and handling Imvamune®. - For guidance on the timing of vaccine administration for transplant recipients and those requiring immunosuppressive therapies, a more comprehensive list of conditions leading to primary immunodeficiency, and for further information on immunosuppressive therapies, refer to Immunization of Immunocompromised Persons in the Canadian Immunization Guide (CIG), Part 3 -Vaccination of Specific Populations.
# Reporting Adverse Events Following Immunization
# Table 2. List of Significantly Immunosuppressive Medications
The table below lists many of the common immunosuppressive medications used in Ontario, but it is not an exhaustive list. If an individual is receiving an immunosuppressive biologic agent and they do not have a prescription, or their medication is not listed below, they can receive a referral form/letter indicating their eligibility due to their immunocompromised status from their health care provider to receive a second dose of the Imvamune® vaccine.
Vaccine providers can refer to Appendix B for guidance on how to verify eligibility.
# Class Generic Name(s) Brand Name(s)
Steroids (>20 mg per day of prednisone or equivalent for at least 2 weeks)
- prednisone
- dexamethasone - Decadron - methylprednisolone - DepoMedrol - SoluMedrol - Medrol
# Roles and Responsibilities
# PHUs
- Proactively develop internal processes and resources as part of their local mpox response. This includes:
- Resources for staff to provide appropriate counseling to individuals identified as contacts of a known mpox case and/or their guardians about PEP with Imvamune® (e.g., risks and benefits of receiving PEP).
- Identifying local pediatric specialist(s) as well as determining the threshold or indications for triggering a pediatric consult for clinical advice and/or support in vaccine administration.
- Where pediatric specialists are not available locally, PHUs should reach out to their regional tertiary pediatric hospital and consult ID (e.g., HSC).
- A process to ensure timely transportation of Imvamune® if requesting an external provider (e.g., a local pediatrician) to support vaccine administration.
- Conduct exposure risk assessment of all contacts of a known/confirmed or suspected case of mpox.
- Obtain and provide the following information when consulting a pediatric specialist: o Clinical question/request (e.g., provide guidance to PHU on counseling, provide direct counseling to parents, request for vaccine administration etc.); and o Contact information for parent/guardian.
# Ministry of Health
- Provide and communicate provincial level guidance on mpox related policies to PHUs, including the establishment of an eligibility criteria for Imvamune® for use of mpox PEP.
# Public Health Ontario (PHO)
- Provide technical and scientific support to PHUs on public health aspects of mpox case and contact management, including questions on:
- Exposure risk assessment o Scientific evidence for Imvamune®
# Pediatric specialist(s)
- Provide guidance/support to PHU when consulted on clinical questions relating to mpox, including the administration of Imvamune®, in pediatric populations.
- When requested by PHU, provide direct counseling to the contact and/or their parents/guardians about the risks and benefits of Imvamune® PEP.
- When requested by PHU, support Imvamune® administration in a child as indicated.
# Appendix A
Moderately to severely immunocompromised is defined as:
- Individuals receiving dialysis (hemodialysis or peritoneal dialysis)
- Individuals receiving active treatment 2 (e.g., chemotherapy, targeted therapies, immunotherapy) for solid tumour or hematologic malignancies
- Recipients of solid-organ transplant and taking immunosuppressive therapy
- Recipients of chimeric antigen receptor (CAR)-T-cell therapy or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy)
- Individuals with moderate to severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome)
- Individuals with HIV with current CD4 count ≤ 200/mm3 or CD4 fraction ≤ 15% or detectable viral load (i.e., not suppressed)
- Individuals receiving active treatment with the following categories of immunosuppressive therapies: anti-B cell therapies 3 (monoclonal antibodies targeting CD19, CD20 and CD22), high-dose systemic corticosteroids (refer to the Canadian Immunization Guide for suggested definition of high dose steroids), alkylating agents, antimetabolites, or tumor-necrosis factor (TNF) inhibitors and other biologic agents that are significantly immunosuppressive (See Table 2).
# Class Generic Name(s) Brand Name(s)
# Class Generic Name(s) Brand Name(s)
Anti-TNF (tumor necrosis factor)
# Appendix B Clinic Guide to Verifying Immunosuppressive Prescriptions for Imvamune® Eligibility
The following information is guidance for vaccination clinics administering Imvamune® to individuals receiving immunosuppressive therapies who present a prescription of their medication (see Appendix A).
Step 1: Verify Prescription Details
- The individual should present a current prescription receipt from a pharmacy, or present a current medication bottle/package that includes the following information:
- Date of prescription To be considered current, the prescription should be prescribed or refilled within the past 6 months.
Active treatment for patients receiving B-cell depleting therapies (monoclonal antibodies targeting CD19, CD20 and CD22) includes patients who have completed treatment within 12 months.
- Patients first and last name The first and last name should be compared to a piece of identification.
- Address and telephone number of the pharmacy
Step 2: Cross-Reference Drug Name
- Confirm that the drug name is listed in Table 2.
- Table 2 provides a list of immunosuppressive medications that qualifies individuals to receive Imvamune®.
- This list may not be comprehensive. If an individual presents a prescription of a medication that is not listed in Table 2, they should be directed to their healthcare provider to receive a referral form/letter for a second dose of Imvamune®
Step 3: Administer Vaccine | # Imvamune® Vaccine
Imvamune® is a live attenuated, non-replicating vaccine that is approved in Canada for protection against smallpox, mpox, and other orthopoxvirus related illness; it is 3rd generation smallpox vaccine. It is produced from the Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) strain of orthopoxvirus and was developed to provide an alternative for the vaccination of immunocompromised individuals and those with atopic dermatitis, who could not safely receive earlier generation (replicating) smallpox vaccines.
Health Canada first approved the use of this vaccine for active immunization against smallpox in a public health emergency in 2013. In 2020, Health Canada expanded approval of Imvamune® to include additional indications, specifically for mpox and related orthopoxvirus infections in adults 18 years of age and older at high risk of exposure. The use of Imvamune® has not been studied in individuals less than 18 years of age or in those who are pregnant or breastfeeding.
Imvamune® can be used as post exposure prophylaxis (PEP) in individuals with a recent high-risk mpox exposure. This is based on evidence extrapolated from animal studies and historical experience with smallpox vaccine in humans which suggest that vaccination after an exposure to mpox infection may prevent infection or lessen disease severity in those who become infected.
Individuals with signs or symptoms of mpox infection should not receive the vaccine as the vaccine is not indicated in the treatment of mpox infection.
# Use of Imvamune® in Ontario
Given the current epidemiology in Ontario, Imvamune® should be offered as a two-dose primary series, with at least 28 days between first and second doses for individuals currently eligible for pre-exposure or post-exposure vaccination.
A full dose, 0.5ml of Imvamune®, should be given via the subcutaneous (SC) route for each dose. This approach will continue to be evaluated with any changes in the epidemiology and evidence surrounding the vaccine.
Imvamune® should be considered for the following:
• Pre-exposure vaccination -when Imvamune® is administered before known exposure to the virus
• Post-exposure vaccination -when Imvamune® is administered for individuals who have had a high-risk exposure to a probable or confirmed case of mpox, or within a setting where transmission is happening.
1) For the Purposes of Pre-Exposure Vaccination a) Two-spirit, non-binary, transgender cisgender, intersex, or gender-queer individuals who self-identify or have sexual partners who self-identify as belonging to the gay, bisexual, pansexual and other men who have sex with men (gbMSM) community AND at least one of the following:
• Had a confirmed sexually transmitted infection within the last year
• Have or are planning to have two or more sexual partners or are in a relationship where at least one of the partners may have other sexual partners,
• Have attended venues for sexual contact (i.e., bath houses, sex clubs) recently or may be planning to, or who work/volunteer in these settings; or
• Have had anonymous sex (e.g., using hookup apps) recently or may be planning to; and/or
• Are a sexual contact of an individual who engages in sex work.
b) Individuals who self-identify as engaging in sex work or are planning to, regardless of self-identified sex or gender.
Household and/or sexual contacts of those identified for pre-exposure vaccination eligibility in parts (a) and (b) above AND who are moderately to severely immunocompromised (see Appendix A) or pregnant may be at higher risk for severe illness from a mpox infection may be considered for pre-exposure vaccine and should contact their healthcare provider (or their local public health unit) for more information. Also see relevant sections under "Special Populations" for additional considerations.
# 2) For the Purposes of Post-Exposure Vaccination throughout Ontario
The provision of Imvamune® for post-exposure vaccination requires an assessment of the risk of exposure by the public health unit. If the identified person has a risk of potential exposure that is expected to continue beyond 28 days following the first 0.5mL SC dose, a second dose , 0.5mL SC, should be offered.
The first dose should be offered ideally within 4 days (up to 14 days) from the date of the last exposure to individuals who are a high risk contact of a confirmed or probable case of mpox. The second dose should be offered at least 28 days after the first dose.
Anyone who self-identifies as a high risk contact of a confirmed or probable case of mpox should contact their local public health unit for further assessment to see if post-exposure vaccination would be recommended.
Intermediate risk contacts may also be offered post-exposure vaccination, following the public health unit's assessment of individual risks and benefits (i.e., to balance the risks from exposure, protection from vaccination and potential side effects from the vaccine).
Post-exposure vaccination is not recommended for low-risk contacts including health care workers (see Table 1).
# Special Populations
# Individuals with History of Previous Smallpox Vaccine
Individuals eligible for Imvamune® as pre-exposure vaccination or post-exposure vaccination who previously received either an older generation replicating (live) smallpox vaccine or Imvamune® can be re-vaccinated:
• For individuals with a history of receiving 1 dose of a live smallpox vaccine, a single dose of Imvamune® is recommended.
• For individuals who completed a 2-dose series of Imvamune® more than 2 years ago, a single booster dose of Imvamune® is recommended.
• For individuals who completed a 2-dose series of Imvamune® within the last 2 years, no further doses are recommended.
# Individuals Who have had Previous Mpox Infection
At this time, individuals who have been diagnosed as a confirmed case of mpox in the current outbreak are NOT recommended to receive the mpox vaccine; this is based on the limited utility of the vaccine given that these persons are expected to have infection-mediated immunity due to recent infection. This recommendation is based on current evidence and may change as more information becomes available.
# Research Laboratory Employees
Research laboratory employees working directly with replicating orthopoxviruses, are eligible to receive two doses of Imvamune® at least 28 days apart as postexposure vaccination or pre-exposure vaccination if there is an ongoing risk of exposure.
# Moderately to Severely Immunocompromised
Individuals who are moderately to severely immunocompromised and are currently eligible for pre-exposure vaccination should receive two doses of the Imvamune® vaccine administered at the recommended interval. Please refer to:
• Appendix A for the definition of moderate to severe immunocompromise; and
• Appendix B for guidance on how to verify eligibility in this population.
Clinical trials of Imvamune® have included people living with human immunodeficiency virus (HIV) with a CD4 count of equal or greater than 100. There is less experience in individuals with severe immunosuppression. Additional risk/benefit discussion is indicated for those with severe immunosuppression prior to receiving vaccine as post-exposure vaccination.
# Allergy/Hypersensitivity
• Individuals who are hypersensitive to this vaccine or to any ingredient in the formulation or component of the container should not receive the vaccine. A list of ingredients can be found in the product monograph.
• Note: Imvamune® may contain trace amounts of antibiotics (gentamicin and ciprofloxacin) and egg products (egg cell DNA and protein) which are used during the vaccine production process. Individuals with known hypersensitivity to these products are still able to safely receive Imvamune® but should be monitored for an additional 15 minutes (30 minutes total) after vaccine administration.
# Pregnancy and Breastfeeding
• There are very limited data on the use of Imvamune® in pregnancy. No clinical trials have been conducted in pregnant individuals, although approximately 300 pregnancies have been reported to the manufacturer with no safety issues identified.
• There are no data on whether the vaccine is excreted in breastmilk, although this is unlikely as the vaccine is non-replicating.
• Additional risk/benefit discussion is indicated for those who are pregnant or breastfeeding prior to receiving vaccine as post-exposure vaccination.
# Children and Youth
• Imvamune® vaccine is not authorized for use in persons under 18 years of age, and has not been studied in this age group, although it has been offered
to children as PEP in previous United Kingdom mpox incidents as cited in UK PEP guidance. Clinical trials have studied other vaccines (TB and malaria)
using Modified Vaccinia Ankara (MVA) as a vector in children with a reassuring safety profile.
• Additional risk/benefit discussion is indicated for persons under 18 years of age prior to receiving vaccine as post-exposure vaccination. For the process of setting up infectious disease consults for mpox post-exposure vaccination in pediatric populations, please refer to Appendix C.
# Persons with Atopic Dermatitis
• Persons with atopic dermatitis may have more frequent and more intense reactions after vaccination. This population was specifically studied in clinical trials as those with a history or presence of atopic dermatitis are contraindicated to receive the previous generation of smallpox vaccine (ACAM2000).
# Potential Side Effects of Imvamune®
The most common side effects include reactions at the injection site like pain, erythema, induration and swelling. The most common systemic reactions observed after vaccination are fatigue, headache, myalgia, and nausea. Most of the reported adverse drug reactions observed in clinical trials were of mild to moderate intensity and resolved within the first seven days following vaccination.
Older generation (i.e., replicating) smallpox vaccines have been associated with myocarditis. No case of myocarditis or pericarditis was identified in clinical trials of Imvamune®, however post market surveillance of vaccine recipients identified cardiac adverse events of special interest (AESIs) including asymptomatic troponin elevation, abnormal ECG findings, tachycardia, and palpitations. Cardiac AESIs were reported to occur in 1.4% (91/6,640) of Imvamune® recipients and 0.2% (3/1,206) of placebo recipients who were smallpox vaccine-naïve. Individuals should be counselled to seek medical attention if cardiac symptoms (i.e., chest pain, shortness of breath, palpitations) develop following vaccination with Imvamune®.
# Informed Consent
The Health Care Consent Act, 1996 provides specific information as to the consent required for treatment. According to the HCCA, and the College of Nurses of Ontario (CNO) and College of Physicians and Surgeons of Ontario (CPSO) standards, nurses and physicians are accountable for obtaining consent when providing treatment. It is therefore the responsibility of the health practitioner who is proposing the treatment to take reasonable steps to ensure that informed consent for that treatment is obtained.
According to the HCCA, consent to treatment for a capable person is informed if, before giving the consent:
a. the person received the information about the treatment that a reasonable person in the same circumstances would require to make a decision; and b. the person received responses to his/her requests for additional information about the treatment.
# This information must include:
• The nature of the treatment
• The expected benefits of the treatment
• The material risks of the treatment
• The material side effects of the treatment
• Alternative courses of action
• The likely consequences of not having the treatment.
The elements required for consent to treatment include:
• The client must have the capacity to consent
• The consent must relate to the treatment
• The consent must be informed
• The consent must be given voluntarily
• The consent must not be obtained through misrepresentation or fraud.
# Evidence of Consent:
Although the HCCA states that consent to treatment may be expressed or implied (i.e., written or verbal), the CNO and CPSO strongly advise nurses and physicians to document that consent was obtained from the client. Examples include: 1) a signed consent form and/or 2) documented consent in the client's health records.
# How to order Imvamune®
To order the vaccine, the local public health unit must complete this electronic form. Please contact the Vaccine Policy & Programs Branch at [email protected] for any questions.
Clinicians who think they have a patient (i.e., a contact of a case) who might be recommended to receive post-exposure vaccination using the criteria above should contact their local public health unit.
# Co-Administration of Imvamune®
Interactions with Imvamune® and other vaccines have not been established. If vaccine timing can be planned, it is recommended to wait at least 4 weeks for live vaccines (or COVID-19 vaccines) or 2 weeks for inactive vaccines before or after administration of Imvamune®. These suggested waiting periods are precautionary but may help prevent erronerous attribution of an AEFI to one particular vaccine or the other.
However, the administration of Imvamune® as pre-or post-exposure vaccination should not be delayed in an individual who has recently received another vaccine. If vaccines must be co-administered, immunization on separate limbs is recommended to minimize the risk of interaction.
# Storage Conditions
Please see mpox Virus (gov.on.ca) for information on storing and handling Imvamune®. • For guidance on the timing of vaccine administration for transplant recipients and those requiring immunosuppressive therapies, a more comprehensive list of conditions leading to primary immunodeficiency, and for further information on immunosuppressive therapies, refer to Immunization of Immunocompromised Persons in the Canadian Immunization Guide (CIG), Part 3 -Vaccination of Specific Populations.
# Reporting Adverse Events Following Immunization
# Table 2. List of Significantly Immunosuppressive Medications
The table below lists many of the common immunosuppressive medications used in Ontario, but it is not an exhaustive list. If an individual is receiving an immunosuppressive biologic agent and they do not have a prescription, or their medication is not listed below, they can receive a referral form/letter indicating their eligibility due to their immunocompromised status from their health care provider to receive a second dose of the Imvamune® vaccine.
Vaccine providers can refer to Appendix B for guidance on how to verify eligibility.
# Class Generic Name(s) Brand Name(s)
Steroids (>20 mg per day of prednisone or equivalent for at least 2 weeks)
• prednisone
• dexamethasone • Decadron • methylprednisolone • DepoMedrol • SoluMedrol • Medrol
# Roles and Responsibilities
# PHUs
• Proactively develop internal processes and resources as part of their local mpox response. This includes:
o Resources for staff to provide appropriate counseling to individuals identified as contacts of a known mpox case and/or their guardians about PEP with Imvamune® (e.g., risks and benefits of receiving PEP).
o Identifying local pediatric specialist(s) as well as determining the threshold or indications for triggering a pediatric consult for clinical advice and/or support in vaccine administration.
o Where pediatric specialists are not available locally, PHUs should reach out to their regional tertiary pediatric hospital and consult ID (e.g., HSC).
o A process to ensure timely transportation of Imvamune® if requesting an external provider (e.g., a local pediatrician) to support vaccine administration.
• Conduct exposure risk assessment of all contacts of a known/confirmed or suspected case of mpox.
• Obtain and provide the following information when consulting a pediatric specialist: o Clinical question/request (e.g., provide guidance to PHU on counseling, provide direct counseling to parents, request for vaccine administration etc.); and o Contact information for parent/guardian.
# Ministry of Health
• Provide and communicate provincial level guidance on mpox related policies to PHUs, including the establishment of an eligibility criteria for Imvamune® for use of mpox PEP.
# Public Health Ontario (PHO)
• Provide technical and scientific support to PHUs on public health aspects of mpox case and contact management, including questions on:
o Exposure risk assessment o Scientific evidence for Imvamune®
# Pediatric specialist(s)
• Provide guidance/support to PHU when consulted on clinical questions relating to mpox, including the administration of Imvamune®, in pediatric populations.
• When requested by PHU, provide direct counseling to the contact and/or their parents/guardians about the risks and benefits of Imvamune® PEP.
• When requested by PHU, support Imvamune® administration in a child as indicated.
# Appendix A
Moderately to severely immunocompromised is defined as:
• Individuals receiving dialysis (hemodialysis or peritoneal dialysis)
• Individuals receiving active treatment 2 (e.g., chemotherapy, targeted therapies, immunotherapy) for solid tumour or hematologic malignancies
• Recipients of solid-organ transplant and taking immunosuppressive therapy
• Recipients of chimeric antigen receptor (CAR)-T-cell therapy or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy)
• Individuals with moderate to severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome)
• Individuals with HIV with current CD4 count ≤ 200/mm3 or CD4 fraction ≤ 15% or detectable viral load (i.e., not suppressed)
• Individuals receiving active treatment with the following categories of immunosuppressive therapies: anti-B cell therapies 3 (monoclonal antibodies targeting CD19, CD20 and CD22), high-dose systemic corticosteroids (refer to the Canadian Immunization Guide for suggested definition of high dose steroids), alkylating agents, antimetabolites, or tumor-necrosis factor (TNF) inhibitors and other biologic agents that are significantly immunosuppressive (See Table 2).
# Class Generic Name(s) Brand Name(s)
# Class Generic Name(s) Brand Name(s)
Anti-TNF (tumor necrosis factor)
# Appendix B Clinic Guide to Verifying Immunosuppressive Prescriptions for Imvamune® Eligibility
The following information is guidance for vaccination clinics administering Imvamune® to individuals receiving immunosuppressive therapies who present a prescription of their medication (see Appendix A).
Step 1: Verify Prescription Details
• The individual should present a current prescription receipt from a pharmacy, or present a current medication bottle/package that includes the following information:
o Date of prescription To be considered current, the prescription should be prescribed or refilled within the past 6 months.
Active treatment for patients receiving B-cell depleting therapies (monoclonal antibodies targeting CD19, CD20 and CD22) includes patients who have completed treatment within 12 months.
o Patients first and last name The first and last name should be compared to a piece of identification.
o Address and telephone number of the pharmacy
Step 2: Cross-Reference Drug Name
• Confirm that the drug name is listed in Table 2.
• Table 2 provides a list of immunosuppressive medications that qualifies individuals to receive Imvamune®.
o This list may not be comprehensive. If an individual presents a prescription of a medication that is not listed in Table 2, they should be directed to their healthcare provider to receive a referral form/letter for a second dose of Imvamune®
Step 3: Administer Vaccine | None | None |
9ef3d0562d44280935defc9e77e727725cee206e | cma | None | The following are frequently asked questions about the COVID-19 vaccine and adult cancer patients. The information is: - related to the Pfizer (Comirnaty TM )and the Moderna (Spikevax TM ) COVID-19 vaccines that use mRNA technology - related to the AstraZeneca COVID-19- (Vaxzevria TM ) vaccine that uses non-replicating viral vectors (adenovirus) - current as of August 8, 2022 The information below may not be appropriate for all patients. Prescribers must determine whether adopting suggested COVID-19 vaccine information is clinically appropriate for individual patients through a risk-benefit assessment. Consult appropriate clinical prescribing guidelines and local institutional guidance for patient prioritization to inform treatment and vaccination decisions. Everyone should receive a COVID-19 vaccination, when available, unless contraindicated. See question 2 "What are the contraindications to the COVID-19 vaccines?" for more information. There are limitations to the current knowledge around the use of COVID-19 vaccines in the cancer population. The advice below is based on the best available evidence at this time. Guidance will be updated as more evidence becomes available. Patients should continue to practice recommended public health measures for prevention of COVID-19 infection regardless of vaccination status. - Note that COVISHIELD (manufactured by Serum Institute of India) and the AstraZeneca COVID-19 vaccine (manufactured by AstraZeneca) are ChAdOx1-S recombinant vaccines developed by AstraZeneca and the University of Oxford. Health Canada has reviewed the manufacturing information for these vaccines and found them to be comparable.COVID-19 vaccines use either conventional or novel mechanisms of action to safely elicit immune responses. Conventional platforms include recombinant viral proteins, live attenuated vaccines and inactivated vaccines, while novel methods include viral vector-based vaccines and mRNA-based vaccines. 8 #
The COVID-19 vaccine is safe for use in cancer patients. Studies demonstrate the safety profile of mRNA vaccines in the immunocompromised population, including patients with cancer, are comparable to what has been observed in the general population, with no unexpected or serious safety signals to date. 17,20 Additionally, prior experience with other protein-based or inactivated vaccines have not reported unique or major side effects in immunocompromised patients. 7 The most frequently reported side effects of COVID-19 vaccine candidates were usually mild or moderate and include pain at the site of injection, fatigue, headache, myalgias and fever (see question 9 below). Live attenuated vaccines carry the risk of disease caused by vaccine strains and are not recommended during and after immunosuppressive therapy (such as chemotherapy). 3 Currently, these are the vaccines available- for use in Ontario for active immunizations to prevent COVID-19:
- Pfizer COVID-19 mRNA vaccine (BNT162b2 or Comirnaty TM ) - Moderna COVID-19 mRNA vaccine (mRNA-1273 SARS-CoV-2 or Spikevax TM ) - AstraZeneca COVID-19 non-replicating adenovirus vaccine (AZD1222 or ChAdOx1-S recombinant or Vaxzevria TM ) - Other vaccines (e.g. Janssen, Novavax, Medicago) may also be available in limited supplies. Refer to the latest Ministry of Health guidance for the most up to date information as new vaccines become available.
The Pfizer, Modena and AstraZeneca vaccines are administered intramuscularly as a series of two doses. The recommended immunization schedules of the 2-dose COVID-19 vaccines are listed in Table 1. Additional dose(s) of an authorized mRNA COVID-19 vaccine are recommended in certain populations. 18,19 For details on a three-dose primary series of COVID-19 vaccine and booster doses, see question 7: Should additional doses of COVID-19 vaccine be considered in patients with cancer? While efforts should be made to vaccinate according to the authorized schedules as per individual vaccine product monographs or local public health guidelines, extended vaccination intervals may not be appropriate in certain patient populations, as described below. 13, 15 b A 12-week interval is preferred for the AstraZeneca COVID-19 vaccine based on available ad hoc analyses of the vaccine clinical trial interval data; efficacy may be lower if interval is less than 12 weeks, in the general population.
The following patient groups should receive the COVID-19 vaccine at the dose interval recommended by the manufacturers: 15 - Transplant recipients (including solid organ transplants and hematopoietic stem cell transplants).
- Patients receiving active treatment (chemotherapy, targeted therapies, immunotherapy, excluding individuals receiving solely hormonal therapy or radiation therapy) with: o Malignant hematologic disorders o Non-hematologic malignant solid tumors Refer to the latest NACI and Ministry of Health recommendations on the use, dosing interval and interchangeability of approved COVID-19 vaccines.
Both the Moderna and Pfizer vaccines use COVID-19's genetic code in the vaccine, exploiting the host cell to translate the code and make the target spike protein, eliciting both neutralizing antibody and cellular immune responses. 4 The AstraZeneca COVID-19 vaccine uses replication deficient adenovirus vectors, to deliver the COVID-19 spike protein genetic sequence into the host cell, locally stimulating neutralizing antibody and cellular immune responses. 11,12,14 As there is no whole, live or replicating virus involved, the vaccines cannot cause disease and, therefore, may be administered to cancer patients after a risk-benefit assessment by the cancer health care team. It is important to note that immunocompromised persons, including individuals receiving immunosuppressant therapy, may not produce a full antibody response and should therefore continue to follow Public Health guidance to avoid exposure, unless otherwise advised by their health care team. 10 Please see Appendix for a complete list of references.
# What are the contraindications to the COVID-19 vaccines?
The Pfizer, Moderna and AstraZeneca COVID-19 vaccines are contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation. 1,2,3,4 The AstraZeneca vaccine is contraindicated in patients who have experienced major venous and/or arterial thrombosis with thrombocytopenia after vaccination with AstraZeneca COVID-19 vaccine. It is also contraindicated in those who have previously experienced episodes of capillary leak syndrome (CLS) as some fatal cases have been observed very rarely following administration of the AstraZeneca vaccine. 3 Refer to the product monographs for the complete description of contraindications.
Please see Appendix for a complete list of references.
# Which patient factors require further consideration before giving a COVID-19 vaccine?
Patients with a history of severe allergy (e.g., anaphylaxis) to the COVID-19 vaccine or any of its components, including PEG, polysorbate or tromethamine should be referred to an allergist, other appropriate physician or nurse practitioner to determine if and how the vaccine can be safely administered. 1,5 See question 10: "Can a cancer patient receive the COVID-19 vaccine if they have allergies?" for more information.
Patients who have experienced a previous cerebral venous sinus thrombosis (CVST) with thrombocytopenia or heparin induced thrombocytopenia (HIT) should only receive the adenovirus-based vaccine if the potential benefits outweigh the potential risks. 2,3 A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, has been observed very rarely following vaccination with adenovirus-based vaccines. In patients with a history of immune thrombocytopenia (ITP), the risks of developing low platelet levels should be considered before vaccination with adenovirus-based vaccines. 2,3 See question 9: "What are possible side effects of the vaccination?" for more information.
Patients who have experienced major venous and/or arterial thrombosis with thrombocytopenia following vaccination with the AstraZeneca COVID-19 vaccine should not receive a second dose of the AstraZeneca COVID-19 vaccine. 2,4 Please see Appendix for a complete list of references.
- Which cancer patients are at a higher risk of becoming infected with COVID-19 and/or having severe complications with COVID-19?
Cancer patients have a higher risk of contracting COVID-19 and some cancer patients are at higher risk for poorer outcomes with the infection. The following patients are at a higher risk:
# Time since diagnosis:
Patients with a recent diagnosis (within the last year) especially those with a hematologic malignancy have an increased risk of mortality with COVID-19 compared to those with a less recent diagnosis.
Patients with a diagnosis 1 to 5 years prior have a higher risk of mortality than patients with a diagnosis beyond 5 years. Patients with hematologic malignancy or following allogeneic stem cell transplant may remain at high risk of infection and mortality even beyond 5 years, as they are often on a prolonged course of treatment or have ongoing significant immunosuppression.
# Cancer type:
In general, patients with hematologic cancers who are at any stage of treatment (especially those ≥ 60 years of age) and patients with lung cancer have a higher risk of mortality compared to patients with other cancer diagnoses.
# Treatment type:
There is some evidence to suggest that patients who are currently or recently (within the last 6 months) treated with immune checkpoint inhibitors are at a higher risk of mortality; however, the population-based data are likely to be influenced by a number of confounding factors. A retrospective study of adult patients with lymphoma identified an association with prolonged hospitalization due to symptoms and a higher risk of death from COVID-19 in patients who were recently treated (within 12 months) with anti-CD20 therapy. Other studies were unable to demonstrate whether systemic treatment types (such as chemotherapy and targeted therapy) increase the risk of mortality from COVID-19. In a population-based study, however, patients with active cancer, particularly those on active treatment, were associated with higher rates of hospitalization, ICU admission, and 30-day mortality. In addition, patients on active treatment may be at an increased risk of neutropenia and development of infections. Patients who have had a stem cell transplant within the last 6 months are also considered to be higher risk. (c) Patients who smoke or have other comorbidities, including obesity, may be at risk for increased hospitalizations and mortality. Follow local public health advice to determine risk based on noncancer related factors. (d) Consideration of COVID-19 vaccination should be given to household or close contacts of cancer patients at higher risk of infection/mortality (based on public health guidance) to reduce the risk of exposure to the virus.
# Rationale:
Current available data suggest that COVID-19 mortality is higher in patients with cancer than in the general population. 1,2,3,4,5,14,15 A pooled analysis of 18,650 found the probability of death to be 25.6% in patients with both a COVID-19 and cancer diagnosis. 3 A multivariate analysis of over 10,000 COVID-19 deaths from the UK found that, relative to patients without cancer, patients with nonhematologic malignancy diagnosed within one year prior to a COVID-19 diagnosis had a 1.8-fold higher risk of death, and a hematologic malignancy carried a fourfold higher risk. 5 The risks were lower for patients diagnosed with cancer 1 to 4.9 years prior to COVID-19 when compared those diagnosed within the preceding year; however, risk was still elevated compared with people without cancer. Beyond five years, risks for death remained elevated for those with hematologic but not for those with nonhematologic malignancies. 5 Most studies show a higher risk of mortality among patients with hematologic and lung cancers. 1,6,7,16 A small Chinese study suggested that lung cancer, metastatic disease, and hematologic malignancy may be associated with higher rates of COVID-19-related death and intensive care unit (ICU) admission. 6 A larger study of 309 cancer patients with a diagnosis of COVID-19 found that hematologic malignancies were associated with increased COVID-19 severity and patients with lung cancer demonstrated higher rates of severe or critical COVID-19 events. 1 Adults with hematologic cancers are reported to be at high risk for progression to severe disease and death from COVID-19, with an estimated mortality of 36% or greater. 19 An analysis of 536 Italian patients with hematologic malignancy and COVID-19 found that mortality was significantly higher than in the general Italian population with COVID-19, regardless of age. 7 A large metaanalysis found the risk of death among adults with hematologic malignancies (n = 3240) was 34 percent, and patients ≥60 years of age had a significantly greater risk of dying than did younger patients (relative risk 1.82, 95% CI 1.45-2.27). 8 A multi-institutional international registry study including 400 patients with thoracic cancer also diagnosed with COVID-19 showed that many patients were hospitalized (78%), and 36 percent of patients died. 9,10 Patients who had received chemotherapy within three months had a higher risk of dying from COVID versus patients who did not (hazard ratio 1.7, 95% CI 1.1-2.6); however, in univariate analysis, there were no factors that were identified, including active cancer treatment, as being associated with mortality. 10 Recent active oncologic therapy did not appear to increase the risk of mortality from COVID-19 in some studies. Jee et al reported that cytotoxic chemotherapy was not significantly associated with a severe or critical COVID-19 event and a systemic review indicated that there was no association between receipt of a particular type of oncologic therapy and mortality. 4 Patients on active immunosuppressive therapy (such as chemotherapy) are, however, more likely to be neutropenic and are at a high risk of developing infection. 12 Robilotti et al analysed 423 patients with cancer and COVID-19 and found that age older than 65 years and treatment with immune checkpoint inhibitors (ICIs) were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not. In this study, treatment with ICI predicted both hospitalization and severe disease, although there was considerable heterogeneity in ICI-treated tumor types, and disease-specific factors could not be individually addressed. 11 A more recent retrospective study looked at adult lymphoma patients (n=111) who were admitted to hospital for COVID-19. The median length of admission was 14 days (range,1-235) and the 6-month overall survival was 69%. In multivariable analyses, recent administration of anti-CD20 therapy (within 12 months) was associated with prolonged hospitalization (sub-distribution hazard ratio 2.26, 95% confidence interval 1.42-3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04-4.52, p = 0.039). An age ≥70 years and relapsed/refractory lymphoma were also associated with prolonged hospitalization and decreased overall survival. 21 Garassino reviewed evidence around ICIs and COVID outcomes, which included further analysis of the Robilotti data. It was concluded that there is insufficient evidence at this time to suggest that ICIs worsen complications from COVID-19 and that the population-based registries reporting on the incidence of COVID-19 in patients with cancer receiving ICI therapy compared with patients with cancer not receiving ICI or individuals without cancer, are likely to be plagued by multiple confounding factors.
A recent population-based study with 323 patients enrolled prior to the pandemic (n=67 cancer patients; n= 256 non-cancer patients) compared COVID-19 outcomes. After adjusting for demographics, smoking status, and comorbidities, a diagnosis of cancer was independently associated with higher odds of hospitalization (odds ratio = 2.16, 95% confidence interval = 1.12 to 4.18) and 30-day mortality (odds ratio = 5.67, 95% confidence interval = 1.49 to 21.59). Notably, older age, Black race, and number of comorbidities were statistically significantly associated with increased odds of hospitalization and ICU admission (all P<.05). In addition, exploratory subgroup analyses were performed to investigate these associations among patients with active cancer (defined as having metastatic disease and/or receiving cancer-directed systemic therapy, radiation therapy, or surgical resection in the 2 months before COVID-19 diagnosis) compared with noncancer patients, as well as those with cancer in remission compared with noncancer patients. The analyses showed that adjusted associations with hospitalization, ICU admission, and 30-day mortality were strongest in the active cancer patient group. The authors concluded that patients with cancer, particularly those receiving active treatment, should be among groups specifically targeted for COVID-19 mitigation and prevention strategies such as vaccination. 14 Lymphopenia at COVID-19 diagnosis was associated with higher rates of severe critical illness. 1 Patients with baseline neutropenia 14-90 days before a COVID-19 diagnosis had worse outcomes. 1 In addition, current literature suggests that the likelihood of a severe illness and death from COVID-19 is higher among adult patients with cancer who have other comorbidities, including obesity. 2 Please see Appendix for a complete list of references.
# When will cancer patients receive immunity (mount an immune response) after the COVID-19 vaccine?
In the general population, individuals may not receive optimal protection until after the vaccine series is completed. 1,2,7,8,9,10,12 Immunocompromised individuals were initially excluded from the earlier Phase 2/3 vaccine clinical trials. 1,2 More recently, studies have indicated that after a full vaccine series, patients with solid tumours demonstrate high rates of immune response; though, immune response may be diminished compared to the general public. 11,14,15,16,17,26,27,33 Evidence suggests that patients with hematologic malignancies mount blunted, less durable and highly variable antibody responses after completing two doses of the primary COVID-19 vaccine series. 32 This is a result of both their underlying condition and treatments affecting the efficacy of COVID-19 vaccines.
In addition to active treatment within the last 6-12 months with BTKIs (Bruton tyrosine kinase inhibitors) and anti-CD19/CD20/CD38 antibody therapies, BCMA directed therapies, PI3-K inhibitors (e.g., alpelisib), JAK2 inhibitors (e.g., ruxolitinib) and venetoclax treatments also negatively affected antibody response, rendering these patients sub-optimally protected from COVID-19. 18-21, 30, 34 Patients on immunomodulators, proteosome inhibitors (or both) mount poorer antibody responses than do untreated patients with hematological malignancies. 21 Other treatments, including hematopoietic stem cell transplantation, may result in a reduced antibody response. 25,31 Although immune response may be sub-optimal, COVID-19 vaccinations still offer some protection, and some protection is better than none. 6 Observational studies in multiple myeloma patients have reported that older age, impaired renal function, low lymphocyte counts, patients who have had more than 2 lines of systemic treatment and those not in complete remission were associated with lower antibody levels. 32 To optimize immune response, individuals on active treatment for malignant hematologic disorders and nonhematologic malignant solid tumors (excluding individuals receiving solely hormonal therapy or radiation therapy) should receive the COVID-19 vaccine at the dose interval indicated in the product monograph. 13 For moderately to severely immunocompromised patients, an additional dose may be required. 25 For details on a three-dose primary series of COVID-19 vaccine and booster doses , refer to question 7: Should additional doses of COVID-19 vaccine be considered in patients with cancer?
Patients should continue to follow Public Health guidance to avoid exposure to COVID-19, unless otherwise advised by their health care team. 1,2 To protect those who are immunocompromised, it also is strongly recommended that all people that come into close contact (e.g., family, friends, caregivers) with these individuals are fully vaccinated according to public health guidelines. 4,24 Please see Appendix for a complete list of references.
# When is the optimal time for cancer patients to receive the COVID-19 vaccine?
Ideally, vaccination should occur at a time when patients are least likely to be immunocompromised as efficacy will depend on patients' ability to mount a response to the vaccine. 26,30 Based on real-world evidence with COVID-19 vaccines and extensive experience with the flu vaccine, response rates can be highly variable.
The effectiveness of the vaccine will depend on underlying disease as well as the type and timing of treatment that could hinder a patient's ability to mount an immune response. 17,18 The following guidance on the timing of the COVID-19 vaccine administration, in relation to treatment for cancer patients has been adapted from information pertaining to the inactivated influenza vaccine and is updated as new evidence emerges.
# General guidelines:
- Clinical judgement should be exercised around administration of the complete series of the vaccine prior to initiation of systemic treatment (chemotherapy or immunotherapy). Prioritization of systemic treatment over vaccination, or vice versa, should be determined via risk assessment, considering factors such as patient's age, comorbidities, treatment intent, type of treatment, etc.
- When feasible, vaccines should be administered at least 2 weeks before initiation of systemic treatment to optimize immunogenicity. 1,2,4,20 - For COVID-19 vaccines given as a 2-dose series:
- If the complete series of the vaccine cannot be administered 2 weeks before the start of treatment, the first dose of the vaccine should be administered at least 2 weeks before initiation of systemic treatment, and the second dose within a few days prior to administration of systemic treatment. Although evidence around timing with systemic treatment varies, this can minimize uncertainty around the cause of flu-like symptoms or infusion-related reactions if vaccine is administered around the day of systemic treatment. 5,6,20,21 o If the second dose cannot be administered within a few days of systemic treatment administration, a risk assessment should be conducted around prioritization of either the treatment schedule or vaccination schedule, with consideration for factors such as patient's age, comorbidities, treatment intent, type of treatment, etc. o If administration of the second dose of the vaccine is delayed, it should be administered as soon as possible. 19 - Patients receiving vaccine during treatment may have an attenuated or absent response to the vaccine and should continue to exercise precautions when possible (wearing a mask when unable to maintain social distance etc.). 1,2,4,20 An additional dose of COVID-19 vaccine may be required. 33 - Patients who are not on active treatment may receive the vaccine after an appropriate time has passed since their last treatment was completed, depending on the agents used.
# Cytotoxic Chemotherapy
- If feasible, allow at least two weeks to pass after the second vaccine dose before starting cytotoxic therapies to allow for memory T cell formation. 22 - During active chemotherapy treatment, all doses of the vaccine should be administered, at minimum, within a few days prior to next chemotherapy cycle, if feasible (i.e. when immunosuppressive effects of cytotoxic chemotherapy are at their lowest and not on the same day of chemotherapy). 5,6,20 - Immunization in patients receiving chemotherapy when blood counts are low is discouraged. 13,14 - Induction Chemotherapy for Leukemia: o Vaccine should be given at least 2 weeks prior to the start of immunosuppressive therapy or when effects of immunosuppressive therapy are at the lowest level. 2 o If the vaccine cannot be given prior to start of induction treatment in acute leukemia, it may be given upon blood count recovery, prior to the start of consolidation treatment.
# Targeted therapy
- Vaccines may be administered at any time during treatment for most targeted therapies. Consideration for timing should be taken for targeted treatments that may cause neutropenia or lymphopenias. 3,20
# Immunotherapy
- Monoclonal antibodies: o If feasible, allow at least two weeks to pass after the second vaccine dose before starting Bcell depleting therapies to allow for memory T cell formation. 22 o Patients receiving maintenance rituximab may receive vaccine at any time during treatment; although there may be a reduced response, evidence suggests it is unlikely to cause harm. 7,20 - Immune checkpoint inhibitors (ICI): o Many trials using ICI do not allow vaccinations due to a concern of increased autoimmune events. However, evidence with inactivated influenza vaccine suggests that patients receiving ICI therapy may not experience an increase in immune-related adverse events when they receive the vaccine within 2 months of treatment. 9,10 Recent research with mRNA vaccines supports this. Cancer patients treated with ICI who received mRNA vaccine were not likely to develop new immune-related side effects or exacerbation of existing immunerelated side effects in the short-term. 31 o For patients receiving a combination of ICI, the risk of increased autoimmune events is uncertain and should be weighed against the definite risk of a patient potentially contracting COVID-19. Experience with vaccinations in this population is mostly with the influenza vaccine and more data will need to be collected before any further recommendations can be made.
# Radiation Therapy
- Patients who are receiving radiation therapy alone (not in combination with chemotherapy) may receive vaccine at any time during treatment. 20
# Stem cell transplant
- If feasible, both doses of the vaccine should be administered at least 2 weeks before initiation of a transplant conditioning regimen, and at least 2 weeks prior to stem cell collection for donors. 2 - Post-transplant, the vaccine may be administered as early as 3 months after transplant. 12,18,22,24
# CAR T-Cell Therapy
- If feasible, both doses of the vaccine should be administered at least 2 weeks before CAR T-cell therapy. 18 - Vaccines should not be administered until at least 3 months after completion of therapy. 22,25
# Corticosteroids
- If feasible, the vaccine should be administered after corticosteroid treatment has been completed or reduced to ≤ 10 mg/day of prednisone or equivalent, due to the immunosuppressive nature of corticosteroids. 32
# Surgery
- Essential urgent surgery should take place, irrespective of vaccination status. Non-urgent elective surgery can also take place soon after vaccination. There is some rationale for separating the date of surgery from vaccination by a few days (at most 1 week) so that any symptoms such as fever might be correctly attributed to the consequences of either vaccination or the operation itself. 23 For surgeries inducing immunosuppression (e.g. splenectomy), a wider window (e.g. 2 weeks) may be recommended. 27
# Cancer Screening
- Since lymphadenopathy is a potential COVID-19 vaccine side effect, screening exams should be conducted before the first dose of a COVID-19 vaccine or 4-6 weeks after the second dose of a COVID-19 vaccine if feasible, and when it does not unjustifiably interrupt management. 28,29 See question 7: "Should a additional doses of COVID-19 vaccine be considered in patients with cancer?" for information around timing of third doses.
Please see Appendix for a complete list of references.
# Should additional doses of COVID-19 vaccine be considered in patients with cancer?
# Three-dose Primary Series for Immunocompromised Patients
Studies have shown decreased immunogenicity in some immunocompromised adults, including patients with malignancy (solid tumour and hematological), when compared to healthy vaccine recipients 1,3,5,13 Emerging data suggest that an additional COVID-19 vaccine dose in immunocompromised patients enhances antibody response and increases the proportion of patients who respond. 7,8,13 NACI recommends that a third dose of an authorized mRNA COVID-19 vaccine should be offered to moderately to severely immunocompromised patients in the authorized age groups. 13 A third dose of a viral vector vaccine should only be considered when other authorized COVID-19 vaccines are contraindicated or inaccessible. Informed consent for an additional dose of viral vector vaccine should include discussion about its lack of evidence as an additional dose in this population, and the increased risk of Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT), Capillary Leak Syndrome (CLS), and Guillain-Barre syndrome (GBS) following viral vector COVID-19 vaccines. 13,14 Moderately to severely immunocompromised cancer patients include those who: 12,13,14 - Are on active treatment for solid tumour or hematologic malignancies that can cause moderate to severe immunosuppression. o Active treatment is defined as chemotherapy, targeted therapies, immunotherapy, and excludes individuals receiving therapy that does not suppress the immune system, e.g. solely hormonal therapy or radiation therapy o Active treatment includes patients who have completed treatment within 3 months, or within 12 months for patients receiving B-cell depleting therapy. - Are on active treatment with the following categories of immunosuppressive therapies: anti-B cell therapies (monoclonal antibodies targeting CD19, CD20 and CD22, e.g., blinatumomab, rituximab, obinutuzumab, inotuzumab ozogamicin), high-dose systemic corticosteroids (prednisone equivalent of ≥ 20 mg/day), alkylating agents (e.g. bendamustine, cyclophosphamide), antimetabolites (e.g. 5fluorouracil, methotrexate), or tumour-necrosis factor (TNF) inhibitors (e.g. infliximab) and other biologic agents that are significantly immunosuppressive. vaccination, and should include booster doses at the appropriate times (e.g., dose 1, 2 and 3 at 3 months, 4 months and 6 months post transplant respectively). Re-vaccination should start 3-6 months after transplant, according to institutional guidelines. A more potent immune response will be obtained if the first vaccine dose is administered closer to the 6-month mark. Patients may end up receiving up to 5 or 6 vaccination doses, depending on whether they were vaccinated pre-transplant.
Refer to the latest NACI recommendations for definition of moderately to severely immunocompromised non-cancer populations.
Ontario guidelines recommend an interval of at least 2 months (8 weeks) between the last dose of the 2dose series and the third dose. As per NACI, the minimum interval should be 28 days; an interval longer than the minimum 28 days between doses is likely to result in a better immune response. If a longer interval is being considered, then risk factors for exposure (including local epidemiology and circulation of variants of concern) and risk of severe disease should also considered. 13,14 Booster Doses 15 Booster doses refer to additional COVID-19 vaccine doses after the primary series is completed.
Individuals with higher risk of severe disease from COVID-19 infection (e.g. moderately to severely immunocompromised, adults 60 years of age and older or living in long-term care homes, or First Nation, Inuit and Métis communities) are strongly recommended to receive booster doses of an authorized mRNA COVID-19 vaccine, as soon as they are eligible.
Booster doses should be administered at least 5 months (minimum 3 months) after completing the primary vaccination series. 14 Booster doses may be a fourth dose in the vaccine series, or more, depending on timing of previous COVID-19 vaccinations.
Please refer to the Ministry of Health -COVID-19 Vaccine Booster Recommendations or local public health units for specific eligibility criteria, dose and timing of COVID-19 vaccine booster doses.
Patients should continue to follow Public Health guidance to avoid exposure to COVID-19, unless otherwise advised by their health care team. To protect those who are immunocompromised, it also is strongly recommended that all people that come into close contact (e.g., family, friends, caregivers) with these individuals are fully vaccinated according to public health guidelines.
Please see Appendix for a complete list of references.
# When should the COVID-19 vaccine be given in relation to other vaccinations?
Currently, it is recommended by Public Health that COVID-19 vaccines may be safely and effectively administered at the same visit, or any time before or after, non-COVID-19 vaccines (including live, non-live, adjuvanted, or unadjuvanted). 1,2,3 Though studies to assess the safety and immunogenicity of concomitant administration of COVID-19 vaccines with other vaccines are ongoing, experience with non-COVID-19 vaccines has demonstrated that immunogenicity and adverse event profiles are generally similar when vaccines are administered simultaneously as when they are administered alone. 1 Although data is still limited in the immunocompromised setting, evidence does not suggest that concomitant administration of COVID-19 vaccines with other non-COVID-19 vaccines (e.g., the flu vaccine) would cause harm or affect efficacy of either vaccine. If more than one type of vaccine is administered at a single visit, they should be administered at different anatomical injection sites. 1,2,3 Patients who are administered vaccines concomitantly should be counseled about the benefits and risks given the limited data available.
# What are possible side effects of the vaccination?
Side effects of the COVID-19 vaccines were usually mild or moderate and generally resolved in a few days. 1,4,6,7,10,11,12 Local reactions for the vaccines included pain, rash, redness or swelling at the injection site. 2,7,11,12,16 Delayed local reactions have been reported. 15 Systemic side effects included fatigue, headache, muscle/joint pain, diarrhea, chills, fever and nausea/vomiting. 2,7,11,12,16 Frequencies of systemic effects for the mRNA COVID-19 vaccines were generally higher after the second dose, and in patients < 56 years of age for the Pfizer vaccine and between 18 to 64 years for the Moderna vaccine. 2,3,7,8 Preliminary data demonstrate side effects after the 3 rd dose of an mRNA vaccine were similar to that of the two-dose series: fatigue, headache, muscle/joint pain and pain at injection site were the most commonly reported side effects, and overall, most symptoms were mild to moderate. 30,31,37 No worsening of underlying disease was reported after immunization. 33 No serious adverse events were deemed to be associated with the additional vaccine dose. The impact of additional doses on rare adverse events, including myocarditis/pericarditis, are unknown. 33 For the AstraZeneca vaccine, fewer and milder adverse reactions were reported after the second dose and reactogenicity reduced with increasing age. 3,10,11 Patients should be educated to seek medical attention if the symptoms last longer than 48-72 hours, due to the similarity with symptoms of COVID-19 or other infections.
Cases of lymphadenopathy occurring in the arm and neck region 24.28 have been reported post all doses of the COVID-19 vaccination, which may mimic metastasis. Following the first and second COVID-19 vaccine doses, vaccine-related lymphadenopathy typically occurs within 7 days of vaccination and generally subsides by 12-14 days. However, vaccine-related lymphadenopathy may persist as far as 4-6 weeks after first and second COVID-19 vaccine administration. 17,21,22,23,26,27 The peak of lymph node activity tends to be earlier after the second vaccination as compared to the first vaccination. 27 Data suggests high grade vaccine-related lymphadenopathy following the third dose has shorter duration (does not usually persists for weeks) and lower uptake intensity after the first 5 days from vaccination. It is unlikely for high grade vaccine-related lymphadenopathy to be observed 6 days from inoculation of the third vaccine dose, and is even less likely in older and obese patients to interfere with imaging interpretations. 38 Consider timing of vaccination and dose number in the vaccine series when assessing patients with new or worsening lymphadenopathy. 2,7,11,12, 13, 14, Very rare cases of moderate-to-severe thrombocytopenia and thrombotic complications at unusual sites (e.g., abdomen, splanchnic vein, sinus or cerebral vein), called vaccine-induced immune thrombotic thrombocytopenia (VITT), have been reported with the AstraZeneca COVID-19 vaccine (some emerging reports with Pfizer or Moderna vaccines in the United States). 3,12,23,25,34,35 In some cases, these have been accompanied by bleeding. 12 VITT typically occurs within 3 weeks following AstraZeneca vaccine administration. 12 Fatalities have been reported. The exact mechanism is still under investigation but appears to be similar to heparin-induced thrombocytopenia (HIT). It is associated with platelet activating antibodies, which stimulate clot formation and thrombocytopenia. Patients should be advised to seek immediate medical attention if they develop symptoms of thromboembolism accompanied by thrombocytopenia, which becomes clinically apparent approximately 4-28 days after receiving a viral vector COVID-19 vaccine and should be monitored for symptoms up to 42 days. 3, 12, 18-20, 23,25 Close monitoring of patients with previous thrombocytopenia is highly recommended as VITT can develop earlier than the expected onset in patients with a history of thrombocytopenia and worsen pre-existing thrombocytopenia. 32 Cases of thrombocytopenia, including immune thrombocytopenia (ITP), have been reported after receiving the AstraZeneca vaccine, typically within the first 4 weeks after vaccination. There were very rare cases of low platelets (< 20 x 10 9 /L) and/or bleeding events, including fatal cases. Some cases occurred in patients with a history of immune thrombocytopenia. 11 Very rare cases of myocarditis and/or pericarditis following vaccination administration of mRNA vaccines have been reported. 2,3,7 The onset of symptoms (including chest pain, shortness of breath and palpitations) have typically occurred within one week after vaccination; cases have occurred more commonly after the second dose, in adolescents, young adults and male patients. 3,36 Available short-term follow-up data suggest that the symptoms are generally mild and resolve in most individuals, but information on long-term sequelae is lacking. Patients receiving an mRNA vaccine should be informed about the very rare risk of myocarditis and/or pericarditis following immunization. Individuals who experienced this adverse effect within 6 weeks of receiving an mRNA vaccine should defer subsequent doses until they have discussed the risks and benefits with their healthcare provider. Cardiology consultation for management and follow up should be considered. 2,3,39 Refer to the COVID-19 vaccine: Canadian Immunization Guide for more information regarding subsequent immunization in individuals who experienced myocarditis.
Bell's Palsy (typically temporary weakness or paralysis on one side of the face) has been reported very rarely after the use of mRNA COVID-19 vaccines. The exact cause is unknown, with symptoms appearing suddenly and generally starting to improve after a few weeks. It is believed to be due to swelling and inflammation of the nerve that controls muscles on one side of the face. 29 Very rare events of demyelinating disorders, such as Guillain-Barré Syndrome, have been reported after vaccination with the AstraZeneca COVID-19 Vaccine. 12 Please see Appendix for a complete list of references.
# Can a cancer patient receive the COVID-19 vaccine if they have allergies?
Severe allergic reactions to the vaccine have been reported. 1,2,4,12,13 Patients with a history of severe allergy (e.g., anaphylaxis) to any of the components of a COVID-19 vaccine, or patients that have had an allergic reaction within 4 hours of receiving a previous dose of a COVID-19 vaccine, should be referred to an allergist, other appropriate physician or nurse practitioner to determine how the vaccine can be safely administered. 15 Polyethylene glycol (PEG), a water-soluble polymer used as a drug delivery vehicle, is a component of both Pfizer and Moderna vaccines and is known to cause mild to severe hypersensitivity reactions. 6,7 Cancer medications containing PEG include (but are not limited to) the following: 1. PEGaspargase (Oncaspar®) 2. Pegfilgrastim (e.g., Neulasta® and others) 3. Liposomal irinotecan (Onivyde®) 4. PEG-liposomal doxorubicin (Caelyx®)
Polysorbate, a surfactant and emulsifier used as an excipient in some drug formulations, 7 is structurally related and has the potential for cross-reactivity to PEG. It is also a component of the AstraZeneca vaccine. 12 Individuals who are allergic to polysorbates should be offered an mRNA vaccine. 16 Cancer medications containing polysorbate include (but are not limited to) the following: 1. Cabazitaxel 2. Docetaxel 3. Etoposide 4. Fosaprepitant (IV) 5. Rituximab (reactions with rituximab are typically a result of cytokine release syndrome and may not be related to polysorbate) 6. Paclitaxel (contains the excipient, Cremophor EL (polyethoxylated castor oil) which has the potential for cross-reactivity with polysorbate) 9 Not all medications that contain PEG or polysorbate will cause allergic reactions and many drugs, including oral medications, may contain PEG or polysorbate in various concentrations, depending on the manufacturer.
Tromethamine is a component of the Moderna vaccine and may cause allergic reactions. It is also a component in contrast media and some oral and parenteral medications (e.g., ketorolac). 14 Individuals who are allergic to tromethamine should be offered the Pfizer-BioNTech COVID19 vaccine if 12 years or age or older. 16 Clinicians should consult individual product monographs for a full list of non-medicinal ingredients if their patients have had a history of anaphylactic reactions to their cancer medications. Patients should be counseled about the risks of developing a severe allergic reaction against the benefits of vaccination.
Refer to Ministry of Health guidance on COVID-19 vaccines and allergies for more information.
Please see Appendix for a complete list of references.
- When should Evusheld (Tixagevimab and Cilgavimab) be given in relation to the COVID-19 vaccine?
In individuals who have received a COVID-19 vaccine, Evusheld should be administered at least 2 weeks after vaccination. 1 If a patient is currently eligible for a COVID-19 vaccine dose, they should receive the vaccine before receiving Evusheld. There are no data available regarding COVID-19 vaccination after Evusheld administration.
Refer to Information about Evusheld (Tixagevimab and Cilgavimab) for more information.
Please see Appendix for a complete list of references.
# Appendix
- Are all COVID-19 vaccines safe for cancer patients? | The following are frequently asked questions about the COVID-19 vaccine and adult cancer patients. The information is: • related to the Pfizer (Comirnaty TM )and the Moderna (Spikevax TM ) COVID-19 vaccines that use mRNA technology • related to the AstraZeneca COVID-19* (Vaxzevria TM ) vaccine that uses non-replicating viral vectors (adenovirus) • current as of August 8, 2022 The information below may not be appropriate for all patients. Prescribers must determine whether adopting suggested COVID-19 vaccine information is clinically appropriate for individual patients through a risk-benefit assessment. Consult appropriate clinical prescribing guidelines and local institutional guidance for patient prioritization to inform treatment and vaccination decisions. Everyone should receive a COVID-19 vaccination, when available, unless contraindicated. See question 2 "What are the contraindications to the COVID-19 vaccines?" for more information. There are limitations to the current knowledge around the use of COVID-19 vaccines in the cancer population. The advice below is based on the best available evidence at this time. Guidance will be updated as more evidence becomes available. Patients should continue to practice recommended public health measures for prevention of COVID-19 infection regardless of vaccination status. * Note that COVISHIELD (manufactured by Serum Institute of India) and the AstraZeneca COVID-19 vaccine (manufactured by AstraZeneca) are ChAdOx1-S recombinant vaccines developed by AstraZeneca and the University of Oxford. Health Canada has reviewed the manufacturing information for these vaccines and found them to be comparable.COVID-19 vaccines use either conventional or novel mechanisms of action to safely elicit immune responses. Conventional platforms include recombinant viral proteins, live attenuated vaccines and inactivated vaccines, while novel methods include viral vector-based vaccines and mRNA-based vaccines. 8 #
The COVID-19 vaccine is safe for use in cancer patients. Studies demonstrate the safety profile of mRNA vaccines in the immunocompromised population, including patients with cancer, are comparable to what has been observed in the general population, with no unexpected or serious safety signals to date. 17,20 Additionally, prior experience with other protein-based or inactivated vaccines have not reported unique or major side effects in immunocompromised patients. 7 The most frequently reported side effects of COVID-19 vaccine candidates were usually mild or moderate and include pain at the site of injection, fatigue, headache, myalgias and fever (see question 9 below). Live attenuated vaccines carry the risk of disease caused by vaccine strains and are not recommended during and after immunosuppressive therapy (such as chemotherapy). 3 Currently, these are the vaccines available* for use in Ontario for active immunizations to prevent COVID-19:
• Pfizer COVID-19 mRNA vaccine (BNT162b2 or Comirnaty TM ) • Moderna COVID-19 mRNA vaccine (mRNA-1273 SARS-CoV-2 or Spikevax TM ) • AstraZeneca COVID-19 non-replicating adenovirus vaccine (AZD1222 or ChAdOx1-S recombinant or Vaxzevria TM ) * Other vaccines (e.g. Janssen, Novavax, Medicago) may also be available in limited supplies. Refer to the latest Ministry of Health guidance for the most up to date information as new vaccines become available.
The Pfizer, Modena and AstraZeneca vaccines are administered intramuscularly as a series of two doses. The recommended immunization schedules of the 2-dose COVID-19 vaccines are listed in Table 1. Additional dose(s) of an authorized mRNA COVID-19 vaccine are recommended in certain populations. 18,19 For details on a three-dose primary series of COVID-19 vaccine and booster doses, see question 7: Should additional doses of COVID-19 vaccine be considered in patients with cancer? While efforts should be made to vaccinate according to the authorized schedules as per individual vaccine product monographs or local public health guidelines, extended vaccination intervals may not be appropriate in certain patient populations, as described below. 13, 15 b A 12-week interval is preferred for the AstraZeneca COVID-19 vaccine based on available ad hoc analyses of the vaccine clinical trial interval data; efficacy may be lower if interval is less than 12 weeks, in the general population.
The following patient groups should receive the COVID-19 vaccine at the dose interval recommended by the manufacturers: 15 • Transplant recipients (including solid organ transplants and hematopoietic stem cell transplants).
• Patients receiving active treatment (chemotherapy, targeted therapies, immunotherapy, excluding individuals receiving solely hormonal therapy or radiation therapy) with: o Malignant hematologic disorders o Non-hematologic malignant solid tumors Refer to the latest NACI and Ministry of Health recommendations on the use, dosing interval and interchangeability of approved COVID-19 vaccines.
Both the Moderna and Pfizer vaccines use COVID-19's genetic code in the vaccine, exploiting the host cell to translate the code and make the target spike protein, eliciting both neutralizing antibody and cellular immune responses. 4 The AstraZeneca COVID-19 vaccine uses replication deficient adenovirus vectors, to deliver the COVID-19 spike protein genetic sequence into the host cell, locally stimulating neutralizing antibody and cellular immune responses. 11,12,14 As there is no whole, live or replicating virus involved, the vaccines cannot cause disease and, therefore, may be administered to cancer patients after a risk-benefit assessment by the cancer health care team. It is important to note that immunocompromised persons, including individuals receiving immunosuppressant therapy, may not produce a full antibody response and should therefore continue to follow Public Health guidance to avoid exposure, unless otherwise advised by their health care team. 10 Please see Appendix for a complete list of references.
# What are the contraindications to the COVID-19 vaccines?
The Pfizer, Moderna and AstraZeneca COVID-19 vaccines are contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation. 1,2,3,4 The AstraZeneca vaccine is contraindicated in patients who have experienced major venous and/or arterial thrombosis with thrombocytopenia after vaccination with AstraZeneca COVID-19 vaccine. It is also contraindicated in those who have previously experienced episodes of capillary leak syndrome (CLS) as some fatal cases have been observed very rarely following administration of the AstraZeneca vaccine. 3 Refer to the product monographs for the complete description of contraindications.
Please see Appendix for a complete list of references.
# Which patient factors require further consideration before giving a COVID-19 vaccine?
Patients with a history of severe allergy (e.g., anaphylaxis) to the COVID-19 vaccine or any of its components, including PEG, polysorbate or tromethamine should be referred to an allergist, other appropriate physician or nurse practitioner to determine if and how the vaccine can be safely administered. 1,5 See question 10: "Can a cancer patient receive the COVID-19 vaccine if they have allergies?" for more information.
Patients who have experienced a previous cerebral venous sinus thrombosis (CVST) with thrombocytopenia or heparin induced thrombocytopenia (HIT) should only receive the adenovirus-based vaccine if the potential benefits outweigh the potential risks. 2,3 A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, has been observed very rarely following vaccination with adenovirus-based vaccines. In patients with a history of immune thrombocytopenia (ITP), the risks of developing low platelet levels should be considered before vaccination with adenovirus-based vaccines. 2,3 See question 9: "What are possible side effects of the vaccination?" for more information.
Patients who have experienced major venous and/or arterial thrombosis with thrombocytopenia following vaccination with the AstraZeneca COVID-19 vaccine should not receive a second dose of the AstraZeneca COVID-19 vaccine. 2,4 Please see Appendix for a complete list of references.
4. Which cancer patients are at a higher risk of becoming infected with COVID-19 and/or having severe complications with COVID-19?
Cancer patients have a higher risk of contracting COVID-19 and some cancer patients are at higher risk for poorer outcomes with the infection. The following patients are at a higher risk:
•
# Time since diagnosis:
Patients with a recent diagnosis (within the last year) especially those with a hematologic malignancy have an increased risk of mortality with COVID-19 compared to those with a less recent diagnosis.
Patients with a diagnosis 1 to 5 years prior have a higher risk of mortality than patients with a diagnosis beyond 5 years. Patients with hematologic malignancy or following allogeneic stem cell transplant may remain at high risk of infection and mortality even beyond 5 years, as they are often on a prolonged course of treatment or have ongoing significant immunosuppression.
# Cancer type:
In general, patients with hematologic cancers who are at any stage of treatment (especially those ≥ 60 years of age) and patients with lung cancer have a higher risk of mortality compared to patients with other cancer diagnoses.
# Treatment type:
There is some evidence to suggest that patients who are currently or recently (within the last 6 months) treated with immune checkpoint inhibitors are at a higher risk of mortality; however, the population-based data are likely to be influenced by a number of confounding factors. A retrospective study of adult patients with lymphoma identified an association with prolonged hospitalization due to symptoms and a higher risk of death from COVID-19 in patients who were recently treated (within 12 months) with anti-CD20 therapy. Other studies were unable to demonstrate whether systemic treatment types (such as chemotherapy and targeted therapy) increase the risk of mortality from COVID-19. In a population-based study, however, patients with active cancer, particularly those on active treatment, were associated with higher rates of hospitalization, ICU admission, and 30-day mortality. In addition, patients on active treatment may be at an increased risk of neutropenia and development of infections. Patients who have had a stem cell transplant within the last 6 months are also considered to be higher risk. (c) Patients who smoke or have other comorbidities, including obesity, may be at risk for increased hospitalizations and mortality. Follow local public health advice to determine risk based on noncancer related factors. (d) Consideration of COVID-19 vaccination should be given to household or close contacts of cancer patients at higher risk of infection/mortality (based on public health guidance) to reduce the risk of exposure to the virus.
# Rationale:
Current available data suggest that COVID-19 mortality is higher in patients with cancer than in the general population. 1,2,3,4,5,14,15 A pooled analysis of 18,650 found the probability of death to be 25.6% in patients with both a COVID-19 and cancer diagnosis. 3 A multivariate analysis of over 10,000 COVID-19 deaths from the UK found that, relative to patients without cancer, patients with nonhematologic malignancy diagnosed within one year prior to a COVID-19 diagnosis had a 1.8-fold higher risk of death, and a hematologic malignancy carried a fourfold higher risk. 5 The risks were lower for patients diagnosed with cancer 1 to 4.9 years prior to COVID-19 when compared those diagnosed within the preceding year; however, risk was still elevated compared with people without cancer. Beyond five years, risks for death remained elevated for those with hematologic but not for those with nonhematologic malignancies. 5 Most studies show a higher risk of mortality among patients with hematologic and lung cancers. 1,6,7,16 A small Chinese study suggested that lung cancer, metastatic disease, and hematologic malignancy may be associated with higher rates of COVID-19-related death and intensive care unit (ICU) admission. 6 A larger study of 309 cancer patients with a diagnosis of COVID-19 found that hematologic malignancies were associated with increased COVID-19 severity and patients with lung cancer demonstrated higher rates of severe or critical COVID-19 events. 1 Adults with hematologic cancers are reported to be at high risk for progression to severe disease and death from COVID-19, with an estimated mortality of 36% or greater. 19 An analysis of 536 Italian patients with hematologic malignancy and COVID-19 found that mortality was significantly higher than in the general Italian population with COVID-19, regardless of age. 7 A large metaanalysis found the risk of death among adults with hematologic malignancies (n = 3240) was 34 percent, and patients ≥60 years of age had a significantly greater risk of dying than did younger patients (relative risk [RR] 1.82, 95% CI 1.45-2.27). 8 A multi-institutional international registry study including 400 patients with thoracic cancer also diagnosed with COVID-19 showed that many patients were hospitalized (78%), and 36 percent of patients died. 9,10 Patients who had received chemotherapy within three months had a higher risk of dying from COVID versus patients who did not (hazard ratio 1.7, 95% CI 1.1-2.6); however, in univariate analysis, there were no factors that were identified, including active cancer treatment, as being associated with mortality. 10 Recent active oncologic therapy did not appear to increase the risk of mortality from COVID-19 in some studies. Jee et al reported that cytotoxic chemotherapy was not significantly associated with a severe or critical COVID-19 event and a systemic review indicated that there was no association between receipt of a particular type of oncologic therapy and mortality. 4 Patients on active immunosuppressive therapy (such as chemotherapy) are, however, more likely to be neutropenic and are at a high risk of developing infection. 12 Robilotti et al analysed 423 patients with cancer and COVID-19 and found that age older than 65 years and treatment with immune checkpoint inhibitors (ICIs) were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not. In this study, treatment with ICI predicted both hospitalization and severe disease, although there was considerable heterogeneity in ICI-treated tumor types, and disease-specific factors could not be individually addressed. 11 A more recent retrospective study looked at adult lymphoma patients (n=111) who were admitted to hospital for COVID-19. The median length of admission was 14 days (range,1-235) and the 6-month overall survival was 69%. In multivariable analyses, recent administration of anti-CD20 therapy (within 12 months) was associated with prolonged hospitalization (sub-distribution hazard ratio 2.26, 95% confidence interval 1.42-3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04-4.52, p = 0.039). An age ≥70 years and relapsed/refractory lymphoma were also associated with prolonged hospitalization and decreased overall survival. 21 Garassino reviewed evidence around ICIs and COVID outcomes, which included further analysis of the Robilotti data. It was concluded that there is insufficient evidence at this time to suggest that ICIs worsen complications from COVID-19 and that the population-based registries reporting on the incidence of COVID-19 in patients with cancer receiving ICI therapy compared with patients with cancer not receiving ICI or individuals without cancer, are likely to be plagued by multiple confounding factors.
A recent population-based study with 323 patients enrolled prior to the pandemic (n=67 cancer patients; n= 256 non-cancer patients) compared COVID-19 outcomes. After adjusting for demographics, smoking status, and comorbidities, a diagnosis of cancer was independently associated with higher odds of hospitalization (odds ratio = 2.16, 95% confidence interval = 1.12 to 4.18) and 30-day mortality (odds ratio = 5.67, 95% confidence interval = 1.49 to 21.59). Notably, older age, Black race, and number of comorbidities were statistically significantly associated with increased odds of hospitalization and ICU admission (all P<.05). In addition, exploratory subgroup analyses were performed to investigate these associations among patients with active cancer (defined as having metastatic disease and/or receiving cancer-directed systemic therapy, radiation therapy, or surgical resection in the 2 months before COVID-19 diagnosis) compared with noncancer patients, as well as those with cancer in remission compared with noncancer patients. The analyses showed that adjusted associations with hospitalization, ICU admission, and 30-day mortality were strongest in the active cancer patient group. The authors concluded that patients with cancer, particularly those receiving active treatment, should be among groups specifically targeted for COVID-19 mitigation and prevention strategies such as vaccination. 14 Lymphopenia at COVID-19 diagnosis was associated with higher rates of severe critical illness. 1 Patients with baseline neutropenia 14-90 days before a COVID-19 diagnosis had worse outcomes. 1 In addition, current literature suggests that the likelihood of a severe illness and death from COVID-19 is higher among adult patients with cancer who have other comorbidities, including obesity. 2 Please see Appendix for a complete list of references.
# When will cancer patients receive immunity (mount an immune response) after the COVID-19 vaccine?
In the general population, individuals may not receive optimal protection until after the vaccine series is completed. 1,2,7,8,9,10,12 Immunocompromised individuals were initially excluded from the earlier Phase 2/3 vaccine clinical trials. 1,2 More recently, studies have indicated that after a full vaccine series, patients with solid tumours demonstrate high rates of immune response; though, immune response may be diminished compared to the general public. 11,14,15,16,17,26,27,33 Evidence suggests that patients with hematologic malignancies mount blunted, less durable and highly variable antibody responses after completing two doses of the primary COVID-19 vaccine series. [15][16][17][18][19][20][21][28][29][30]32 This is a result of both their underlying condition and treatments affecting the efficacy of COVID-19 vaccines.
In addition to active treatment within the last 6-12 months with BTKIs (Bruton tyrosine kinase inhibitors) and anti-CD19/CD20/CD38 antibody therapies, BCMA directed therapies, PI3-K inhibitors (e.g., alpelisib), JAK2 inhibitors (e.g., ruxolitinib) and venetoclax treatments also negatively affected antibody response, rendering these patients sub-optimally protected from COVID-19. 18-21, 30, 34 Patients on immunomodulators, proteosome inhibitors (or both) mount poorer antibody responses than do untreated patients with hematological malignancies. 21 Other treatments, including hematopoietic stem cell transplantation, may result in a reduced antibody response. 25,31 Although immune response may be sub-optimal, COVID-19 vaccinations still offer some protection, and some protection is better than none. 6 Observational studies in multiple myeloma patients have reported that older age, impaired renal function, low lymphocyte counts, patients who have had more than 2 lines of systemic treatment and those not in complete remission were associated with lower antibody levels. 32 To optimize immune response, individuals on active treatment for malignant hematologic disorders and nonhematologic malignant solid tumors (excluding individuals receiving solely hormonal therapy or radiation therapy) should receive the COVID-19 vaccine at the dose interval indicated in the product monograph. 13 For moderately to severely immunocompromised patients, an additional dose may be required. 25 For details on a three-dose primary series of COVID-19 vaccine and booster doses , refer to question 7: Should additional doses of COVID-19 vaccine be considered in patients with cancer?
Patients should continue to follow Public Health guidance to avoid exposure to COVID-19, unless otherwise advised by their health care team. 1,2 To protect those who are immunocompromised, it also is strongly recommended that all people that come into close contact (e.g., family, friends, caregivers) with these individuals are fully vaccinated according to public health guidelines. 4,24 Please see Appendix for a complete list of references.
# When is the optimal time for cancer patients to receive the COVID-19 vaccine?
Ideally, vaccination should occur at a time when patients are least likely to be immunocompromised as efficacy will depend on patients' ability to mount a response to the vaccine. 26,30 Based on real-world evidence with COVID-19 vaccines and extensive experience with the flu vaccine, response rates can be highly variable.
The effectiveness of the vaccine will depend on underlying disease as well as the type and timing of treatment that could hinder a patient's ability to mount an immune response. 17,18 The following guidance on the timing of the COVID-19 vaccine administration, in relation to treatment for cancer patients has been adapted from information pertaining to the inactivated influenza vaccine and is updated as new evidence emerges.
# General guidelines:
• Clinical judgement should be exercised around administration of the complete series of the vaccine prior to initiation of systemic treatment (chemotherapy or immunotherapy). Prioritization of systemic treatment over vaccination, or vice versa, should be determined via risk assessment, considering factors such as patient's age, comorbidities, treatment intent, type of treatment, etc.
• When feasible, vaccines should be administered at least 2 weeks before initiation of systemic treatment to optimize immunogenicity. 1,2,4,20 • For COVID-19 vaccines given as a 2-dose series:
o If the complete series of the vaccine cannot be administered 2 weeks before the start of treatment, the first dose of the vaccine should be administered at least 2 weeks before initiation of systemic treatment, and the second dose within a few days prior to administration of systemic treatment. Although evidence around timing with systemic treatment varies, this can minimize uncertainty around the cause of flu-like symptoms or infusion-related reactions if vaccine is administered around the day of systemic treatment. 5,6,20,21 o If the second dose cannot be administered within a few days of systemic treatment administration, a risk assessment should be conducted around prioritization of either the treatment schedule or vaccination schedule, with consideration for factors such as patient's age, comorbidities, treatment intent, type of treatment, etc. o If administration of the second dose of the vaccine is delayed, it should be administered as soon as possible. 19 • Patients receiving vaccine during treatment may have an attenuated or absent response to the vaccine and should continue to exercise precautions when possible (wearing a mask when unable to maintain social distance etc.). 1,2,4,20 An additional dose of COVID-19 vaccine may be required. 33 • Patients who are not on active treatment may receive the vaccine after an appropriate time has passed since their last treatment was completed, depending on the agents used.
# Cytotoxic Chemotherapy
• If feasible, allow at least two weeks to pass after the second vaccine dose before starting cytotoxic therapies to allow for memory T cell formation. 22 • During active chemotherapy treatment, all doses of the vaccine should be administered, at minimum, within a few days prior to next chemotherapy cycle, if feasible (i.e. when immunosuppressive effects of cytotoxic chemotherapy are at their lowest and not on the same day of chemotherapy). 5,6,20 • Immunization in patients receiving chemotherapy when blood counts are low is discouraged. 13,14 • Induction Chemotherapy for Leukemia: o Vaccine should be given at least 2 weeks prior to the start of immunosuppressive therapy or when effects of immunosuppressive therapy are at the lowest level. 2 o If the vaccine cannot be given prior to start of induction treatment in acute leukemia, it may be given upon blood count recovery, prior to the start of consolidation treatment.
# Targeted therapy
• Vaccines may be administered at any time during treatment for most targeted therapies. Consideration for timing should be taken for targeted treatments that may cause neutropenia or lymphopenias. 3,20
# Immunotherapy
• Monoclonal antibodies: o If feasible, allow at least two weeks to pass after the second vaccine dose before starting Bcell depleting therapies to allow for memory T cell formation. 22 o Patients receiving maintenance rituximab may receive vaccine at any time during treatment; although there may be a reduced response, evidence suggests it is unlikely to cause harm. 7,20 • Immune checkpoint inhibitors (ICI): o Many trials using ICI do not allow vaccinations due to a concern of increased autoimmune events. However, evidence with inactivated influenza vaccine suggests that patients receiving ICI therapy may not experience an increase in immune-related adverse events when they receive the vaccine within 2 months of treatment. 9,10 Recent research with mRNA vaccines supports this. Cancer patients treated with ICI who received mRNA vaccine were not likely to develop new immune-related side effects or exacerbation of existing immunerelated side effects in the short-term. 31 o For patients receiving a combination of ICI, the risk of increased autoimmune events is uncertain and should be weighed against the definite risk of a patient potentially contracting COVID-19. Experience with vaccinations in this population is mostly with the influenza vaccine and more data will need to be collected before any further recommendations can be made.
# Radiation Therapy
• Patients who are receiving radiation therapy alone (not in combination with chemotherapy) may receive vaccine at any time during treatment. 20
# Stem cell transplant
• If feasible, both doses of the vaccine should be administered at least 2 weeks before initiation of a transplant conditioning regimen, and at least 2 weeks prior to stem cell collection for donors. 2 • Post-transplant, the vaccine may be administered as early as 3 months after transplant. 12,18,22,24
# CAR T-Cell Therapy
• If feasible, both doses of the vaccine should be administered at least 2 weeks before CAR T-cell therapy. 18 • Vaccines should not be administered until at least 3 months after completion of therapy. 22,25
# Corticosteroids
• If feasible, the vaccine should be administered after corticosteroid treatment has been completed or reduced to ≤ 10 mg/day of prednisone or equivalent, due to the immunosuppressive nature of corticosteroids. 32
# Surgery
• Essential urgent surgery should take place, irrespective of vaccination status. Non-urgent elective surgery can also take place soon after vaccination. There is some rationale for separating the date of surgery from vaccination by a few days (at most 1 week) so that any symptoms such as fever might be correctly attributed to the consequences of either vaccination or the operation itself. 23 For surgeries inducing immunosuppression (e.g. splenectomy), a wider window (e.g. 2 weeks) may be recommended. 27
# Cancer Screening
• Since lymphadenopathy is a potential COVID-19 vaccine side effect, screening exams should be conducted before the first dose of a COVID-19 vaccine or 4-6 weeks after the second dose of a COVID-19 vaccine if feasible, and when it does not unjustifiably interrupt management. 28,29 See question 7: "Should a additional doses of COVID-19 vaccine be considered in patients with cancer?" for information around timing of third doses.
Please see Appendix for a complete list of references.
# Should additional doses of COVID-19 vaccine be considered in patients with cancer?
# Three-dose Primary Series for Immunocompromised Patients
Studies have shown decreased immunogenicity in some immunocompromised adults, including patients with malignancy (solid tumour and hematological), when compared to healthy vaccine recipients 1,3,5,13 Emerging data suggest that an additional COVID-19 vaccine dose in immunocompromised patients enhances antibody response and increases the proportion of patients who respond. 7,8,13 NACI recommends that a third dose of an authorized mRNA COVID-19 vaccine should be offered to moderately to severely immunocompromised patients in the authorized age groups. 13 A third dose of a viral vector vaccine should only be considered when other authorized COVID-19 vaccines are contraindicated or inaccessible. Informed consent for an additional dose of viral vector vaccine should include discussion about its lack of evidence as an additional dose in this population, and the increased risk of Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT), Capillary Leak Syndrome (CLS), and Guillain-Barre syndrome (GBS) following viral vector COVID-19 vaccines. 13,14 Moderately to severely immunocompromised cancer patients include those who: 12,13,14 • Are on active treatment for solid tumour or hematologic malignancies that can cause moderate to severe immunosuppression. o Active treatment is defined as chemotherapy, targeted therapies, immunotherapy, and excludes individuals receiving therapy that does not suppress the immune system, e.g. solely hormonal therapy or radiation therapy o Active treatment includes patients who have completed treatment within 3 months, or within 12 months for patients receiving B-cell depleting therapy. • Are on active treatment with the following categories of immunosuppressive therapies: anti-B cell therapies (monoclonal antibodies targeting CD19, CD20 and CD22, e.g., blinatumomab, rituximab, obinutuzumab, inotuzumab ozogamicin), high-dose systemic corticosteroids (prednisone equivalent of ≥ 20 mg/day), alkylating agents (e.g. bendamustine, cyclophosphamide), antimetabolites (e.g. 5fluorouracil, methotrexate), or tumour-necrosis factor (TNF) inhibitors (e.g. infliximab) and other biologic agents that are significantly immunosuppressive. vaccination, and should include booster doses at the appropriate times (e.g., dose 1, 2 and 3 at 3 months, 4 months and 6 months post transplant respectively). Re-vaccination should start 3-6 months after transplant, according to institutional guidelines. A more potent immune response will be obtained if the first vaccine dose is administered closer to the 6-month mark. Patients may end up receiving up to 5 or 6 vaccination doses, depending on whether they were vaccinated pre-transplant.
Refer to the latest NACI recommendations for definition of moderately to severely immunocompromised non-cancer populations.
Ontario guidelines recommend an interval of at least 2 months (8 weeks) between the last dose of the 2dose series and the third dose. As per NACI, the minimum interval should be 28 days; an interval longer than the minimum 28 days between doses is likely to result in a better immune response. If a longer interval is being considered, then risk factors for exposure (including local epidemiology and circulation of variants of concern) and risk of severe disease should also considered. 13,14 Booster Doses 15 Booster doses refer to additional COVID-19 vaccine doses after the primary series is completed.
Individuals with higher risk of severe disease from COVID-19 infection (e.g. moderately to severely immunocompromised, adults 60 years of age and older or living in long-term care homes, or First Nation, Inuit and Métis communities) are strongly recommended to receive booster doses of an authorized mRNA COVID-19 vaccine, as soon as they are eligible.
Booster doses should be administered at least 5 months (minimum 3 months) after completing the primary vaccination series. 14 Booster doses may be a fourth dose in the vaccine series, or more, depending on timing of previous COVID-19 vaccinations.
Please refer to the Ministry of Health -COVID-19 Vaccine Booster Recommendations or local public health units for specific eligibility criteria, dose and timing of COVID-19 vaccine booster doses.
Patients should continue to follow Public Health guidance to avoid exposure to COVID-19, unless otherwise advised by their health care team. To protect those who are immunocompromised, it also is strongly recommended that all people that come into close contact (e.g., family, friends, caregivers) with these individuals are fully vaccinated according to public health guidelines.
Please see Appendix for a complete list of references.
# When should the COVID-19 vaccine be given in relation to other vaccinations?
Currently, it is recommended by Public Health that COVID-19 vaccines may be safely and effectively administered at the same visit, or any time before or after, non-COVID-19 vaccines (including live, non-live, adjuvanted, or unadjuvanted). 1,2,3 Though studies to assess the safety and immunogenicity of concomitant administration of COVID-19 vaccines with other vaccines are ongoing, experience with non-COVID-19 vaccines has demonstrated that immunogenicity and adverse event profiles are generally similar when vaccines are administered simultaneously as when they are administered alone. 1 Although data is still limited in the immunocompromised setting, evidence does not suggest that concomitant administration of COVID-19 vaccines with other non-COVID-19 vaccines (e.g., the flu vaccine) would cause harm or affect efficacy of either vaccine. If more than one type of vaccine is administered at a single visit, they should be administered at different anatomical injection sites. 1,2,3 Patients who are administered vaccines concomitantly should be counseled about the benefits and risks given the limited data available.
# What are possible side effects of the vaccination?
Side effects of the COVID-19 vaccines were usually mild or moderate and generally resolved in a few days. 1,4,6,7,10,11,12 Local reactions for the vaccines included pain, rash, redness or swelling at the injection site. 2,7,11,12,16 Delayed local reactions have been reported. 15 Systemic side effects included fatigue, headache, muscle/joint pain, diarrhea, chills, fever and nausea/vomiting. 2,7,11,12,16 Frequencies of systemic effects for the mRNA COVID-19 vaccines were generally higher after the second dose, and in patients < 56 years of age for the Pfizer vaccine and between 18 to 64 years for the Moderna vaccine. 2,3,7,8 Preliminary data demonstrate side effects after the 3 rd dose of an mRNA vaccine were similar to that of the two-dose series: fatigue, headache, muscle/joint pain and pain at injection site were the most commonly reported side effects, and overall, most symptoms were mild to moderate. 30,31,37 No worsening of underlying disease was reported after immunization. 33 No serious adverse events were deemed to be associated with the additional vaccine dose. The impact of additional doses on rare adverse events, including myocarditis/pericarditis, are unknown. 33 For the AstraZeneca vaccine, fewer and milder adverse reactions were reported after the second dose and reactogenicity reduced with increasing age. 3,10,11 Patients should be educated to seek medical attention if the symptoms last longer than 48-72 hours, due to the similarity with symptoms of COVID-19 or other infections.
Cases of lymphadenopathy occurring in the arm and neck region 24.28 have been reported post all doses of the COVID-19 vaccination, which may mimic metastasis. Following the first and second COVID-19 vaccine doses, vaccine-related lymphadenopathy typically occurs within 7 days of vaccination and generally subsides by 12-14 days. However, vaccine-related lymphadenopathy may persist as far as 4-6 weeks after first and second COVID-19 vaccine administration. 17,21,22,23,26,27 The peak of lymph node activity tends to be earlier after the second vaccination as compared to the first vaccination. 27 Data suggests high grade vaccine-related lymphadenopathy following the third dose has shorter duration (does not usually persists for weeks) and lower uptake intensity after the first 5 days from vaccination. It is unlikely for high grade vaccine-related lymphadenopathy to be observed 6 days from inoculation of the third vaccine dose, and is even less likely in older and obese patients to interfere with imaging interpretations. 38 Consider timing of vaccination and dose number in the vaccine series when assessing patients with new or worsening lymphadenopathy. 2,7,11,12, 13, 14, Very rare cases of moderate-to-severe thrombocytopenia and thrombotic complications at unusual sites (e.g., abdomen, splanchnic vein, sinus or cerebral vein), called vaccine-induced immune thrombotic thrombocytopenia (VITT), have been reported with the AstraZeneca COVID-19 vaccine (some emerging reports with Pfizer or Moderna vaccines in the United States). 3,12,23,25,34,35 In some cases, these have been accompanied by bleeding. 12 VITT typically occurs within 3 weeks following AstraZeneca vaccine administration. 12 Fatalities have been reported. The exact mechanism is still under investigation but appears to be similar to heparin-induced thrombocytopenia (HIT). It is associated with platelet activating antibodies, which stimulate clot formation and thrombocytopenia. Patients should be advised to seek immediate medical attention if they develop symptoms of thromboembolism accompanied by thrombocytopenia, which becomes clinically apparent approximately 4-28 days after receiving a viral vector COVID-19 vaccine and should be monitored for symptoms up to 42 days. 3, 12, 18-20, 23,25 Close monitoring of patients with previous thrombocytopenia is highly recommended as VITT can develop earlier than the expected onset in patients with a history of thrombocytopenia and worsen pre-existing thrombocytopenia. 32 Cases of thrombocytopenia, including immune thrombocytopenia (ITP), have been reported after receiving the AstraZeneca vaccine, typically within the first 4 weeks after vaccination. There were very rare cases of low platelets (< 20 x 10 9 /L) and/or bleeding events, including fatal cases. Some cases occurred in patients with a history of immune thrombocytopenia. 11 Very rare cases of myocarditis and/or pericarditis following vaccination administration of mRNA vaccines have been reported. 2,3,7 The onset of symptoms (including chest pain, shortness of breath and palpitations) have typically occurred within one week after vaccination; cases have occurred more commonly after the second dose, in adolescents, young adults and male patients. 3,36 Available short-term follow-up data suggest that the symptoms are generally mild and resolve in most individuals, but information on long-term sequelae is lacking. Patients receiving an mRNA vaccine should be informed about the very rare risk of myocarditis and/or pericarditis following immunization. Individuals who experienced this adverse effect within 6 weeks of receiving an mRNA vaccine should defer subsequent doses until they have discussed the risks and benefits with their healthcare provider. Cardiology consultation for management and follow up should be considered. 2,3,39 Refer to the COVID-19 vaccine: Canadian Immunization Guide for more information regarding subsequent immunization in individuals who experienced myocarditis.
Bell's Palsy (typically temporary weakness or paralysis on one side of the face) has been reported very rarely after the use of mRNA COVID-19 vaccines. The exact cause is unknown, with symptoms appearing suddenly and generally starting to improve after a few weeks. It is believed to be due to swelling and inflammation of the nerve that controls muscles on one side of the face. 29 Very rare events of demyelinating disorders, such as Guillain-Barré Syndrome, have been reported after vaccination with the AstraZeneca COVID-19 Vaccine. 12 Please see Appendix for a complete list of references.
# Can a cancer patient receive the COVID-19 vaccine if they have allergies?
Severe allergic reactions to the vaccine have been reported. 1,2,4,12,13 Patients with a history of severe allergy (e.g., anaphylaxis) to any of the components of a COVID-19 vaccine, or patients that have had an allergic reaction within 4 hours of receiving a previous dose of a COVID-19 vaccine, should be referred to an allergist, other appropriate physician or nurse practitioner to determine how the vaccine can be safely administered. 15 Polyethylene glycol (PEG), a water-soluble polymer used as a drug delivery vehicle, is a component of both Pfizer and Moderna vaccines and is known to cause mild to severe hypersensitivity reactions. 6,7 Cancer medications containing PEG include (but are not limited to) the following: 1. PEGaspargase (Oncaspar®) 2. Pegfilgrastim (e.g., Neulasta® and others) 3. Liposomal irinotecan (Onivyde®) 4. PEG-liposomal doxorubicin (Caelyx®)
Polysorbate, a surfactant and emulsifier used as an excipient in some drug formulations, 7 is structurally related and has the potential for cross-reactivity to PEG. It is also a component of the AstraZeneca vaccine. 12 Individuals who are allergic to polysorbates should be offered an mRNA vaccine. 16 Cancer medications containing polysorbate include (but are not limited to) the following: 1. Cabazitaxel 2. Docetaxel 3. Etoposide 4. Fosaprepitant (IV) 5. Rituximab (reactions with rituximab are typically a result of cytokine release syndrome and may not be related to polysorbate) 6. Paclitaxel (contains the excipient, Cremophor EL (polyethoxylated castor oil) which has the potential for cross-reactivity with polysorbate) 9 Not all medications that contain PEG or polysorbate will cause allergic reactions and many drugs, including oral medications, may contain PEG or polysorbate in various concentrations, depending on the manufacturer.
Tromethamine is a component of the Moderna vaccine and may cause allergic reactions. It is also a component in contrast media and some oral and parenteral medications (e.g., ketorolac). 14 Individuals who are allergic to tromethamine should be offered the Pfizer-BioNTech COVID19 vaccine if 12 years or age or older. 16 Clinicians should consult individual product monographs for a full list of non-medicinal ingredients if their patients have had a history of anaphylactic reactions to their cancer medications. Patients should be counseled about the risks of developing a severe allergic reaction against the benefits of vaccination.
Refer to Ministry of Health guidance on COVID-19 vaccines and allergies for more information.
Please see Appendix for a complete list of references.
11. When should Evusheld (Tixagevimab and Cilgavimab) be given in relation to the COVID-19 vaccine?
In individuals who have received a COVID-19 vaccine, Evusheld should be administered at least 2 weeks after vaccination. 1 If a patient is currently eligible for a COVID-19 vaccine dose, they should receive the vaccine before receiving Evusheld. There are no data available regarding COVID-19 vaccination after Evusheld administration.
Refer to Information about Evusheld (Tixagevimab and Cilgavimab) for more information.
Please see Appendix for a complete list of references.
# Appendix
1. Are all COVID-19 vaccines safe for cancer patients? | None | None |
be5e3a7d5738e619d2850c10c683e00557d2013a | cma | None | # Background
Cancers of the biliary tract are rare tumors. Although surgery for early-stage disease may offer patients a chance for a cure, most cases are inoperable at the time of diagnosis. They often only produce non-specific symptoms (e.g.: nausea, emesis, anorexia, weight loss, abdominal pain, jaundice). Gallbladder carcinomas and cholangiocarcinomas are tumors with different biology. However, due to the relative rarity of each, they are frequently combined in clinical trials. This guideline was developed to outline the management recommendations for patients with cholangiocarcinoma and adenocarcinoma of the gallbladder. For specific recommendations for the management of malignant biliary obstruction, please refer to the Malignant Biliary Obstruction clinical practice guideline
# Guideline Questions
- What are the management recommendations for adult patients with localized and potentially resectable cancers of the biliary tree or gallbladder? - What are the management recommendations for adult patients with unresectable or metastatic cancers of the biliary tree or gallbladder?
# Search Strategy
This guideline was developed to promote evidence-based practice in Alberta. It was compiled from the results of randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data. The 2023 update did not necessitate a full literature review and focused on adjuvant therapy. Recommendations were modified based on a consensus discussion at the 2023 Annual Gastrointestinal Tumour Team Meeting.
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with cancers of the biliary tree and gallbladder. Different principles may apply to pediatric patients.
# Recommendations and Discussion
# Suggested Diagnostic Work-Up
A complete diagnostic work-up provides the multidisciplinary team with the necessary information required to define and offer the optimal care to patients with biliary cancers. The multidisciplinary team should be composed of radiologists, general and hepatobiliary surgeons, gastroenterologists and hepatologists, and oncologists. The diagnostic work-up should evaluate the liver for local and vascular extension/invasion.
Unresectable or metastatic disease represents an incurable situation for which palliative options should be considered.
An abdominal ultrasound confirms biliary duct dilation, localizes the site of obstruction, and excludes gallstones. A three-phase CT scan detects the disease, locates the level of biliary obstruction, and identifies any regional lymphadenopathy or metastatic disease.
# Proximal Cholangiocarcinoma and Gallbladder Carcinoma:
To establish resectability, the diagnostic work-up should define the proximal extent of the tumor in both lobes of the liver. This can be achieved with MR cholangiopancreatography (MRCP), but percutaneous transhepatic cholangiography (PTC) may be required. Patients should not undergo percutaneous biopsy prior to surgical assessment.
MR cholangiopancreatography is preferred over an endoscopic retrograde cholangiopancreatogram (ERCP) for proximal tumors because of the lower risk of septic complications. If MRCP is not possible, then PTC is preferred over ERCP. Non-interventional imaging studies (e.g.: MRCP) should precede interventional procedures (e.g.: PTC, ERCP, stent placement).
Endoechosonography obtains a biopsy to distinguish between a benign stricture and a cholangiocarcinoma.
# Distal Cholangiocarcinoma:
ERCP is a useful procedure in patients with distal cholangiocarcinomas. MRCP should be reserved for those patients in whom biliary drainage is not imminently required. The other staging procedures are the same as for proximal cholangiocarcinomas.
# Goals of Therapy
To render the patient free of disease, to delay or prevent recurrence, and to improve or prolong survival.
# Recommendations
All patients without overt metastatic disease should be referred to a hepatobiliary surgeon or surgical oncologist for assessment of resectability. Adenocarcinoma of the Gallbladder: - If a gallbladder cancer is suspected pre-operatively, an attempt at laparoscopic resection is contraindicated. Refer patients to a hepatobiliary surgeon or surgical oncologist. - For patients with Tis-1aN0M0 disease identified incidentally at pathologic review of the cholecystectomy specimen, no further therapy is necessary provided an "R0" margin (microscopically negative) is achieved . - When an "R0" (microscopically negative) margin is anticipated for T2-3N0M0 disease, a hepatobiliary surgeon or surgical oncologist may consider a partial hepatectomy with peri-portal lymph node dissection. Consider a laparoscopy to exclude previously unrecognized peritoneal metastases before proceeding to laparotomy 12 . The role of radical surgery is controversial for T1b tumors. Cholangiocarcinoma: - Assessment for resectability should precede instrumentation (e.g.: ERCP, PTC) and biopsy. - Resectability depends upon the extent of tumor within the biliary tree and hepatic parenchyma as well as the absence of invasion into the vasculature, unilateral hepatic lobar atrophy with contralateral extension of disease into the segmental bile ducts, regional lymphadenopathy, and metastatic disease.
- For tumors that involve the confluence of the bile ducts, an "R0" resection involves excision of the tumor, regional lymphadenectomy, cholecystectomy, and (often) partial hepatectomy (possibly to include the caudate lobe). - When an "R0" (microscopically negative) margin is anticipated, lesions distal to the cystic duct require a pancreaticoduodenectomy. Multidisciplinary assessment by hepatology, radiology, and hepatobiliary surgery is crucial. Patients who are poor candidates for surgical resection may be offered locoregional therapy or other approaches.
- The BILCAP trial demonstrated an improvement in overall survival (OS) in the per protocol analysis for patients randomized to 8 cycles of capecitabine versus observation after complete resection of cholangiocarcinoma or gallbladder, median OS was 53 months for Capecitabine and 36 months for Observation, HR 0.75 (95%CI 0.58-0.97; p = 0.028). In this trial, patients with ECOG PS ≤2, were randomized 1:1 to Capecitabine (1250 mg/m2 D1-14 every 21 days, for 8 cycles) or observation [n=447, resection margins: R0 in 279 (62%) and R1 in 168 (38%); 207 (46%) were node-negative. In the intent to treat population, there was a clinically relevant improvement in OS (median OS 51 months with capecitabine versus 36 months for observation, HR 0.80, CI95% 0.63-1.04; p = 0.097). Sensitivity analyses with adjustment for nodal status, grade of disease and gender indicated HR 0.71 (95%CI 0.55 -0.92 p < 0.01) 16,17 . The dose of capecitabine may be determined by institutional and regional practices.
# Unresectable or Metastatic Disease
- Offer palliative maneuvers to maintain and/or improve quality of life. Once resection has been deemed impossible, relieve biliary obstruction (if possible) by stent placement via either ERCP or PTC. In certain circumstances, radiotherapy or palliative surgery may be considered. Consider early referral to palliative care symptom management and palliative care guidelines can be found here . - Tissue diagnosis is important to confirm the histology and for potential involvement in clinical trials. Patients with adenocarcinoma of the gallbladder, cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma are treated similarly, although the prognosis may vary according to the subtype. - Patients should have adequate biliary drainage, acceptable liver and kidney function, and a reasonable performance status. - Preferred: Durvalumab with Gemcitabine and Cisplatin for up to eight cycles followed by durvalumab . The double-blind phase III TOPAZ-1 trial randomized advanced biliary tract cancer patients 1:1 to Gemcitabine and Cisplatin + durvalumab or placebo. Patients had an ECOG status of 0-1 and recurred more than 6 months after curative surgery or the last dose of adjuvant therapy. The hazard ratio for death in the durvalumab arm was 0.80 (95%CI: 0.66-0.97, p=0.021). The hazard ratio for PFS was 0.75 (95%CI:0.63-0.89, p=0.001). The incidences of grade ≥3 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively. 19 The treatment option is Health Canada approved, pCODR recommended, but at the time of publication of this guideline not funded in Alberta.
# Appendix A Staging
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GI Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GI Tumour Team who were not involved in the guideline's development, including surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in March 2010.
# Levels of Evidence | # Background
Cancers of the biliary tract are rare tumors. Although surgery for early-stage disease may offer patients a chance for a cure, most cases are inoperable at the time of diagnosis. They often only produce non-specific symptoms (e.g.: nausea, emesis, anorexia, weight loss, abdominal pain, jaundice). Gallbladder carcinomas and cholangiocarcinomas are tumors with different biology. However, due to the relative rarity of each, they are frequently combined in clinical trials. This guideline was developed to outline the management recommendations for patients with cholangiocarcinoma and adenocarcinoma of the gallbladder. For specific recommendations for the management of malignant biliary obstruction, please refer to the Malignant Biliary Obstruction clinical practice guideline
# Guideline Questions
• What are the management recommendations for adult patients with localized and potentially resectable cancers of the biliary tree or gallbladder? • What are the management recommendations for adult patients with unresectable or metastatic cancers of the biliary tree or gallbladder?
# Search Strategy
This guideline was developed to promote evidence-based practice in Alberta. It was compiled from the results of randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data. The 2023 update did not necessitate a full literature review and focused on adjuvant therapy. Recommendations were modified based on a consensus discussion at the 2023 Annual Gastrointestinal Tumour Team Meeting.
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with cancers of the biliary tree and gallbladder. Different principles may apply to pediatric patients.
# Recommendations and Discussion
# Suggested Diagnostic Work-Up
A complete diagnostic work-up provides the multidisciplinary team with the necessary information required to define and offer the optimal care to patients with biliary cancers. The multidisciplinary team should be composed of radiologists, general and hepatobiliary surgeons, gastroenterologists and hepatologists, and oncologists. The diagnostic work-up should evaluate the liver for local and vascular extension/invasion.
Unresectable or metastatic disease represents an incurable situation for which palliative options should be considered.
An abdominal ultrasound confirms biliary duct dilation, localizes the site of obstruction, and excludes gallstones. A three-phase CT scan detects the disease, locates the level of biliary obstruction, and identifies any regional lymphadenopathy or metastatic disease.
# Proximal Cholangiocarcinoma and Gallbladder Carcinoma:
To establish resectability, the diagnostic work-up should define the proximal extent of the tumor in both lobes of the liver. This can be achieved with MR cholangiopancreatography (MRCP), but percutaneous transhepatic cholangiography (PTC) may be required. Patients should not undergo percutaneous biopsy prior to surgical assessment.
MR cholangiopancreatography is preferred over an endoscopic retrograde cholangiopancreatogram (ERCP) for proximal tumors because of the lower risk of septic complications. If MRCP is not possible, then PTC is preferred over ERCP. Non-interventional imaging studies (e.g.: MRCP) should precede interventional procedures (e.g.: PTC, ERCP, stent placement).
Endoechosonography obtains a biopsy to distinguish between a benign stricture and a cholangiocarcinoma.
# Distal Cholangiocarcinoma:
ERCP is a useful procedure in patients with distal cholangiocarcinomas. MRCP should be reserved for those patients in whom biliary drainage is not imminently required. The other staging procedures are the same as for proximal cholangiocarcinomas.
# Goals of Therapy
To render the patient free of disease, to delay or prevent recurrence, and to improve or prolong survival.
# Recommendations
All patients without overt metastatic disease should be referred to a hepatobiliary surgeon or surgical oncologist for assessment of resectability. Adenocarcinoma of the Gallbladder: [1][2][3][4][5] • If a gallbladder cancer is suspected pre-operatively, an attempt at laparoscopic resection is contraindicated. Refer patients to a hepatobiliary surgeon or surgical oncologist. • For patients with Tis-1aN0M0 disease identified incidentally at pathologic review of the cholecystectomy specimen, no further therapy is necessary provided an "R0" margin (microscopically negative) is achieved [6][7][8] . • When an "R0" (microscopically negative) margin is anticipated for T2-3N0M0 disease, a hepatobiliary surgeon or surgical oncologist may consider a partial hepatectomy with peri-portal lymph node dissection. Consider a laparoscopy to exclude previously unrecognized peritoneal metastases before proceeding to laparotomy 12 . The role of radical surgery is controversial for T1b tumors. Cholangiocarcinoma: [13][14][15] • Assessment for resectability should precede instrumentation (e.g.: ERCP, PTC) and biopsy. • Resectability depends upon the extent of tumor within the biliary tree and hepatic parenchyma as well as the absence of invasion into the vasculature, unilateral hepatic lobar atrophy with contralateral extension of disease into the segmental bile ducts, regional lymphadenopathy, and metastatic disease.
• For tumors that involve the confluence of the bile ducts, an "R0" resection involves excision of the tumor, regional lymphadenectomy, cholecystectomy, and (often) partial hepatectomy (possibly to include the caudate lobe). • When an "R0" (microscopically negative) margin is anticipated, lesions distal to the cystic duct require a pancreaticoduodenectomy. Multidisciplinary assessment by hepatology, radiology, and hepatobiliary surgery is crucial. Patients who are poor candidates for surgical resection may be offered locoregional therapy or other approaches.
• The BILCAP trial demonstrated an improvement in overall survival (OS) in the per protocol analysis for patients randomized to 8 cycles of capecitabine versus observation after complete resection of cholangiocarcinoma or gallbladder, median OS was 53 months for Capecitabine and 36 months for Observation, HR 0.75 (95%CI 0.58-0.97; p = 0.028). In this trial, patients with ECOG PS ≤2, were randomized 1:1 to Capecitabine (1250 mg/m2 D1-14 every 21 days, for 8 cycles) or observation [n=447, resection margins: R0 in 279 (62%) and R1 in 168 (38%); 207 (46%) were node-negative. In the intent to treat population, there was a clinically relevant improvement in OS (median OS 51 months with capecitabine versus 36 months for observation, HR 0.80, CI95% 0.63-1.04; p = 0.097). Sensitivity analyses with adjustment for nodal status, grade of disease and gender indicated HR 0.71 (95%CI 0.55 -0.92 p < 0.01) 16,17 . The dose of capecitabine may be determined by institutional and regional practices.
# Unresectable or Metastatic Disease
• Offer palliative maneuvers to maintain and/or improve quality of life. Once resection has been deemed impossible, relieve biliary obstruction (if possible) by stent placement via either ERCP or PTC. In certain circumstances, radiotherapy or palliative surgery may be considered. Consider early referral to palliative care symptom management and palliative care guidelines can be found here [link]. • Tissue diagnosis is important to confirm the histology and for potential involvement in clinical trials. Patients with adenocarcinoma of the gallbladder, cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma are treated similarly, although the prognosis may vary according to the subtype. • Patients should have adequate biliary drainage, acceptable liver and kidney function, and a reasonable performance status. • Preferred: Durvalumab with Gemcitabine and Cisplatin for up to eight cycles followed by durvalumab [Level of Evidence I Grade of Recommendation A]. The double-blind phase III TOPAZ-1 trial randomized advanced biliary tract cancer patients 1:1 to Gemcitabine and Cisplatin + durvalumab or placebo. Patients had an ECOG status of 0-1 and recurred more than 6 months after curative surgery or the last dose of adjuvant therapy. The hazard ratio for death in the durvalumab arm was 0.80 (95%CI: 0.66-0.97, p=0.021). The hazard ratio for PFS was 0.75 (95%CI:0.63-0.89, p=0.001). The incidences of grade ≥3 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively. 19 The treatment option is Health Canada approved, pCODR recommended, but at the time of publication of this guideline not funded in Alberta.
# Appendix A Staging
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GI Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GI Tumour Team who were not involved in the guideline's development, including surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in March 2010.
# Levels of Evidence
| None | None |
69cd29f1b0d6d12975a3c26cae5f7396c9e71b38 | cma | None | # Background
Thrombocytosis, defined as a platelet count of ≥ 450 x 10 9 /L, is common in clinical practice and can be related to primary or secondary causes. Essential thrombocythemia (ET), a primary cause, is a Philadelphia-negative classical myeloproliferative neoplasm (MPN) defined by clonal thrombocytosis 1 . Similar to other classical MPNs, mutually exclusive driver mutations including JAK2, CALR and MPL are responsible for the pathogenesis of ET with the most frequent mutation JAK2V617F found in 55% of ET, 15-30% having CALR and 4-8% having MPL, while 10-20% lack a driver mutation and are referred to as "triple negative" 2 . ET is complicated by thrombosis and bleeding risk with potential of transformation to myelofibrosis or alternative aggressive myeloid neoplasm. This guideline is to provide information regarding the diagnosis and management of ET based on our current standards.
Guideline Questions
# Search Strategy
This guideline was generated using systematic literature searches of PubMed and MEDLINE databases, ASCO, EHA abstracts and proceedings, and ASH abstracts and proceedings. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The guidelines were also adapted from the NCCN, AJH and BJH guidelines.
# Target Population
Patients who are ≥18 years of age who are suspected of, or diagnosed with essential thrombocythemia.
# Recommendations
- In patients with persistent thrombocytosis with platelet count ≥ 450 x 10 9 /L diagnostic evaluation for ET is suggested once secondary causes of thrombocytosis are ruled out. 2. Diagnosis of ET requires a bone marrow biopsy and is based on recent 2016 WHO criteria. 3. The risk of thrombosis is based on the IPSET thrombosis score (Link). 4. Low-dose ASA therapy (81 mg PO once daily) is suggested for all patients with the exception of those with very low risk disease (younger than 60yrs, CALR mutated, without cardiovascular risk factors). ASA should be avoided in those with extreme thrombocytosis (plts ≥1500 x 10 9 /L) who may have acquired vWD (see point #9) or have alternative bleeding diathesis. In the setting of patients already on a form of anticoagulation or antiplatelet therapy for other comorbidities, addition of low dose ASA is not indicated. 5. Treatment with cytoreduction is suggested for: high risk disease (ET patients ≥60 yrs and/or history of prior arterial/venous thrombosis). 6. First line cytoreductive therapy is hydroxyurea or IFN/PEG-IFN/ROPEG. 7. Second line therapy can include an alternative first line cytoreductive agent, anagrelide or consider combination therapy. 8. The goal of cytoreduction is to normalize the platelet count ideally 1000 x 10 9 /L) results in higher risk of bleeding due to potential for acquired VWD and may require holding ASA therapy if the platelet count is ≥1500 x 10 9 /L, if clinical evidence of bleeding and/or VWF activity levels < 30% 10. The treatment of thrombosis in ET is based on standard thrombosis guidelines. Current practice guidelines suggest primary anticoagulation use of LMWH and VKA therapy. The use of DOACs for treatment of venous thrombosis in MPNs is limited. Discuss cases with local thrombosis experts and manage on a case by case basis. Recurrence of thrombosis is higher among MPN patients with the majority of patients benefiting from lifelong anticoagulation in the setting of unprovoked thrombosis. Lifelong anticoagulation is also suggested for atypical thrombosis particularly in the setting of splanchnic vein and/or cerebral vein thrombosis.
(Thrombosis Canada Link) 11. ET patients have higher rates of pregnancy related complications. ASA therapy is suggested during all MPN pregnancies to improve live birth rates. Prophylactic LMWH is suggested for 6 weeks postpartum. Cytoreduction using IFN, is suggested for high risk pregnancies with prior indication for cytoreduction and those with a high risk pregnancy.
# Pathogenesis
ET is a clonal stem cell disorder resulting in excessive platelet production with increased platelet counts in the peripheral blood. Approximately 90 percent of cases have a somatically acquired driver mutation such as JAK2, CALR, or MPL that results in the upregulation of JAK-STAT pathway and pathogenesis of ET 3 . JAK2V617 is the most frequent driver mutation in ET occurring in ~50-65% of cases followed by 15-30% CALR mutated and 4-8% MPL mutated and 10-20% lack all three mutations and are known at triple negative 4 . The majority of cases of ET are sporadic, although families with an increased incidence of ET have been described, with affected members having the same or different MPN type 5 6 . It is suspected that this is due to a genetic predisposition to acquire somatic mutations and subsequently develop an MPN, rather than a direct inheritance of germline mutations.
# Epidemiology
ET represents one-third of cases of BCR-ABL-negative myeloproliferative neoplasms in the developed world 7 . The incidence rate for ET is 1 to 2.5 new cases/100,000 population per year and varies based on age, sex and race with female to male ratio of 2:1 7,8 The prevalence is higher and estimated to be 9-24 cases per 100,000 population . Median age at diagnosis is 60 years, although up to 20 percent are < 40 years of age 3 . More recent reports suggest younger median age (56 years compared to 60 years) 12 . Extreme thrombocytosis (platelet count ≥ 1 million/L) occurs in less than 2 % of population 13 .
# Clinical Manifestations
Patients present with sustained and progressive thrombocytosis which often can be found incidentally associated with no symptoms. A variable proportion of patients have mild splenomegaly and leukocytosis 14,15 . Up to 40% of patients report being variably symptomatic for fatigue, early satiety, inactivity, concentration issues, and abdominal discomfort, with a consequent decrease in quality of life 16,17 18 .
In addition, patients, may experience arterial and/or venous thrombotic complications with a history of thrombosis occurring at or before diagnosis in ~20% of patients. 3 The overall median thrombotic risk is 1-3%/patients-year 19 with reports of risk of non-fatal arterial and venous thrombosis being 1.2% and 0.6%/patients-year, respectively 20 .
Patient age and history of thrombosis have been considered the main risk factors for vascular complications in MPNs based on ELN classification whereby patients are defined as high risk (HR) if they are at least 60 years and/or have a history of thrombosis, versus low risk (LR) if they do not have either factor 21 . Risk of thrombosis among LR patients is not significantly higher from that of the general population 22 . A more integrated and accurate clinical molecular prognostic score for thrombosis risk in ET, named IPSET-t (International Prognostic Score of thrombosis in Essential Thrombocythemia) has been developed. 23 (IPSET Calculator: Link). It was subsequently, reanalyzed, and validated, with the inclusion of an additional risk group ('very low', VLR) in a revised IPSET-t (Link). Of note, CALR mutations have been associated with lower thrombotic risk compared with JAK2 2 . 24 .
In contrast, risk of bleeding events in ET can occur although less frequently and varies from 5% to 30% 25,26 . The most frequent sites are gastrointestinal and urogenital, but intracranial bleeding may also occur 25 . Extreme thrombocytosis (platelet count > 1000-1500*10 9 /L) is the biggest predictive factor for bleeding as it can be associated with acquired von Willebrand disease (AVWD) 27,28 . This arises due to adsorption of large VW factor multimers by the platelet membrane in the setting of high platelet counts 29 . In cases of extreme thrombocytosis in particular if bleeding has occurred, measure the ristocetin activity and VW factor antigen level. If VWF activity levels are < 30%, antiplatelet therapy should be discontinued. Concomitant use of antiplatelet therapy and prior hemorrhagic event increase risk of hemorrhage while other potential factors may include: leukocytosis 30 and JAK2 mutation. 31
# Diagnostic Evaluation
Thrombocytosis defined as a platelet count ≥ 450 x 109/L has a prevalence of approximately 2% among ambulatory patients ≥ 65 years of age 32 . There are primary and secondary causes for thrombocytosis 33 . The most common causes of secondary or reactive thrombocytosis are: infection, inflammation and/or trauma, and iron deficiency. Initial assessment of patients is necessary to carefully rule out secondary causes.
All patients require a complete history and physical examination. Review diseases and/or conditions associated with thrombocytosis: iron deficiency, malignancy, inflammatory bowel disease, rheumatological disorders, trauma, splenectomy, bleeding. A careful review of thrombotic history including both venous thrombosis and arterial thrombosis and a history of hemorrhagic complications is important. In addition, inquire about microcirculatory/vasomotor symptoms, such as headaches, dizziness, visual disturbances, burning dysesthesia of the palms and soles (erythromelalgia), paresthesia, acrocyanosis as well as constitutional symptoms (night sweats, fevers, weight loss) and signs/symptoms of splenomegaly.
Assess for cardiovascular risk factors, including hypertension, diabetes mellitus, active tobacco use, and hyperlipidemia (considered within IPSET-t score). Review patient's family history of myeloproliferative and thrombosis disease. The diagnosis of ET requires a sustained thrombocytosis of ≥ 450 x 109/L with exclusion of reactive causes. A diagnostic algorithm is shown in Figure 1. A bone marrow examination (aspirate and trephine biopsy) is required based on recent WHO 2016 Criteria 1 . The World Health Organization (WHO) diagnosis of ET (Table 1) requires a platelet count of ≥450 x 10 9/ L, presence of a driver mutation and/or exclusion of an alternative cause of thrombocytosis along with bone marrow morphological consistent pathology 1 . Differential diagnosis of primary (clonal) thrombocytosis includes: primary myelofibrosis (prefibrotic or fibrotic), polycythemia, MPN-U, or variants of MDS. Most patients with MDS/MPN-RS-T carry a SF3B1 mutation 34,35 .
In ET, the bone marrow is normocellular or mildly hypercellular with megakaryocytes increased in number with occasional small loose clusters. Large or giant megakaryocytes with hyperlobation are referred to as "staghorn", nuclei may be prominent. Reticulin is not increased with grade 0/3 expected, Recently WHO classification has defined prefibrotic MF as a separate entity from both ET and overt myelofibrosis (see Table 1). 1 On exam, assess spleen and liver for organomegaly and if any associated features of portal hypertension although splenomegaly is rare in ET compared to alternative MPNs. Likewise, it is important to look for findings' suggestion of thrombosis and/or clinical signs of bleeding/bruising.
PLT
Laboratory studies, including a complete blood count with differential and review of the peripheral smear, and chemistries with liver and renal function and electrolytes in addition to iron studies including transferrin saturation and ferritin should be performed. CRP level can be performed to assess for inflammatory status. If causes of reactive thrombocytosis are ruled out, then additional testing can be performed to rule in an MPN. Peripheral blood testing for JAK2V617F mutation can be done initially and if negative, reflexive testing for mutations of CALR exon 9, and MPL exon 10 can be obtained at some centers by peripheral blood PCR testing (Edmonton) or alternatively will be tested from a bone marrow aspirate sampling (via NGS). The detection of a driver mutation confirms the diagnosis of a myeloid neoplasm but a BM aspirate/biopsy is still required and the absence of a driver mutation does not rule out the diagnosis given cases of triple negative disease 37,38 . Ultimately if an MPN is suspected based on current standards, a bone marrow aspirate and biopsy is required and mutational testing can be obtained from the aspirate if PB sampling not possible. For patients with clinical evidence of bleeding or platelet counts >1000 x 10 9 /L we suggest hemostasis testing (VWF antigen and activity levels) for possible acquired von Willebrand syndrome.
MDS/MPN with ringed sideroblasts and thrombocytosis ( MDS/MPN-RS-t) can mimic ET with patients presenting with mild anemia and thrombocytosis. However, these patients often have a combination of the SF3B1 mutation driver as well as JAK, CALR or MPL (sub clone) but it should be considered as 1/3 of patients will have SF3B1 wildtype 36 . A bone marrow aspirate and biopsy should be performed to differentiate this from ET. In ET, the bone marrow is normocellular for age or mildly hypercellular. Megakaryocytes are increased in number with occasional loose clusters of enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei. Erythropoiesis and granulopoesis is normal with lack of dysplastic morphology and reticulin is not increased grade 0/3. 1 Recommendations 1. Diagnosis of ET requires comprehensive review of secondary/reactive causes and diagnosis of ET requires a bone marrow examination to diagnose primary causes. 2. Driver mutations are mutually exclusive with majority of ET patients possessing one of three driver mutations JAK2, CALR or MPL
# Prognosis
The median estimate of survival among ET patients is 20 years. However, depending on age of presentation, this varies and as a result median survival of patients younger than 60 years of age approaches 33 years 39 . The most common cause of morbidity and mortality is thrombosis which occurs among 20% of ET patients compared to bleeding complications in 10% of this population 3,8 . The IPSET score was developed in order to better stratify prognosis of patients at time of diagnosis.
Patients are determined as low, intermediate or high risk with median survival of: not reached among low risk patients, 24 years and 14 years among intermediate and high risk patients, respectively 40 (Link). Moreover, recent observations suggest that women with ET live longer than male patients and that gender may supersede history of thrombosis as a risk variable for overall survival. 41 Thrombosis and hemorrhage represent two of the main causes of morbidity and mortality in patients with ET. In a study of 891 ET patients, after a median follow-up of 6.2 years, 109 (12%) patients experienced arterial (n = 79) or venous (n = 37) thrombosis. Predictors of arterial thrombosis were: age > 60 years, prior thrombosis, cardiovascular (CV) risk factors (including tobacco use, hypertension, or diabetes mellitus), leukocytosis (> 11 × 10 9 /L), and JAK2V617F mutation 12 . In contrast, predictors of venous thrombosis were only male gender. Elevated platelet count > 1000 × 10 9 /L was associated with a lower risk of arterial thrombosis. Mutant CALR (vs JAK2) was associated with lower incidence of thrombotic events. 42 Current thrombosis risk can be calculated using a revised IPSET-thrombosis prognostic score based on 1019 WHO defined ET patients which takes into account: age, prior thrombosis, JAK mutation status and additional cardiovascular risk factors to further categorize patients into: "very low", low, intermediate and high risk 43,44 (Link) (Table 2) illustrate how each risk factor can influence thrombosis risk. Likewise, pre-PMF can be accurately stratified using similar score as developed for ET. 45 Based on the recent distinction of WHO defined ET and pre-fibrotic MF, the incidence of arterial and venous thrombosis prior to diagnosis is not significantly different 46 (23% vs 20 and 9 vs 8%) and thrombotic complications were also similar during the follow-up 47,48 . However, the overall prognosis varies between ET and prefibrotic MF whereby 10-year survival was found to be 89% vs 76%, with leukemic transformation of 0.7% vs 5.8% and MF transformation 0.8% vs. 12.3%, respectively, in large studies 48 .
# Transformation
The range of transformation risk to post-ET MF has been found to be 0.8-4.9% at 10 years and 4-11% at 15 years. This compares to post-ET AML occurring in 0.7-3% of ET patients at 10 years and 2.1-5.3% at 15 years. Diagnosis of transformation to post ET Myelofibrosis (PET-MF) requires fulfilling the criteria developed, through consensus by the IWG-MRT 49 as outlined in Table 3. Risk factors for progression to PET-MF include pre-PMF morphology, advanced age, and anemia, whereas the presence of JAK2V617F was associated with a lower risk of fibrotic progression 50 .
Risk factors for post-ET AML include: advanced age, leukocytosis, anemia, extreme thrombocytosis, thrombosis, reticulin fibrosis, TP53 or RUNX1 mutations 51 . In a study of over 1100 patients with ET or pre-fibrotic PMF, risk factors for leukemia-free survival were pre-fibrotic PMF, BM morphology, thrombosis, and extreme thrombocytosis (platelets > 1000 × 10 9 /L) 48 . Mutation enhanced prognostic scores have been published 52 whereby spliceosome mutations enhance survival prediction in ET and PV and identify patients at risk for fibrotic progression while TP53 mutations predict leukemic transformation in ET.
Ultimately, transformation of all MPNs leads to poor outcomes and management remains challenging.
Further understanding of the molecular events leading to disease transformation are currently being investigated. 53 The survival for secondary MF differs than that in primary MF and can be calculated using this MYSEC-PM score: (Link). The Treatment of post ET MF is managed similarly based on current AHS Myelofibrosis guidelines (Link).
Transformation of essential thrombocythemia (ET) to myelodysplastic syndromes or acute myeloid leukemia is rare again comprising 1-5% of cases but confers dismal clinical outcome 54 . Post ET AML is defined as ≥ 20% blasts in peripheral blood and/or bone marrow and is prognostically worse and those fit for allogeneic SCT should receive induction chemotherapy and be referred for allogeneic SCT.
EXELS, was the largest prospective study of high-risk essential thrombocythemia (ET) patients, 3460 patients exposed to hydroxyurea (HU), anagrelide (ANA), or both, with an observation time of 5 years. EXELS found higher event rates of acute leukemia transformation in patients treated with HU although this was statistically inconclusive, with more than 90% of the patients having been treated with either ANA or HC. Sixty-seven cases of AML and 19 cases of MDS were recorded. Overall, 39 of 67 AML cases were found in the HU group (8970 person-years of treatment) and another 20 AML patients were found in the group that switched from HC to ANA (2934 person-years of treatment) while three cases were found in the group switching from ANA to HC during the study. Acute leukemia being a known complication of ET occurs in the absence of treatment and based on all available studies one cannot conclude whether or not hydroxyurea or anagrelide are truly leukemogenic 55 .
# Required criteria
- Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria. - Bone marrow fibrosis grade 2-3 (on 0-3 scale).
# Additional criteria (two are required)
- Anemia and a >20g/L decrease from baseline hemoglobin level.
- A leukoerythroblastic peripheral blood picture.
- Increasing splenomegaly defined as either an increase in palpable splenomegaly of > 5cm or the appearance of a newly palpable splenomegaly. - Increased LDH (above reference level) - Development of >1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5°C)
Abnormal karyotype is infrequent in ET and its prognostic relevance uncertain 57
# Treatment
The main goal of therapy is to prevent thrombotic complications, particularly in high risk patients.
Treatment is suggested based on risk adapted prognostic models with "high" risk patients being those older than 60yrs and/or with previous thrombosis (arterial and/or venous) The current IPSET scores 43,59 (Table 2) provides prognostic information and was not directly developed for treatment decisions but provides insight on risk stratification.
# Figure 2. Risk adapted treatment for ET patients
Low dose ASA therapy showed benefit for secondary thrombotic prevention as shown in PV based on the ECLAP study and has been extrapolated to use for ET patients 60 . Low dose ASA (81-100 mg PO daily) has been suggested in all ET patients with exception of "very low" risk (Table 4) and/or those with extreme thrombocytosis (≥1500 x 10 9 /L/1.5 million/L)) and/or bleeding complications 21 61 .
Clopidogrel can be used as alternative agent if ASA allergy. Antiplatelet therapy reduces risks of venous thrombosis in JAK+ ET and lowers arterial thrombosis in ET patients with cardiovascular risk factors however may be ineffective for remaining low risk ET patients. In contrast, CALR-mutated patients have not had thrombosis risk reduction with antiplatelet therapy but rather an increased incidence of bleeding. CALR, MPL and triple negative patients have lower thromboembolic risk in comparison to JAK2 mutated patients 62 . Therefore, we suggest ASA therapy for all high-risk ET patients based on Figure 2. Use low dose ASA in low risk patients if JAK mutated, presence of additional cardiovascular risk factors, and microvascular symptoms with low bleeding risk profile.
Testing for aVWD can be considered if platelets counts are equal to or greater than 1 million/L or in setting of clinical bleeding. ASA therapy is not suggested in the event of VWF levels of less than 30% or if patient is deemed to be at high risk of bleeding based on past or current clinical status. The benefits of ASA antiplatelet therapy have been inferred from polycythemia 60 studies and retrospective studies in ET . In addition, use of twice daily ASA has been suggested among patients with additional cardiovascular risk factors however this has not been formally evaluated.
Patients may be on anticoagulation for alternative comorbidities such as atrial fibrillation and/or prior thrombosis and in this setting it is not suggested that this be replaced by low dose ASA nor do patients require low dose ASA in addition to their baseline anticoagulant or alternative antiplatelet agent (ie. clopidogrel).
# Cytoreduction
Patients found to have conventional high risk disease (age >60yrs or history of thrombosis) or "intermediate" or "high risk" based on IPSET-thrombosis model should receive cytoreduction. In addition, in the setting of extreme thrombocytosis it is suggested to minimize risks of bleeding. Often a threshold of plts ≥1500 x 10 9 /L is selected as time for starting cytoreduction. The target platelet count is variable among various studies and generally one attempts to achieve normalization of platelet count. Experts often suggest a platelet count between 450 x 10 9 /L to 600 x 10 9 /L as acceptable with attempts to achieve control while minimizes additional cytopenias and side effects of treatment. Many studies indicate risk of thrombosis is associated with high leukocyte count rather than actual platelet count 12, .
First line cytoreduction is hydroxyurea and/or interferon-alfa 2a (IFN). In those with high risk disease, use of hydroxyurea (HU) has been shown to reduce thrombotic events compared to no cytoreduction 3.6% vs 24% (p=0.003) 71 . Starting dose is often 1000mg PO daily or 10-15mg/kg/day and can be titrated upwards with maximal dose being 2.5g/day. The ELN recommends hydroxyurea as first-line cytoreduction for any age although caution should be considered in patients younger than 40 years whereby hydroxyurea is teratogenic and should be avoided in those of child-bearing age 21 . Overall hydroxyurea is more widely used based on findings of the PT-1 trial assessing 809 high risk ET patients with findings of hydroxyurea being superior to anagrelide in terms of reducing atrial thrombosis, serious hemorrhage and myelofibrotic progression 72 . An open-label RCT (n=382) showed no benefit to Hydroxyurea plus ASA therapy in ET patients 40-59 yrs lacking high risk features (thrombosis, hemorrhage, ischemia, plts >1500 x 10 9 /L) therefore cytoreduction is being restricted to higher risk disease 73 .
Hydroxyurea is an antimetabolite that inhibits ribonucleoside diphosphate-reductase slowing down DNA synthesis and repair. Side effects of hydroxyurea are often self-limited and/or reversible and include bone marrow suppression, anorexia/nausea/diarrhea and skin alterations such as alopecia, rash, leg ulcers and increased risk of nonmelanomatous skin cancer. Rarer complications are fever, pneumonitis, liver injury, azoospermia and it is considered teratogenic 72 . Its risk for leukemogenic is controversial and not well supported in long term studies .
Currently we follow ELN criteria for clinicohematological response 77 (See appendix A).
Patients require optimal follow up and may require monthly lab work in the setting of cytoreductive therapies with clinical assessments on a 6-12 month basis. In the event of suspected myelofibrotic or leukemic transformation a repeat bone marrow aspirate/biopsy and/or abdominal ultrasound can be additionally performed. Baseline ultrasound and abdominal diagnostic imaging are not routinely performed.
# Hydroxyurea resistance/intolerance
Hydroxyurea resistance and/or intolerance has been defined by ELN (Table 4).
Inadequate control of platelet count can occur for which options may include: relaxing platelet target (i.e. to less than 600 x 10 9 /L) or switch to second line therapy or consider combination therapy (i.e. HU and anagrelide ) 81 . Relaxed plt targets were studied by Cortelazzo et al 71 whereby there was no significant increased incidence of thrombosis compared to more stringent plt control of 400 x 10 9 /L among the PT-1 study 72 . Patents with a history of thrombosis should receive the most optimal cytoreduction that can be attained. In a retrospective series of 166 patients treated with hydroxyurea for a median of 4.5 years, 70% were able to achieve CR at 1 year. The best discriminating factor for resistance was detection of anemia. Twenty percent of this population met ELN criteria for resistance/intolerance and this resulted in poorer survival with 6 fold higher risks of death and median subsequent survival from onset of anemia was only 2.4 years. There was a lack of correlation between CR status and lower thrombosis incidence suggesting a particular platelet threshold is not the only factor resulting in thrombosis to consider 82 .
# Definition of resistance/intolerance to HU in patients with ET
- Platelet count > 600 x 10 9 / L after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight >80kg) - Platelet count > 400 x 10 9 /Land WBC l 400 x 10 9 /L and Hb less than 100g/L at any dose of HU - Presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HU - HU-related fever Anagrelide is a second-line option for cytoreduction if hydroxyurea resistance/intolerance occurs as discovered in the ANAHYDRET trial (n=259) to be non-inferior to hydroxyurea in preventing vascular events 83 . Alternative studies have illustrated superiority of hydroxyurea in combination with low dose ASA compared to anagrelide and low dose ASA for high risk ET patients in the ability of reducing vascular events. Thus, anagrelide remains a second line option and also poses concerning side effects particularly its potential cardiotoxicity 72 . Common side effects include: palpitations, headaches, GI upset but serious tachyarrhythmias can occur and a baseline ECG is suggested and consider further cardiac evaluation prior to use. Anagrelide has been associated with renal insufficiency, cardiac complications, arrhythmias and cardiomyopathy . Anagrelide has been associated with higher risk for myelofibrosis transformation so consider this risk especially among younger patients. The starting dose of anagrelide is 0.5mg PO OD BID and it can be titrated to maximum 10 mg per day. Alternative agents to anagrelide such as busulfan are leukemogenic and in practice have not been used at our local site recently.
# Interferon (IFN)
Interferon (IFN) is a second-line option for those with hydroxyurea resistance/intolerance and a frontline option in patients who are younger (particularly <40yrs). There is preference to utilize interferon given teratogenic effects of hydroxyurea and long term mutagenic potential has been of concern although observational studies have not shown an increased leukemic transformation rate 75 . Interferon is an immunomodulatory agent that suppresses pluripotent and lineage committed hematopoietic progenitors and directly inhibitors thrombopoietin induced megakaryocytic growth 88 . IFN side effects include depression, fatigue, hepatitis and pneumonitis with approximately one third of patients discontinuing therapy secondary to intolerance 89 . Prior to initiation of treatment assess thyroid and liver function and rule out presence of autoimmune disorder and/or psychiatric history. Generally, it is initiated at 3 x 10 6 /million units three times a week with titration. Given the anticipated flu-like symptoms, consider prophylactic treatment with acetaminophen.
The benefits of interferon consist of high hematologic and molecular remissions, with the latter suggesting potential for disease modification 90,91 . Newer formulations that are PEGylated (PEG) allow for weekly administration with the aim of reducing the side effect profile and ameliorating use and compliance including both PEG-IFNa-2B and PEG-IFN-2a. PEGylated interferon-2a has been shown to induce hematologic and complete molecular response in a subset of JAK mutated ET patients that may be sustained after drug discontinuation 91,92,93. Therapy can be initiated at 45ug and titrated up to 180ug SC weekly as tolerated. In a recent systemic review and meta-analysis of IFN therapy in ET (730 ET patients) treated with various formulations of IFN over a period of more than three decades, the ORR was reported by all 30 ET studies and was 80.6% (95% CI 76.6-84.1%) Here, the complete hematologic remission/complete remission (CHR/CR) rate was 59.0% (95% CI 51.5-66.1%) with significant heterogeneity among the studies. The CHR/CR rate was not statistically significantly different (p = 0.23) between peg-IFN compared to non-peg-IFN and adverse events and discontinuation rates were reported as very similar 94 .
Similarly, the Phase III DALIAH trial randomized 205 previously untreated MPN patients to interferon alfa-2a, interferon alfa-2b, or hydroxyurea (HU). Patients ≤ 60 years were assigned to INF-α-2a vs 2b only (1:1 randomization), whereas patients > 60 years were randomized (1:1:1) to all three agents to include the standard of HU. The interim analysis observed a 49% ORR in ET, PV, and pre-MF patients treated with interferon alfa which was lower than the 75% response rate seen with HU. Drugrelated discontinuation was higher in the r-IFNα group (34-45% vs 13% for HU), with grade ≥ 3 adverse events (AEs) was similar in all groups. 95 The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy in high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%). CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. PEG discontinuation related to AEs occurred in only 13.9% of subjects. 96 The MPN-RC-112 was a randomized, open label, phase 3 clinical trial comparing HU and PEG in pts with high risk ET/PV. After a median follow-up of 89.9 weeks (in patients treated > 24 months), PEG-IFN provided non-significantly higher rate of ORR (60% vs 41% for HU, p = 0.22). Interestingly, treatment with HU was associated with a higher rate of bone marrow best response (33% vs 17% PEG-IFN, p = 0.05). Six pts randomized to HU never received treatment due to study withdrawal prior to initiation of treatment. A higher incidence of grade ≥ 3 AE occurred for those on PEG-IFN (46.3% vs 27.5% for HU). 97 Newer formulations such as Ropegintereferon alfa 2b (Ropeg, Besremi®) are available. These show promise with the ease of weekly or q2weekly subcutaneous injections being preferred and infers less injection related toxicity with newer IFN formulations being favored among patients and physicians. Ropeg was compared against HU in the phase 3, randomized, multicenter PROUD-PV study (continuing after 12 months as CONTINUATION-PV) in PV patients, who were either treatment naïve or who had already been treated with HU for <3 years and were neither intolerant nor complete responders. In 2019, Ropeg (Besremi®) received approval via European Medicines agency as a monotherapy in PV patients without symptomatic splenomegaly, independent of previous HU exposure. Future studies are pending in ET.
# JAK inhibitors
JAK1/2 Inhibitor, Ruxolitinib, is approved in Canada as second line treatment for PV patients resistant or intolerant to hydroxyurea based on its superiority shown in RESPONSE and RESPONSE-2 studies 99 , 100 . However, Ruxolitinib is not currently approved for ET. The MAJIC-ET study did not find any advantage to the use of Ruxolitinib compared to best available treatment (BAT) among ET patients with hydroxyurea resistance/intolerance (n=110). At 1 year CHR rates were 46.6% for ruxolitinib treated compared to 44.2% for BAT treated patients (p=0.40) with no difference in thrombosis, hemorrhage or transformation rates at 2 years. Improvement in disease related symptoms was noted among ruxolitinib treated arm 101 . It should be acknowledged that symptom burden is often high among MPN patients and consideration should be made into alternative therapies in order to address ongoing symptom management and improving QOL among ET patients 102 . The comparison of anagrelide to ruxolitinib is currently under evaluation (NCT031235888).
# Recommendations
- Low-dose ASA therapy (81 mg PO once daily) is suggested for all patients with the exception of those with very low risk disease (younger than 60yrs, CALR mutated, without cardiovascular risk factors). ASA should be avoided in those with extreme thrombocytosis (plts >1500 x 10 9 /L) who may have acquired vWD (see point #9) or have alternative bleeding diathesis. In the setting of patients already on a form of anticoagulation or antiplatelet therapy for other comorbidities, addition of low dose ASA is not indicated. 2. Treatment with cytoreduction is suggested for: high risk disease (ET patients ≥60 yrs and/or history of prior arterial/venous thrombosis) 3. First line cytoreductive therapy is hydroxyurea or IFN/PEG-IFN/ROPEG 4. Second line therapy can include an alternative first line cytoreductive agent, anagrelide or consider combination therapy. 5. The goal of cytoreduction is to normalize the platelet count ideally <450 x10 9 /L. This is to be achieved without development of alternative severe cytopenias and/or side effects.
# Special Considerations in ET Extreme Thrombocytosis:
Extreme thrombocytosis is defined as platelet count >1000 x 10 9 /L. Although thrombosis is the most commonly feared complication related to ET, bleeding is in fact the complication of extreme thrombocytosis. This risk arises as a result of functional von Willebrand factor deficiency due to more platelet binding to large VWF multimers resulting in their increased clearance from the plasma 28,103 . Consideration for testing for acquired VWD via ristocetin cofactor activity level is suggested if using aspirin in setting of extreme thrombocytosis. Likewise, the use of antiplatelet agents in patients with low-risk ET and extreme thrombocytosis is associated with increased risk of bleeding 62 .
Cytoreduction should be initiated to reduce platelet counts in the setting of bleeding while also discontinuing antiplatelet and/or anticoagulants in the setting of bleeding relating to aVWD. MPNassociated acquired von Willebrand's disease will resolves once platelet counts normalize.
Desmopressin and tranexamic acid may also be used in cases of severe acute bleeding, while platelet transfusions, von Willebrand factor-containing concentrates, or other factor concentrates are restricted to more severe or life-threatening bleeding 104 .
Not every patient with extreme thrombocytosis requires cytoreduction and the threshold to initiate cytoreduction is variable. Particularly, in asymptomatic patients with low risk disease medical monitoring may be considered. In a cohort of 445 ET patients with 99 being young (age 1000 x 10 9 /L, 75 received cytoreduction therapy with either hydroxyurea or anagrelide compared to 24 patients who had treatment deferred until occurrence of a vascular event. The incidence of post diagnosis major thrombosis was 33% vs 18% (p=0.17) revealing no difference in the prevalence of thrombotic nor hemorrhagic complications and this included when using a cut-off age of 40 years or when excluding those with microvascular symptoms from the overall analysis 105 . Further data is needed in this area including the best platelet threshold to initiate cytoreduction and the goal platelet target among these asymptomatic low risk patients.
# Thrombosis:
Thrombosis and bleeding are major causes of death in ET, with case-fatality rates of 33% to 51% and 1% to 10% 20,59 . Based on a Canadian systematic review, 21 ET studies (15 comparative and 6 single-group) examined thrombosis. They found a median thrombosis risk of 19.9 events per 1000 patient-years without antiplatelet therapy and a modest relative risk reduction (26%) with use of antiplatelet therapy. Median estimates of the risk for bleeding among ET patients without antithrombotic medications were 7.8 and 8.5 events per 1000 patient-years for any bleeding and 5.9 and 6.4 events per 1000 patient-years for major bleeding. Antiplatelet agents were associated with a median increased risk for bleeding (median increase in major bleeding 30%). Evidence on the potential effects of antiplatelet agents on mortality and disease transformation was insufficient to draw a formal conclusion.
This confirms that ET patients are at high thrombotic risk. Particularly a risk for cardiovascular events of 10 to 20 events per 1000 patient-years (10% to 20% 10-year risk). The use of antiplatelet therapy results in 26% risk reduction which is consistent with that in the general population (12% to 18%) but thrombotic risk in ET remains high despite the use of antiplatelet therapy 106 .
In the event of a thrombotic event, acute thrombosis management is based on standard arterial and venous thrombosis guidelines. (Add thrombosis Canada link: /) Individual arterial and venous thrombosis risk factors need to be aggressively managed and controlled. Optimization of platelet count is important to avoid recurrent thrombosis. MPNs typically present with unusual or atypical thrombosis including splanchnic vein thrombosis. Thrombosis can occur in context of normal peripheral blood findings and many be a presenting feature of MPN.
The rate of recurrent VTE in the general population is 5-7% pt-years. Post-discontinuation of anticoagulation in the general population leads to a recurrence rate of 30% at 5 years after an unprovoked VTE, respectively, and 15% after provoked VTE . The rate of recurrent thrombosis in Ph-neg MPN patients is 7.6% pt-years 20 3.4 % on VKAs and 9.4% off VKAs, respectively (p = 0.016) 114 After stopping VKAs, the recurrence rate was 42.3% at 5 years; this being higher than the 29.1% rate observed at 5 years in the non-MPN patients 66 .
Atypical thrombosis is more prone to recurrences and are generally seen more commonly among MPN patients. The efficacy of hydroxyurea in preventing thrombosis is significant for arterial thrombosis but limited for venous thrombosis 115 . Likewise, one must consider bleeding risk of Ph-neg MPN patients, with the incidence of major bleeding being 0.9-2.4% pt-years on VKAs and 0.7-1.5 off VKAs and up to 2.8% pt-years when combining VKAs and aspirin 66,114,116 .
Overall there is heterogeneity in treatment practices for thrombosis in MPN patients with the recent consensus statements suggesting a prolongation of anticoagulation after unprovoked VTE, a lifethreatening VTE or a VTE recurrence but there are no controlled studies that provide evidence directing our management 107, .
# Recommendations:
- The treatment of thrombosis in ET is based on standard thrombosis guidelines. 2. Current practice guidelines suggest primary anticoagulation use of LMWH and VKA therapy. 3. The use of DOACs for treatment of venous thrombosis in MPNs is limited. Discuss cases with local thrombosis experts and manage on a case by case basis. 4. Recurrence of thrombosis is higher among MPN patients with the majority of patients benefiting from lifelong anticoagulation in the setting of unprovoked thrombosis. Lifelong anticoagulation is also suggested for atypical thrombosis particularly in the setting of splanchnic vein and/or cerebral vein thrombosis.
# Pregnancy and hormone therapy:
Approximately 20% of patients with essential thrombocythemia are younger than 40 years at diagnosis 120 and of child bearing age. Pregnant MPN patients should ideally be under joint care of a consultant obstetrician experienced in the care of patients with high-risk pregnancies and a hematologist. Historically, platelet counts decline during pregnancy but do increase postpartum 121 and careful monitoring of MPN patients is required. Many expert opinions and guidelines have been published regarding best management practices. Essential thrombocythemia is associated with complications of eclampsia, placental abruption, intrauterine growth retardation and still birth 125 . Spontaneous abortion rates are reported in 25-50% of cases of ET pregnancy mainly in first trimester 126 Of note the overall risk rate of spontaneous abortion (≤20th week) in normal pregnancies is 11% and is accounting for 80% of all fetal losses 127 . The overall risk of stillbirth (intrauterine death >20th week and infant born showing no signs of life) in normal pregnancies is observed in 0.43% 127 . The rate of premature delivery is about 9% 128 and rates of miscarriage rate range between 10-15% 129 .
In report by Griesshammer et al of 793 pregnancies in 492 women with ET a successful birth rate was achieved in 68.5% (543 live births in 793 pregnancies) with a miscarriage rate of 31.5% (250 miscarriages in 793 pregnancies). First trimester abortion (≤20th week) was the most frequent complication in 26.5% (210 spontaneous abortions in 793 pregnancies). Stillbirth, defined as fetal loss >20th week, occurred in 4.8%, which is more than 10 times higher than the overall risk of stillbirth in non-MPN pregnancies. Preterm delivery (birth <37th week) was found in 8.6% (43 of 502 evaluable pregnancies) and appears comparable to the rate in normal pregnancy with 9%. 122 Aspirin has been used for prevention of uteroplacental insufficiency in high-risk groups because aspirin inhibits platelet aggregation and results in a reduction of oxidative stress and inflammation 130 .
In a meta-analysis, aspirin reduced the risk of preterm birth in high-risk pregnancies by 14% (relative risk, 0. unadjusted odds ratio, 9.7; 95% CI, 2.3-41.0) were associated with 9 to 10-fold higher odds of live births. However, the addition of low doses of LMWH or unfractionated heparin to aspirin was not associated with significantly different odds of live birth (6 studies, 96 pregnancies; unadjusted OR, 2.1 for aspirin with heparin vs aspirin alone; 95% CI, 0.5-9.0; I 2 = 0%). The administration of LMWH alone was not associated with significantly different odds of live birth (unadjusted OR, 6.0; 95% CI, 0.40-90.1; I 2 = 0%). 134 Low molecular weight heparin is safe and effective for treating and preventing thrombosis in pregnancy 135 . Whether or not LMWH is beneficial in maternal VTE risk reduction for ET patients was studied in 756 ET pregnancies in which antepartum and postpartum VTE risk was identified as 2.5% vs 4.4% respectively, with a defined threshold of 3% at which LMWH prophylaxis is recommended. 133 The analysis led to recommendations that LMWH prophylaxis should be considered based on the presence of additional risk factors and a preference and values-based discussion, given a modest absolute risk of VTE. For women with ET during the post-partum period, use of LMWH prophylaxis to prevent thrombosis is suggested.
In particular "high risk" MPN pregnancies may benefit from adding prophylactic low dose molecular weight heparin (dalteparin 5000 IU or enoxaparin 40 mg once daily) to low-dose aspirin throughout pregnancy and for 6 weeks postpartum. 21 A "high-risk" MPN pregnancy is considered, if any of the following factors is present: 21,122 1. Prior thrombosis or severe hemorrhage in MPN patient. 2. Previous pregnancy complication like spontaneous abortion, intrauterine death or stillbirth, preeclampsia necessitating preterm delivery 45-50%. 3. Marked sustained increase in platelet count to greater than 1,500 × 10 9 /L.
The local approach is to offer antenatal LMWH thromboprophylaxis in the presence of prior thrombosis or in the presence of one additional "high risk" factor. All women are offered six weeks post-partum thromboprophylaxis with LMWH. These recommendations are independent of aspirin, which should be continued concurrently.
If cytoreduction is needed which also applies to "high risk" MPN pregnancies, interferon alpha (IFN) based therapy is the drug of choice. Pegylated interferon alpha should be preferred due to better tolerability and efficacy. Griesshammer et al. summarized the literature regarding IFN over 90 MPN pregnancies. 122 Importantly, in the event of planning pregnancy, preconception recommendations are to discontinue the use of possible teratogenic drugs such as hydroxyurea with a 3-6 months washout period being advised. Both men and women who are considering family growth should attempt this 3-6 month wash out period under the consultation of their physician. Alternative cytoreduction should be considered such as IFN based therapy if indicated based on ET risk status or begin administration if high-risk pregnancy with complications (as above). Platelet counts should not exceed 1500 × 10 9 /lL due to an acquired von Willebrand's syndrome and risk of peripartum bleeding. 122 Uterine artery Doppler is a predictive test for the development of pregnancy complications such as pre-eclampsia, intra-uterine growth restriction, abruption and fetal death and should be performed between 18 and 24 weeks in all MPN pregnancies. A systematic review and meta-analysis have shown that an increased pulsatility index (PI) was the best predictor of pre-eclampsia (positive likelihood ratio 210 among high-risk patients and 75 among low-risk patients). It was also the best predictor of overall (positive likelihood ratio 91) and severe (positive likelihood ratio 146) intrauterine growth restriction among low-risk patients 136 . In women with a positive test (i.e. mean uterine artery PI > 14) consider escalating anticoagulant therapy and enhancing screening with serial growth scans. 124 With respect to breastfeeding, heparins are not excreted in breast milk and may be used safely when breast feeding. Aspirin and LMWH are not contraindicated in a breast-feeding woman. 124 Hydroxyurea, and possibly anagrelide are excreted in breast milk. Interferon α is variably excreted in breast milk and may be active orally; however, there is an absence of safety data rather than evidence of harm to the neonate. The recent HELPS trial 137 Hydroxyurea Exposure in Lactation: a Pharmacokinetics (PK) Study, illustrated that breastfeeding mothers will transfer only a small amount of hydroxyurea to their infants, so lactation during hydroxyurea treatment should not be contraindicated.
# Hormones:
There is currently insufficient data available to evaluate the effects of combined OCP, hormonal replacement or ovarian stimulation in ET. In a series of 305 female patients with ET, the use of estrogen-containing hormone therapy was not associated with an increase in venous or arterial thrombotic events. However, the use of oral contraceptives was associated with a threefold increased risk of venous thrombosis (23 versus 7 percent) and a fivefold increased risk of splanchnic thrombosis (15 versus 3 percent). 138 Overall it is suggested hormonal therapy be avoided in MPN patients.
# Surgery:
Generally, MPNs are associated with higher odds of any surgery-related complications (OR, 1.37; P = .0099). 139 ET patients have a 5-6-fold higher risk of thrombosis perioperative 140 . Controlling of platelet count preoperatively with ideal normalization of count is suggested preoperatively. Of note, complications of blood loss and postoperative infection may result in reactive thrombocytosis and should be considered if reinitiating of cytoreduction postoperatively, Likewise, hydroxyurea can impair would healing so this needs to be reviewed and considered if delays in post-operative recovery are noted. Postoperative thromboprophylaxis is suggested although not necessary to extend beyond normal postoperative recommendations and/or hospitalization on the basis of MPN existence.
Appendix A: ELN criteria for response 21,75 Type of response Criteria Complete remission -Durable (at least 12 weeks) resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement AND -Durable peripheral blood count remission (platelet count ≤400 x 10 9 /L, leukocyte count grade 1 reticulin fibrosis Partial remission -Durable resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement AND -Durable peripheral blood count remission (platelet count ≤400 x 10 9 /L, leukocyte count <10x10 9 /L, absence of leukoerythroblastosis) AND -No signs of progressive disease, absence of any hemorrhagic or thrombotic events AND -No marrow histological remission defined as the persistence of megakaryocyte hyperplasia No response Any response that does not satisfy partial remission Progressive disease
# Transformation into PV, PET MF, MDS or s-AML
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Hematology Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, hematologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Hematology Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2021.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations | # Background
Thrombocytosis, defined as a platelet count of ≥ 450 x 10 9 /L, is common in clinical practice and can be related to primary or secondary causes. Essential thrombocythemia (ET), a primary cause, is a Philadelphia-negative classical myeloproliferative neoplasm (MPN) defined by clonal thrombocytosis 1 . Similar to other classical MPNs, mutually exclusive driver mutations including JAK2, CALR and MPL are responsible for the pathogenesis of ET with the most frequent mutation JAK2V617F found in 55% of ET, 15-30% having CALR and 4-8% having MPL, while 10-20% lack a driver mutation and are referred to as "triple negative" 2 . ET is complicated by thrombosis and bleeding risk with potential of transformation to myelofibrosis or alternative aggressive myeloid neoplasm. This guideline is to provide information regarding the diagnosis and management of ET based on our current standards.
Guideline Questions
# Search Strategy
This guideline was generated using systematic literature searches of PubMed and MEDLINE databases, ASCO, EHA abstracts and proceedings, and ASH abstracts and proceedings. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The guidelines were also adapted from the NCCN, AJH and BJH guidelines.
# Target Population
Patients who are ≥18 years of age who are suspected of, or diagnosed with essential thrombocythemia.
# Recommendations
1. In patients with persistent thrombocytosis with platelet count ≥ 450 x 10 9 /L diagnostic evaluation for ET is suggested once secondary causes of thrombocytosis are ruled out. 2. Diagnosis of ET requires a bone marrow biopsy and is based on recent 2016 WHO criteria. 3. The risk of thrombosis is based on the IPSET thrombosis score (Link). 4. Low-dose ASA therapy (81 mg PO once daily) is suggested for all patients with the exception of those with very low risk disease (younger than 60yrs, CALR mutated, without cardiovascular risk factors). ASA should be avoided in those with extreme thrombocytosis (plts ≥1500 x 10 9 /L) who may have acquired vWD (see point #9) or have alternative bleeding diathesis. In the setting of patients already on a form of anticoagulation or antiplatelet therapy for other comorbidities, addition of low dose ASA is not indicated. 5. Treatment with cytoreduction is suggested for: high risk disease (ET patients ≥60 yrs and/or history of prior arterial/venous thrombosis). 6. First line cytoreductive therapy is hydroxyurea or IFN/PEG-IFN/ROPEG. 7. Second line therapy can include an alternative first line cytoreductive agent, anagrelide or consider combination therapy. 8. The goal of cytoreduction is to normalize the platelet count ideally < 450 x10 9 /L. This is to be achieved without development of alternative severe cytopenias and/or side effects. 9. Extreme thrombocytosis (plts ≥ 1 million/L or >1000 x 10 9 /L) results in higher risk of bleeding due to potential for acquired VWD and may require holding ASA therapy if the platelet count is ≥1500 x 10 9 /L, if clinical evidence of bleeding and/or VWF activity levels < 30% 10. The treatment of thrombosis in ET is based on standard thrombosis guidelines. Current practice guidelines suggest primary anticoagulation use of LMWH and VKA therapy. The use of DOACs for treatment of venous thrombosis in MPNs is limited. Discuss cases with local thrombosis experts and manage on a case by case basis. Recurrence of thrombosis is higher among MPN patients with the majority of patients benefiting from lifelong anticoagulation in the setting of unprovoked thrombosis. Lifelong anticoagulation is also suggested for atypical thrombosis particularly in the setting of splanchnic vein and/or cerebral vein thrombosis.
(Thrombosis Canada Link) 11. ET patients have higher rates of pregnancy related complications. ASA therapy is suggested during all MPN pregnancies to improve live birth rates. Prophylactic LMWH is suggested for 6 weeks postpartum. Cytoreduction using IFN, is suggested for high risk pregnancies with prior indication for cytoreduction and those with a high risk pregnancy.
# Pathogenesis
ET is a clonal stem cell disorder resulting in excessive platelet production with increased platelet counts in the peripheral blood. Approximately 90 percent of cases have a somatically acquired driver mutation such as JAK2, CALR, or MPL that results in the upregulation of JAK-STAT pathway and pathogenesis of ET 3 . JAK2V617 is the most frequent driver mutation in ET occurring in ~50-65% of cases followed by 15-30% CALR mutated and 4-8% MPL mutated and 10-20% lack all three mutations and are known at triple negative 4 . The majority of cases of ET are sporadic, although families with an increased incidence of ET have been described, with affected members having the same or different MPN type 5 6 . It is suspected that this is due to a genetic predisposition to acquire somatic mutations and subsequently develop an MPN, rather than a direct inheritance of germline mutations.
# Epidemiology
ET represents one-third of cases of BCR-ABL-negative myeloproliferative neoplasms in the developed world 7 . The incidence rate for ET is 1 to 2.5 new cases/100,000 population per year and varies based on age, sex and race with female to male ratio of 2:1 7,8 The prevalence is higher and estimated to be 9-24 cases per 100,000 population [9][10][11] . Median age at diagnosis is 60 years, although up to 20 percent are < 40 years of age 3 . More recent reports suggest younger median age (56 years compared to 60 years) 12 . Extreme thrombocytosis (platelet count ≥ 1 million/L) occurs in less than 2 % of population 13 .
# Clinical Manifestations
Patients present with sustained and progressive thrombocytosis which often can be found incidentally associated with no symptoms. A variable proportion of patients have mild splenomegaly and leukocytosis 14,15 . Up to 40% of patients report being variably symptomatic for fatigue, early satiety, inactivity, concentration issues, and abdominal discomfort, with a consequent decrease in quality of life 16,17 18 .
In addition, patients, may experience arterial and/or venous thrombotic complications with a history of thrombosis occurring at or before diagnosis in ~20% of patients. 3 The overall median thrombotic risk is 1-3%/patients-year 19 with reports of risk of non-fatal arterial and venous thrombosis being 1.2% and 0.6%/patients-year, respectively 20 .
Patient age and history of thrombosis have been considered the main risk factors for vascular complications in MPNs based on ELN classification whereby patients are defined as high risk (HR) if they are at least 60 years and/or have a history of thrombosis, versus low risk (LR) if they do not have either factor 21 . Risk of thrombosis among LR patients is not significantly higher from that of the general population 22 . A more integrated and accurate clinical molecular prognostic score for thrombosis risk in ET, named IPSET-t (International Prognostic Score of thrombosis in Essential Thrombocythemia) has been developed. 23 (IPSET Calculator: Link). It was subsequently, reanalyzed, and validated, with the inclusion of an additional risk group ('very low', VLR) in a revised IPSET-t (Link). Of note, CALR mutations have been associated with lower thrombotic risk compared with JAK2 2 . 24 .
In contrast, risk of bleeding events in ET can occur although less frequently and varies from 5% to 30% 25,26 . The most frequent sites are gastrointestinal and urogenital, but intracranial bleeding may also occur 25 . Extreme thrombocytosis (platelet count > 1000-1500*10 9 /L) is the biggest predictive factor for bleeding as it can be associated with acquired von Willebrand disease (AVWD) 27,28 . This arises due to adsorption of large VW factor multimers by the platelet membrane in the setting of high platelet counts 29 . In cases of extreme thrombocytosis in particular if bleeding has occurred, measure the ristocetin activity and VW factor antigen level. If VWF activity levels are < 30%, antiplatelet therapy should be discontinued. Concomitant use of antiplatelet therapy and prior hemorrhagic event increase risk of hemorrhage while other potential factors may include: leukocytosis 30 and JAK2 mutation. 31
# Diagnostic Evaluation
Thrombocytosis defined as a platelet count ≥ 450 x 109/L has a prevalence of approximately 2% among ambulatory patients ≥ 65 years of age 32 . There are primary and secondary causes for thrombocytosis 33 . The most common causes of secondary or reactive thrombocytosis are: infection, inflammation and/or trauma, and iron deficiency. Initial assessment of patients is necessary to carefully rule out secondary causes.
All patients require a complete history and physical examination. Review diseases and/or conditions associated with thrombocytosis: iron deficiency, malignancy, inflammatory bowel disease, rheumatological disorders, trauma, splenectomy, bleeding. A careful review of thrombotic history including both venous thrombosis and arterial thrombosis and a history of hemorrhagic complications is important. In addition, inquire about microcirculatory/vasomotor symptoms, such as headaches, dizziness, visual disturbances, burning dysesthesia of the palms and soles (erythromelalgia), paresthesia, acrocyanosis as well as constitutional symptoms (night sweats, fevers, weight loss) and signs/symptoms of splenomegaly.
Assess for cardiovascular risk factors, including hypertension, diabetes mellitus, active tobacco use, and hyperlipidemia (considered within IPSET-t score). Review patient's family history of myeloproliferative and thrombosis disease. The diagnosis of ET requires a sustained thrombocytosis of ≥ 450 x 109/L with exclusion of reactive causes. A diagnostic algorithm is shown in Figure 1. A bone marrow examination (aspirate and trephine biopsy) is required based on recent WHO 2016 Criteria 1 . The World Health Organization (WHO) diagnosis of ET (Table 1) requires a platelet count of ≥450 x 10 9/ L, presence of a driver mutation and/or exclusion of an alternative cause of thrombocytosis along with bone marrow morphological consistent pathology 1 . Differential diagnosis of primary (clonal) thrombocytosis includes: primary myelofibrosis (prefibrotic or fibrotic), polycythemia, MPN-U, or variants of MDS. Most patients with MDS/MPN-RS-T carry a SF3B1 mutation 34,35 .
In ET, the bone marrow is normocellular or mildly hypercellular with megakaryocytes increased in number with occasional small loose clusters. Large or giant megakaryocytes with hyperlobation are referred to as "staghorn", nuclei may be prominent. Reticulin is not increased with grade 0/3 expected, Recently WHO classification has defined prefibrotic MF as a separate entity from both ET and overt myelofibrosis (see Table 1). 1 On exam, assess spleen and liver for organomegaly and if any associated features of portal hypertension although splenomegaly is rare in ET compared to alternative MPNs. Likewise, it is important to look for findings' suggestion of thrombosis and/or clinical signs of bleeding/bruising.
PLT
Laboratory studies, including a complete blood count with differential and review of the peripheral smear, and chemistries with liver and renal function and electrolytes in addition to iron studies including transferrin saturation and ferritin should be performed. CRP level can be performed to assess for inflammatory status. If causes of reactive thrombocytosis are ruled out, then additional testing can be performed to rule in an MPN. Peripheral blood testing for JAK2V617F mutation can be done initially and if negative, reflexive testing for mutations of CALR exon 9, and MPL exon 10 can be obtained at some centers by peripheral blood PCR testing (Edmonton) or alternatively will be tested from a bone marrow aspirate sampling (via NGS). The detection of a driver mutation confirms the diagnosis of a myeloid neoplasm but a BM aspirate/biopsy is still required and the absence of a driver mutation does not rule out the diagnosis given cases of triple negative disease 37,38 . Ultimately if an MPN is suspected based on current standards, a bone marrow aspirate and biopsy is required and mutational testing can be obtained from the aspirate if PB sampling not possible. For patients with clinical evidence of bleeding or platelet counts >1000 x 10 9 /L we suggest hemostasis testing (VWF antigen and activity levels) for possible acquired von Willebrand syndrome.
MDS/MPN with ringed sideroblasts and thrombocytosis ( MDS/MPN-RS-t) can mimic ET with patients presenting with mild anemia and thrombocytosis. However, these patients often have a combination of the SF3B1 mutation driver as well as JAK, CALR or MPL (sub clone) but it should be considered as 1/3 of patients will have SF3B1 wildtype 36 . A bone marrow aspirate and biopsy should be performed to differentiate this from ET. In ET, the bone marrow is normocellular for age or mildly hypercellular. Megakaryocytes are increased in number with occasional loose clusters of enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei. Erythropoiesis and granulopoesis is normal with lack of dysplastic morphology and reticulin is not increased grade 0/3. 1 Recommendations 1. Diagnosis of ET requires comprehensive review of secondary/reactive causes and diagnosis of ET requires a bone marrow examination to diagnose primary causes. 2. Driver mutations are mutually exclusive with majority of ET patients possessing one of three driver mutations JAK2, CALR or MPL
# Prognosis
The median estimate of survival among ET patients is 20 years. However, depending on age of presentation, this varies and as a result median survival of patients younger than 60 years of age approaches 33 years 39 . The most common cause of morbidity and mortality is thrombosis which occurs among 20% of ET patients compared to bleeding complications in 10% of this population 3,8 . The IPSET score was developed in order to better stratify prognosis of patients at time of diagnosis.
Patients are determined as low, intermediate or high risk with median survival of: not reached among low risk patients, 24 years and 14 years among intermediate and high risk patients, respectively 40 (Link). Moreover, recent observations suggest that women with ET live longer than male patients and that gender may supersede history of thrombosis as a risk variable for overall survival. 41 Thrombosis and hemorrhage represent two of the main causes of morbidity and mortality in patients with ET. In a study of 891 ET patients, after a median follow-up of 6.2 years, 109 (12%) patients experienced arterial (n = 79) or venous (n = 37) thrombosis. Predictors of arterial thrombosis were: age > 60 years, prior thrombosis, cardiovascular (CV) risk factors (including tobacco use, hypertension, or diabetes mellitus), leukocytosis (> 11 × 10 9 /L), and JAK2V617F mutation 12 . In contrast, predictors of venous thrombosis were only male gender. Elevated platelet count > 1000 × 10 9 /L was associated with a lower risk of arterial thrombosis. Mutant CALR (vs JAK2) was associated with lower incidence of thrombotic events. 42 Current thrombosis risk can be calculated using a revised IPSET-thrombosis prognostic score based on 1019 WHO defined ET patients which takes into account: age, prior thrombosis, JAK mutation status and additional cardiovascular risk factors to further categorize patients into: "very low", low, intermediate and high risk 43,44 (Link) (Table 2) illustrate how each risk factor can influence thrombosis risk. Likewise, pre-PMF can be accurately stratified using similar score as developed for ET. 45 Based on the recent distinction of WHO defined ET and pre-fibrotic MF, the incidence of arterial and venous thrombosis prior to diagnosis is not significantly different 46 (23% vs 20 and 9 vs 8%) and thrombotic complications were also similar during the follow-up 47,48 . However, the overall prognosis varies between ET and prefibrotic MF whereby 10-year survival was found to be 89% vs 76%, with leukemic transformation of 0.7% vs 5.8% and MF transformation 0.8% vs. 12.3%, respectively, in large studies 48 .
# Transformation
The range of transformation risk to post-ET MF has been found to be 0.8-4.9% at 10 years and 4-11% at 15 years. This compares to post-ET AML occurring in 0.7-3% of ET patients at 10 years and 2.1-5.3% at 15 years. Diagnosis of transformation to post ET Myelofibrosis (PET-MF) requires fulfilling the criteria developed, through consensus by the IWG-MRT 49 as outlined in Table 3. Risk factors for progression to PET-MF include pre-PMF morphology, advanced age, and anemia, whereas the presence of JAK2V617F was associated with a lower risk of fibrotic progression 50 .
Risk factors for post-ET AML include: advanced age, leukocytosis, anemia, extreme thrombocytosis, thrombosis, reticulin fibrosis, TP53 or RUNX1 mutations 51 . In a study of over 1100 patients with ET or pre-fibrotic PMF, risk factors for leukemia-free survival were pre-fibrotic PMF, BM morphology, thrombosis, and extreme thrombocytosis (platelets > 1000 × 10 9 /L) 48 . Mutation enhanced prognostic scores have been published 52 whereby spliceosome mutations enhance survival prediction in ET and PV and identify patients at risk for fibrotic progression while TP53 mutations predict leukemic transformation in ET.
Ultimately, transformation of all MPNs leads to poor outcomes and management remains challenging.
Further understanding of the molecular events leading to disease transformation are currently being investigated. 53 The survival for secondary MF differs than that in primary MF and can be calculated using this MYSEC-PM score: (Link). The Treatment of post ET MF is managed similarly based on current AHS Myelofibrosis guidelines (Link).
Transformation of essential thrombocythemia (ET) to myelodysplastic syndromes or acute myeloid leukemia is rare again comprising 1-5% of cases but confers dismal clinical outcome 54 . Post ET AML is defined as ≥ 20% blasts in peripheral blood and/or bone marrow and is prognostically worse and those fit for allogeneic SCT should receive induction chemotherapy and be referred for allogeneic SCT.
EXELS, was the largest prospective study of high-risk essential thrombocythemia (ET) patients, 3460 patients exposed to hydroxyurea (HU), anagrelide (ANA), or both, with an observation time of 5 years. EXELS found higher event rates of acute leukemia transformation in patients treated with HU although this was statistically inconclusive, with more than 90% of the patients having been treated with either ANA or HC. Sixty-seven cases of AML and 19 cases of MDS were recorded. Overall, 39 of 67 AML cases were found in the HU group (8970 person-years of treatment) and another 20 AML patients were found in the group that switched from HC to ANA (2934 person-years of treatment) while three cases were found in the group switching from ANA to HC during the study. Acute leukemia being a known complication of ET occurs in the absence of treatment and based on all available studies one cannot conclude whether or not hydroxyurea or anagrelide are truly leukemogenic 55 .
# Required criteria
• Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria. • Bone marrow fibrosis grade 2-3 (on 0-3 scale).
# Additional criteria (two are required)
• Anemia and a >20g/L decrease from baseline hemoglobin level.
• A leukoerythroblastic peripheral blood picture.
• Increasing splenomegaly defined as either an increase in palpable splenomegaly of > 5cm or the appearance of a newly palpable splenomegaly. • Increased LDH (above reference level) • Development of >1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5°C)
Abnormal karyotype is infrequent in ET and its prognostic relevance uncertain 57
# Treatment
The main goal of therapy is to prevent thrombotic complications, particularly in high risk patients.
Treatment is suggested based on risk adapted prognostic models with "high" risk patients being those older than 60yrs and/or with previous thrombosis (arterial and/or venous) The current IPSET scores 43,59 (Table 2) provides prognostic information and was not directly developed for treatment decisions but provides insight on risk stratification.
# Figure 2. Risk adapted treatment for ET patients
Low dose ASA therapy showed benefit for secondary thrombotic prevention as shown in PV based on the ECLAP study and has been extrapolated to use for ET patients 60 . Low dose ASA (81-100 mg PO daily) has been suggested in all ET patients with exception of "very low" risk (Table 4) and/or those with extreme thrombocytosis (≥1500 x 10 9 /L/1.5 million/L)) and/or bleeding complications 21 61 .
Clopidogrel can be used as alternative agent if ASA allergy. Antiplatelet therapy reduces risks of venous thrombosis in JAK+ ET and lowers arterial thrombosis in ET patients with cardiovascular risk factors however may be ineffective for remaining low risk ET patients. In contrast, CALR-mutated patients have not had thrombosis risk reduction with antiplatelet therapy but rather an increased incidence of bleeding. CALR, MPL and triple negative patients have lower thromboembolic risk in comparison to JAK2 mutated patients 62 . Therefore, we suggest ASA therapy for all high-risk ET patients based on Figure 2. Use low dose ASA in low risk patients if JAK mutated, presence of additional cardiovascular risk factors, and microvascular symptoms with low bleeding risk profile.
Testing for aVWD can be considered if platelets counts are equal to or greater than 1 million/L or in setting of clinical bleeding. ASA therapy is not suggested in the event of VWF levels of less than 30% or if patient is deemed to be at high risk of bleeding based on past or current clinical status. The benefits of ASA antiplatelet therapy have been inferred from polycythemia 60 studies and retrospective studies in ET [62][63][64][65][66] . In addition, use of twice daily ASA has been suggested among patients with additional cardiovascular risk factors however this has not been formally evaluated.
Patients may be on anticoagulation for alternative comorbidities such as atrial fibrillation and/or prior thrombosis and in this setting it is not suggested that this be replaced by low dose ASA nor do patients require low dose ASA in addition to their baseline anticoagulant or alternative antiplatelet agent (ie. clopidogrel).
# Cytoreduction
Patients found to have conventional high risk disease (age >60yrs or history of thrombosis) or "intermediate" or "high risk" based on IPSET-thrombosis model should receive cytoreduction. In addition, in the setting of extreme thrombocytosis it is suggested to minimize risks of bleeding. Often a threshold of plts ≥1500 x 10 9 /L is selected as time for starting cytoreduction. The target platelet count is variable among various studies and generally one attempts to achieve normalization of platelet count. Experts often suggest a platelet count between 450 x 10 9 /L to 600 x 10 9 /L as acceptable with attempts to achieve control while minimizes additional cytopenias and side effects of treatment. Many studies indicate risk of thrombosis is associated with high leukocyte count rather than actual platelet count 12,[67][68][69][70] .
First line cytoreduction is hydroxyurea and/or interferon-alfa 2a (IFN). In those with high risk disease, use of hydroxyurea (HU) has been shown to reduce thrombotic events compared to no cytoreduction 3.6% vs 24% (p=0.003) 71 . Starting dose is often 1000mg PO daily or 10-15mg/kg/day and can be titrated upwards with maximal dose being 2.5g/day. The ELN recommends hydroxyurea as first-line cytoreduction for any age although caution should be considered in patients younger than 40 years whereby hydroxyurea is teratogenic and should be avoided in those of child-bearing age 21 . Overall hydroxyurea is more widely used based on findings of the PT-1 trial assessing 809 high risk ET patients with findings of hydroxyurea being superior to anagrelide in terms of reducing atrial thrombosis, serious hemorrhage and myelofibrotic progression 72 . An open-label RCT (n=382) showed no benefit to Hydroxyurea plus ASA therapy in ET patients 40-59 yrs lacking high risk features (thrombosis, hemorrhage, ischemia, plts >1500 x 10 9 /L) therefore cytoreduction is being restricted to higher risk disease 73 .
Hydroxyurea is an antimetabolite that inhibits ribonucleoside diphosphate-reductase slowing down DNA synthesis and repair. Side effects of hydroxyurea are often self-limited and/or reversible and include bone marrow suppression, anorexia/nausea/diarrhea and skin alterations such as alopecia, rash, leg ulcers and increased risk of nonmelanomatous skin cancer. Rarer complications are fever, pneumonitis, liver injury, azoospermia and it is considered teratogenic 72 . Its risk for leukemogenic is controversial and not well supported in long term studies [74][75][76] .
Currently we follow ELN criteria for clinicohematological response 77 (See appendix A).
Patients require optimal follow up and may require monthly lab work in the setting of cytoreductive therapies with clinical assessments on a 6-12 month basis. In the event of suspected myelofibrotic or leukemic transformation a repeat bone marrow aspirate/biopsy and/or abdominal ultrasound can be additionally performed. Baseline ultrasound and abdominal diagnostic imaging are not routinely performed.
# Hydroxyurea resistance/intolerance
Hydroxyurea resistance and/or intolerance has been defined by ELN [78][79][80] (Table 4).
Inadequate control of platelet count can occur for which options may include: relaxing platelet target (i.e. to less than 600 x 10 9 /L) or switch to second line therapy or consider combination therapy (i.e. HU and anagrelide ) 81 . Relaxed plt targets were studied by Cortelazzo et al 71 whereby there was no significant increased incidence of thrombosis compared to more stringent plt control of 400 x 10 9 /L among the PT-1 study 72 . Patents with a history of thrombosis should receive the most optimal cytoreduction that can be attained. In a retrospective series of 166 patients treated with hydroxyurea for a median of 4.5 years, 70% were able to achieve CR at 1 year. The best discriminating factor for resistance was detection of anemia. Twenty percent of this population met ELN criteria for resistance/intolerance and this resulted in poorer survival with 6 fold higher risks of death and median subsequent survival from onset of anemia was only 2.4 years. There was a lack of correlation between CR status and lower thrombosis incidence suggesting a particular platelet threshold is not the only factor resulting in thrombosis to consider 82 .
# Definition of resistance/intolerance to HU in patients with ET
• Platelet count > 600 x 10 9 / L after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight >80kg) • Platelet count > 400 x 10 9 /Land WBC l< 2.5 x 10 9 /L at any dose of HU • Platelet count > 400 x 10 9 /L and Hb less than 100g/L at any dose of HU • Presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HU • HU-related fever Anagrelide is a second-line option for cytoreduction if hydroxyurea resistance/intolerance occurs as discovered in the ANAHYDRET trial (n=259) to be non-inferior to hydroxyurea in preventing vascular events 83 . Alternative studies have illustrated superiority of hydroxyurea in combination with low dose ASA compared to anagrelide and low dose ASA for high risk ET patients in the ability of reducing vascular events. Thus, anagrelide remains a second line option and also poses concerning side effects particularly its potential cardiotoxicity 72 . Common side effects include: palpitations, headaches, GI upset but serious tachyarrhythmias can occur and a baseline ECG is suggested and consider further cardiac evaluation prior to use. Anagrelide has been associated with renal insufficiency, cardiac complications, arrhythmias and cardiomyopathy [84][85][86][87] . Anagrelide has been associated with higher risk for myelofibrosis transformation so consider this risk especially among younger patients. The starting dose of anagrelide is 0.5mg PO OD BID and it can be titrated to maximum 10 mg per day. Alternative agents to anagrelide such as busulfan are leukemogenic and in practice have not been used at our local site recently.
# Interferon (IFN)
Interferon (IFN) is a second-line option for those with hydroxyurea resistance/intolerance and a frontline option in patients who are younger (particularly <40yrs). There is preference to utilize interferon given teratogenic effects of hydroxyurea and long term mutagenic potential has been of concern although observational studies have not shown an increased leukemic transformation rate 75 . Interferon is an immunomodulatory agent that suppresses pluripotent and lineage committed hematopoietic progenitors and directly inhibitors thrombopoietin induced megakaryocytic growth 88 . IFN side effects include depression, fatigue, hepatitis and pneumonitis with approximately one third of patients discontinuing therapy secondary to intolerance 89 . Prior to initiation of treatment assess thyroid and liver function and rule out presence of autoimmune disorder and/or psychiatric history. Generally, it is initiated at 3 x 10 6 /million units three times a week with titration. Given the anticipated flu-like symptoms, consider prophylactic treatment with acetaminophen.
The benefits of interferon consist of high hematologic and molecular remissions, with the latter suggesting potential for disease modification 90,91 . Newer formulations that are PEGylated (PEG) allow for weekly administration with the aim of reducing the side effect profile and ameliorating use and compliance including both PEG-IFNa-2B and PEG-IFN-2a. PEGylated interferon-2a has been shown to induce hematologic and complete molecular response in a subset of JAK mutated ET patients that may be sustained after drug discontinuation 91,92,93. Therapy can be initiated at 45ug and titrated up to 180ug SC weekly as tolerated. In a recent systemic review and meta-analysis of IFN therapy in ET (730 ET patients) treated with various formulations of IFN over a period of more than three decades, the ORR was reported by all 30 ET studies and was 80.6% (95% CI 76.6-84.1%) Here, the complete hematologic remission/complete remission (CHR/CR) rate was 59.0% (95% CI 51.5-66.1%) with significant heterogeneity among the studies. The CHR/CR rate was not statistically significantly different (p = 0.23) between peg-IFN compared to non-peg-IFN and adverse events and discontinuation rates were reported as very similar 94 .
Similarly, the Phase III DALIAH trial randomized 205 previously untreated MPN patients to interferon alfa-2a, interferon alfa-2b, or hydroxyurea (HU). Patients ≤ 60 years were assigned to INF-α-2a vs 2b only (1:1 randomization), whereas patients > 60 years were randomized (1:1:1) to all three agents to include the standard of HU. The interim analysis observed a 49% ORR in ET, PV, and pre-MF patients treated with interferon alfa which was lower than the 75% response rate seen with HU. Drugrelated discontinuation was higher in the r-IFNα group (34-45% vs 13% for HU), with grade ≥ 3 adverse events (AEs) was similar in all groups. 95 The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy in high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%). CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. PEG discontinuation related to AEs occurred in only 13.9% of subjects. 96 The MPN-RC-112 was a randomized, open label, phase 3 clinical trial comparing HU and PEG in pts with high risk ET/PV. After a median follow-up of 89.9 weeks (in patients treated > 24 months), PEG-IFN provided non-significantly higher rate of ORR (60% vs 41% for HU, p = 0.22). Interestingly, treatment with HU was associated with a higher rate of bone marrow best response (33% vs 17% PEG-IFN, p = 0.05). Six pts randomized to HU never received treatment due to study withdrawal prior to initiation of treatment. A higher incidence of grade ≥ 3 AE occurred for those on PEG-IFN (46.3% vs 27.5% for HU). 97 Newer formulations such as Ropegintereferon alfa 2b (Ropeg, Besremi®) are available. These show promise with the ease of weekly or q2weekly subcutaneous injections being preferred and infers less injection related toxicity with newer IFN formulations being favored among patients and physicians. Ropeg was compared against HU in the phase 3, randomized, multicenter PROUD-PV study (continuing after 12 months as CONTINUATION-PV) in PV patients, who were either treatment naïve or who had already been treated with HU for <3 years and were neither intolerant nor complete responders. In 2019, Ropeg (Besremi®) received approval via European Medicines agency as a monotherapy in PV patients without symptomatic splenomegaly, independent of previous HU exposure. Future studies are pending in ET.
# JAK inhibitors
JAK1/2 Inhibitor, Ruxolitinib, is approved in Canada as second line treatment for PV patients resistant or intolerant to hydroxyurea based on its superiority shown in RESPONSE and RESPONSE-2 studies 99 , 100 . However, Ruxolitinib is not currently approved for ET. The MAJIC-ET study did not find any advantage to the use of Ruxolitinib compared to best available treatment (BAT) among ET patients with hydroxyurea resistance/intolerance (n=110). At 1 year CHR rates were 46.6% for ruxolitinib treated compared to 44.2% for BAT treated patients (p=0.40) with no difference in thrombosis, hemorrhage or transformation rates at 2 years. Improvement in disease related symptoms was noted among ruxolitinib treated arm 101 . It should be acknowledged that symptom burden is often high among MPN patients and consideration should be made into alternative therapies in order to address ongoing symptom management and improving QOL among ET patients 102 . The comparison of anagrelide to ruxolitinib is currently under evaluation (NCT031235888).
# Recommendations
1. Low-dose ASA therapy (81 mg PO once daily) is suggested for all patients with the exception of those with very low risk disease (younger than 60yrs, CALR mutated, without cardiovascular risk factors). ASA should be avoided in those with extreme thrombocytosis (plts >1500 x 10 9 /L) who may have acquired vWD (see point #9) or have alternative bleeding diathesis. In the setting of patients already on a form of anticoagulation or antiplatelet therapy for other comorbidities, addition of low dose ASA is not indicated. 2. Treatment with cytoreduction is suggested for: high risk disease (ET patients ≥60 yrs and/or history of prior arterial/venous thrombosis) 3. First line cytoreductive therapy is hydroxyurea or IFN/PEG-IFN/ROPEG 4. Second line therapy can include an alternative first line cytoreductive agent, anagrelide or consider combination therapy. 5. The goal of cytoreduction is to normalize the platelet count ideally <450 x10 9 /L. This is to be achieved without development of alternative severe cytopenias and/or side effects.
# Special Considerations in ET Extreme Thrombocytosis:
Extreme thrombocytosis is defined as platelet count >1000 x 10 9 /L. Although thrombosis is the most commonly feared complication related to ET, bleeding is in fact the complication of extreme thrombocytosis. This risk arises as a result of functional von Willebrand factor deficiency due to more platelet binding to large VWF multimers resulting in their increased clearance from the plasma 28,103 . Consideration for testing for acquired VWD via ristocetin cofactor activity level is suggested if using aspirin in setting of extreme thrombocytosis. Likewise, the use of antiplatelet agents in patients with low-risk ET and extreme thrombocytosis is associated with increased risk of bleeding 62 .
Cytoreduction should be initiated to reduce platelet counts in the setting of bleeding while also discontinuing antiplatelet and/or anticoagulants in the setting of bleeding relating to aVWD. MPNassociated acquired von Willebrand's disease will resolves once platelet counts normalize.
Desmopressin and tranexamic acid may also be used in cases of severe acute bleeding, while platelet transfusions, von Willebrand factor-containing concentrates, or other factor concentrates are restricted to more severe or life-threatening bleeding 104 .
Not every patient with extreme thrombocytosis requires cytoreduction and the threshold to initiate cytoreduction is variable. Particularly, in asymptomatic patients with low risk disease medical monitoring may be considered. In a cohort of 445 ET patients with 99 being young (age <60years) with extreme thrombocytosis plt >1000 x 10 9 /L, 75 received cytoreduction therapy with either hydroxyurea or anagrelide compared to 24 patients who had treatment deferred until occurrence of a vascular event. The incidence of post diagnosis major thrombosis was 33% vs 18% (p=0.17) revealing no difference in the prevalence of thrombotic nor hemorrhagic complications and this included when using a cut-off age of 40 years or when excluding those with microvascular symptoms from the overall analysis 105 . Further data is needed in this area including the best platelet threshold to initiate cytoreduction and the goal platelet target among these asymptomatic low risk patients.
# Thrombosis:
Thrombosis and bleeding are major causes of death in ET, with case-fatality rates of 33% to 51% and 1% to 10% 20,59 . Based on a Canadian systematic review, 21 ET studies (15 comparative and 6 single-group) examined thrombosis. They found a median thrombosis risk of 19.9 events per 1000 patient-years without antiplatelet therapy and a modest relative risk reduction (26%) with use of antiplatelet therapy. Median estimates of the risk for bleeding among ET patients without antithrombotic medications were 7.8 and 8.5 events per 1000 patient-years for any bleeding and 5.9 and 6.4 events per 1000 patient-years for major bleeding. Antiplatelet agents were associated with a median increased risk for bleeding (median increase in major bleeding 30%). Evidence on the potential effects of antiplatelet agents on mortality and disease transformation was insufficient to draw a formal conclusion.
This confirms that ET patients are at high thrombotic risk. Particularly a risk for cardiovascular events of 10 to 20 events per 1000 patient-years (10% to 20% 10-year risk). The use of antiplatelet therapy results in 26% risk reduction which is consistent with that in the general population (12% to 18%) but thrombotic risk in ET remains high despite the use of antiplatelet therapy 106 .
In the event of a thrombotic event, acute thrombosis management is based on standard arterial and venous thrombosis guidelines. (Add thrombosis Canada link: https://thrombosiscanada.ca/clinicalguides/) Individual arterial and venous thrombosis risk factors need to be aggressively managed and controlled. Optimization of platelet count is important to avoid recurrent thrombosis. MPNs typically present with unusual or atypical thrombosis including splanchnic vein thrombosis. Thrombosis can occur in context of normal peripheral blood findings and many be a presenting feature of MPN.
The rate of recurrent VTE in the general population is 5-7% pt-years. Post-discontinuation of anticoagulation in the general population leads to a recurrence rate of 30% at 5 years after an unprovoked VTE, respectively, and 15% after provoked VTE [111][112][113] . The rate of recurrent thrombosis in Ph-neg MPN patients is 7.6% pt-years 20 3.4 % on VKAs and 9.4% off VKAs, respectively (p = 0.016) 114 After stopping VKAs, the recurrence rate was 42.3% at 5 years; this being higher than the 29.1% rate observed at 5 years in the non-MPN patients 66 .
Atypical thrombosis is more prone to recurrences and are generally seen more commonly among MPN patients. The efficacy of hydroxyurea in preventing thrombosis is significant for arterial thrombosis but limited for venous thrombosis 115 . Likewise, one must consider bleeding risk of Ph-neg MPN patients, with the incidence of major bleeding being 0.9-2.4% pt-years on VKAs and 0.7-1.5 off VKAs and up to 2.8% pt-years when combining VKAs and aspirin 66,114,116 .
Overall there is heterogeneity in treatment practices for thrombosis in MPN patients with the recent consensus statements suggesting a prolongation of anticoagulation after unprovoked VTE, a lifethreatening VTE or a VTE recurrence but there are no controlled studies that provide evidence directing our management 107,[117][118][119] .
# Recommendations:
1. The treatment of thrombosis in ET is based on standard thrombosis guidelines. 2. Current practice guidelines suggest primary anticoagulation use of LMWH and VKA therapy. 3. The use of DOACs for treatment of venous thrombosis in MPNs is limited. Discuss cases with local thrombosis experts and manage on a case by case basis. 4. Recurrence of thrombosis is higher among MPN patients with the majority of patients benefiting from lifelong anticoagulation in the setting of unprovoked thrombosis. Lifelong anticoagulation is also suggested for atypical thrombosis particularly in the setting of splanchnic vein and/or cerebral vein thrombosis.
# Pregnancy and hormone therapy:
Approximately 20% of patients with essential thrombocythemia are younger than 40 years at diagnosis 120 and of child bearing age. Pregnant MPN patients should ideally be under joint care of a consultant obstetrician experienced in the care of patients with high-risk pregnancies and a hematologist. Historically, platelet counts decline during pregnancy but do increase postpartum 121 and careful monitoring of MPN patients is required. Many expert opinions and guidelines have been published regarding best management practices. [122][123][124] Essential thrombocythemia is associated with complications of eclampsia, placental abruption, intrauterine growth retardation and still birth 125 . Spontaneous abortion rates are reported in 25-50% of cases of ET pregnancy mainly in first trimester 126 Of note the overall risk rate of spontaneous abortion (≤20th week) in normal pregnancies is 11% and is accounting for 80% of all fetal losses 127 . The overall risk of stillbirth (intrauterine death >20th week and infant born showing no signs of life) in normal pregnancies is observed in 0.43% 127 . The rate of premature delivery is about 9% 128 and rates of miscarriage rate range between 10-15% 129 .
In report by Griesshammer et al of 793 pregnancies in 492 women with ET a successful birth rate was achieved in 68.5% (543 live births in 793 pregnancies) with a miscarriage rate of 31.5% (250 miscarriages in 793 pregnancies). First trimester abortion (≤20th week) was the most frequent complication in 26.5% (210 spontaneous abortions in 793 pregnancies). Stillbirth, defined as fetal loss >20th week, occurred in 4.8%, which is more than 10 times higher than the overall risk of stillbirth in non-MPN pregnancies. Preterm delivery (birth <37th week) was found in 8.6% (43 of 502 evaluable pregnancies) and appears comparable to the rate in normal pregnancy with 9%. 122 Aspirin has been used for prevention of uteroplacental insufficiency in high-risk groups because aspirin inhibits platelet aggregation and results in a reduction of oxidative stress and inflammation 130 .
In a meta-analysis, aspirin reduced the risk of preterm birth in high-risk pregnancies by 14% (relative risk, 0. unadjusted odds ratio, 9.7; 95% CI, 2.3-41.0) were associated with 9 to 10-fold higher odds of live births. However, the addition of low doses of LMWH or unfractionated heparin to aspirin was not associated with significantly different odds of live birth (6 studies, 96 pregnancies; unadjusted OR, 2.1 for aspirin with heparin vs aspirin alone; 95% CI, 0.5-9.0; I 2 = 0%). The administration of LMWH alone was not associated with significantly different odds of live birth (unadjusted OR, 6.0; 95% CI, 0.40-90.1; I 2 = 0%). 134 Low molecular weight heparin is safe and effective for treating and preventing thrombosis in pregnancy 135 . Whether or not LMWH is beneficial in maternal VTE risk reduction for ET patients was studied in 756 ET pregnancies in which antepartum and postpartum VTE risk was identified as 2.5% vs 4.4% respectively, with a defined threshold of 3% at which LMWH prophylaxis is recommended. 133 The analysis led to recommendations that LMWH prophylaxis should be considered based on the presence of additional risk factors and a preference and values-based discussion, given a modest absolute risk of VTE. For women with ET during the post-partum period, use of LMWH prophylaxis to prevent thrombosis is suggested.
In particular "high risk" MPN pregnancies may benefit from adding prophylactic low dose molecular weight heparin (dalteparin 5000 IU or enoxaparin 40 mg once daily) to low-dose aspirin throughout pregnancy and for 6 weeks postpartum. 21 A "high-risk" MPN pregnancy is considered, if any of the following factors is present: 21,122 1. Prior thrombosis or severe hemorrhage in MPN patient. 2. Previous pregnancy complication like spontaneous abortion, intrauterine death or stillbirth, preeclampsia necessitating preterm delivery 45-50%. 3. Marked sustained increase in platelet count to greater than 1,500 × 10 9 /L.
The local approach is to offer antenatal LMWH thromboprophylaxis in the presence of prior thrombosis or in the presence of one additional "high risk" factor. All women are offered six weeks post-partum thromboprophylaxis with LMWH. These recommendations are independent of aspirin, which should be continued concurrently.
If cytoreduction is needed which also applies to "high risk" MPN pregnancies, interferon alpha (IFN) based therapy is the drug of choice. Pegylated interferon alpha should be preferred due to better tolerability and efficacy. Griesshammer et al. summarized the literature regarding IFN over 90 MPN pregnancies. 122 Importantly, in the event of planning pregnancy, preconception recommendations are to discontinue the use of possible teratogenic drugs such as hydroxyurea with a 3-6 months washout period being advised. Both men and women who are considering family growth should attempt this 3-6 month wash out period under the consultation of their physician. Alternative cytoreduction should be considered such as IFN based therapy if indicated based on ET risk status or begin administration if high-risk pregnancy with complications (as above). Platelet counts should not exceed 1500 × 10 9 /lL due to an acquired von Willebrand's syndrome and risk of peripartum bleeding. 122 Uterine artery Doppler is a predictive test for the development of pregnancy complications such as pre-eclampsia, intra-uterine growth restriction, abruption and fetal death and should be performed between 18 and 24 weeks in all MPN pregnancies. A systematic review and meta-analysis have shown that an increased pulsatility index (PI) was the best predictor of pre-eclampsia (positive likelihood ratio 21•0 among high-risk patients and 7•5 among low-risk patients). It was also the best predictor of overall (positive likelihood ratio 9•1) and severe (positive likelihood ratio 14•6) intrauterine growth restriction among low-risk patients 136 . In women with a positive test (i.e. mean uterine artery PI > 1•4) consider escalating anticoagulant therapy and enhancing screening with serial growth scans. 124 With respect to breastfeeding, heparins are not excreted in breast milk and may be used safely when breast feeding. Aspirin and LMWH are not contraindicated in a breast-feeding woman. 124 Hydroxyurea, and possibly anagrelide are excreted in breast milk. Interferon α is variably excreted in breast milk and may be active orally; however, there is an absence of safety data rather than evidence of harm to the neonate. The recent HELPS trial 137 Hydroxyurea Exposure in Lactation: a Pharmacokinetics (PK) Study, illustrated that breastfeeding mothers will transfer only a small amount of hydroxyurea to their infants, so lactation during hydroxyurea treatment should not be contraindicated.
# Hormones:
There is currently insufficient data available to evaluate the effects of combined OCP, hormonal replacement or ovarian stimulation in ET. In a series of 305 female patients with ET, the use of estrogen-containing hormone therapy was not associated with an increase in venous or arterial thrombotic events. However, the use of oral contraceptives was associated with a threefold increased risk of venous thrombosis (23 versus 7 percent) and a fivefold increased risk of splanchnic thrombosis (15 versus 3 percent). 138 Overall it is suggested hormonal therapy be avoided in MPN patients.
# Surgery:
Generally, MPNs are associated with higher odds of any surgery-related complications (OR, 1.37; P = .0099). 139 ET patients have a 5-6-fold higher risk of thrombosis perioperative 140 . Controlling of platelet count preoperatively with ideal normalization of count is suggested preoperatively. Of note, complications of blood loss and postoperative infection may result in reactive thrombocytosis and should be considered if reinitiating of cytoreduction postoperatively, Likewise, hydroxyurea can impair would healing so this needs to be reviewed and considered if delays in post-operative recovery are noted. Postoperative thromboprophylaxis is suggested although not necessary to extend beyond normal postoperative recommendations and/or hospitalization on the basis of MPN existence.
#
Appendix A: ELN criteria for response 21,75 Type of response Criteria Complete remission -Durable (at least 12 weeks) resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement AND -Durable peripheral blood count remission (platelet count ≤400 x 10 9 /L, leukocyte count <10x10 9 /L, absence of leukoerythroblastosis) AND -No signs of progressive disease, absence of any hemorrhagic or thrombotic events AND -Bone marrow histological remission defined as disappearance of megakaryocyte hyperplasia and absence of > grade 1 reticulin fibrosis Partial remission -Durable resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement AND -Durable peripheral blood count remission (platelet count ≤400 x 10 9 /L, leukocyte count <10x10 9 /L, absence of leukoerythroblastosis) AND -No signs of progressive disease, absence of any hemorrhagic or thrombotic events AND -No marrow histological remission defined as the persistence of megakaryocyte hyperplasia No response Any response that does not satisfy partial remission Progressive disease
# Transformation into PV, PET MF, MDS or s-AML
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Hematology Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, hematologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Hematology Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2021.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial Hematology Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2021) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of Cancer Care Alberta's evidence-based clinical practice guidelines and supporting materials comes from the Cancer Care Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Sonia Cerquozzi reports personal fees, non-financial support and other from Novartis, personal fees, non-financial support and other from Celgene, personal fees from Pfizer, outside the submitted work.
Derek Tilley has nothing to disclose. | None | None |
2d25c06254bdbc1848f7930e1fc79d852c5d2577 | cma | None | People with acquired or congenital heart disease who are pregnant are at intermediate to high risk of cardiovascular complications during their pregnancy. The risk level can be determined using a combination of CARPREG II (Cardiac Disease in Pregnancy Study) risk score and World Health Organization (WHO) classification. Higher CARPREG II scores are associated with increased risk of maternal cardiac events. 1 #
The UK Maternal Cardiology Society had advised the following pregnant people with one or more of the following conditions can be considered to have significant heart disease 2 o impaired left ventricular function of any cause; o a systemic right ventricle (congenitally corrected transposition of the great arteries, Senning/Mustard surgery) even if well-functioning; o hypertrophic cardiomyopathy with abnormal systolic or diastolic function and/or outflow tract obstruction; o hypertensive heart disease with left ventricular hypertrophy; o Fontan circulation; o pulmonary arterial hypertension of any cause; o cyanotic conditions (i.e., saturation in air <92%); o moderate or severe valvar (subvalvar/supravalvar) stenosis; severe valvar regurgitation (and moderate if symptomatic); o symptomatic coronary artery disease Is COVID-19 immunization recommended for pregnant people with heart disease? COVID-19 vaccines should be encouraged for pregnant people with heart disease and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
- Most pregnant people who become infected with SARS-CoV-2 will have mild to moderate symptoms and many can be asymptomatic. - Canadian and international data demonstrate that approximately 8-11% of pregnant people will require hospitalization for COVID related morbidity and between 2-4% of pregnant people will require admission to an intensive care unit. 6,7 Pregnant individuals are at increased risk of requiring the use of invasive ventilation (i.e., intubation and mechanical ventilation) with an equivalent mortality to age-matched peers. 3,5 Clinical Guidance on COVID-19 Vaccines for Pregnant People with Acquired or Congenital Heart Disease Updated: April 18, 2023 2
- The risk of severe morbidity from COVID-19 in pregnant people appears to be associated with risk factors including age ≥ 35 years old, heart disease, as well as other comorbidities including asthma, obesity, pre-existing diabetes, and pre-existing hypertension. 3,5 - Canadian and U.S. data 3,7,8 show an increased risk of preterm birth associated with COVID-19 infection in pregnancy which will cause consequent morbidity to the infant related to prematurity. While data specific to the safety and efficacy of COVID-19 vaccines in pregnant people with heart disease is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 11 It is reasonable to anticipate that given the risk factors for pregnant people with heart disease, the risk to the fetus associated with immunization is low in comparison to the risk of contracting COVID-19 for both the pregnant individual and their fetus and the benefits of protection from the COVID-19 virus. 3 The authors of this guidance agree that the benefits of vaccineinduced immunity against COVID-19 immunization with these vaccines outweigh any theoretical risks associated with immunization.
Is the COVID-19 vaccine efficacious and safe for pregnant people with heart disease?
Clinical trials of COVID-19 vaccines all excluded pregnant or breastfeeding individuals from their trials, although some participants reported pregnancies during the trial (see below). 10 While no adverse effects were reported among these individuals, the number of individuals who reported pregnancies are small and thus, the potential risks of vaccination to a pregnant individual are not clear. However, it is known that an unvaccinated pregnant individual remains at risk of COVID-19 infection and is also at heightened risk of severe morbidity if infected compared to non-pregnant counterparts. 4,9 - In the Pfizer-BioNTech trial, there were 23 pregnant people (12 in the vaccine group and 11 in the placebo group) who reported pregnancies during the trial. They are being followed without any report of adverse effects related to the pregnancy to date. 6 - In the Moderna trial, there were 13 people (six in the vaccine group and seven in the placebo group) who reported pregnancies during the trial without any report of adverse effects related to the pregnancy to date. - In the AstraZeneca trial pregnant and breastfeeding people were excluded from the third phase of the trials; however 21 pregnancies (12 in the vaccine group and nine in the placebo group) were reported without any adverse effects related to their pregnancy to date.
A complete vaccine series with a COVID-19 vaccine may be offered to pregnant individuals who do not have contraindications to the vaccine and are eligible in the current phase of B.C.'s COVID-19 Immunization Plan, if a risk assessment between the provider and the pregnant individual deems that the benefits outweigh the potential risks for the individual and the fetus, and if informed consent includes discussion about the quasi-absence of evidence on the use of COVID-19 vaccine in this population. 10 Society of Obstetricians and Gynaecologist of Canada, as well as American College of Obstetricians and Gynecologists, and Society for Maternal-Fetal Medicine supports offering COVID-19 vaccine to pregnant individuals.
Are there any specific contraindications or exceptions for pregnant people with heart disease?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 12 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. Are there specific recommendations or considerations for safe and/or most effective administration?
Timing considerations for the administration of the COVID-19 vaccine relative to pregnancy care:
- There is no evidence for avoiding immunization at any point during pregnancy; there are no known teratogenic properties associated with the mRNA vaccines. 5 - Patient preference may include avoiding immunization during the first trimester (12 weeks).
As recommended by NACI 6 , as a matter of informed consent, people who are pregnant should be counselled about the lack of safety and efficacy data for the currently approved mRNA and adenovirus vaccines in people who are pregnant. However, they should also be reassured that expert consensus 5 is that benefits of immunization outweigh the risks. | People with acquired or congenital heart disease who are pregnant are at intermediate to high risk of cardiovascular complications during their pregnancy. The risk level can be determined using a combination of CARPREG II (Cardiac Disease in Pregnancy Study) risk score and World Health Organization (WHO) classification. Higher CARPREG II scores are associated with increased risk of maternal cardiac events. 1 #
The UK Maternal Cardiology Society had advised the following pregnant people with one or more of the following conditions can be considered to have significant heart disease 2 o impaired left ventricular function of any cause; o a systemic right ventricle (congenitally corrected transposition of the great arteries, Senning/Mustard surgery) even if well-functioning; o hypertrophic cardiomyopathy with abnormal systolic or diastolic function and/or outflow tract obstruction; o hypertensive heart disease with left ventricular hypertrophy; o Fontan circulation; o pulmonary arterial hypertension of any cause; o cyanotic conditions (i.e., saturation in air <92%); o moderate or severe valvar (subvalvar/supravalvar) stenosis; severe valvar regurgitation (and moderate if symptomatic); o symptomatic coronary artery disease Is COVID-19 immunization recommended for pregnant people with heart disease? COVID-19 vaccines should be encouraged for pregnant people with heart disease and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
• Most pregnant people who become infected with SARS-CoV-2 will have mild to moderate symptoms and many can be asymptomatic. [3][4][5] • Canadian and international data demonstrate that approximately 8-11% of pregnant people will require hospitalization for COVID related morbidity and between 2-4% of pregnant people will require admission to an intensive care unit. 6,7 Pregnant individuals are at increased risk of requiring the use of invasive ventilation (i.e., intubation and mechanical ventilation) with an equivalent mortality to age-matched peers. 3,5 Clinical Guidance on COVID-19 Vaccines for Pregnant People with Acquired or Congenital Heart Disease Updated: April 18, 2023 2
• The risk of severe morbidity from COVID-19 in pregnant people appears to be associated with risk factors including age ≥ 35 years old, heart disease, as well as other comorbidities including asthma, obesity, pre-existing diabetes, and pre-existing hypertension. 3,5 • Canadian and U.S. data 3,7,8 show an increased risk of preterm birth associated with COVID-19 infection in pregnancy which will cause consequent morbidity to the infant related to prematurity. [8][9][10] While data specific to the safety and efficacy of COVID-19 vaccines in pregnant people with heart disease is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 11 It is reasonable to anticipate that given the risk factors for pregnant people with heart disease, the risk to the fetus associated with immunization is low in comparison to the risk of contracting COVID-19 for both the pregnant individual and their fetus and the benefits of protection from the COVID-19 virus. 3 The authors of this guidance agree that the benefits of vaccineinduced immunity against COVID-19 immunization with these vaccines outweigh any theoretical risks associated with immunization.
Is the COVID-19 vaccine efficacious and safe for pregnant people with heart disease?
Clinical trials of COVID-19 vaccines all excluded pregnant or breastfeeding individuals from their trials, although some participants reported pregnancies during the trial (see below). 10 While no adverse effects were reported among these individuals, the number of individuals who reported pregnancies are small and thus, the potential risks of vaccination to a pregnant individual are not clear. However, it is known that an unvaccinated pregnant individual remains at risk of COVID-19 infection and is also at heightened risk of severe morbidity if infected compared to non-pregnant counterparts. 4,9 • In the Pfizer-BioNTech trial, there were 23 pregnant people (12 in the vaccine group and 11 in the placebo group) who reported pregnancies during the trial. They are being followed without any report of adverse effects related to the pregnancy to date. 6 • In the Moderna trial, there were 13 people (six in the vaccine group and seven in the placebo group) who reported pregnancies during the trial without any report of adverse effects related to the pregnancy to date. • In the AstraZeneca trial pregnant and breastfeeding people were excluded from the third phase of the trials; however 21 pregnancies (12 in the vaccine group and nine in the placebo group) were reported without any adverse effects related to their pregnancy to date.
A complete vaccine series with a COVID-19 vaccine may be offered to pregnant individuals who do not have contraindications to the vaccine and are eligible in the current phase of B.C.'s COVID-19 Immunization Plan, if a risk assessment between the provider and the pregnant individual deems that the benefits outweigh the potential risks for the individual and the fetus, and if informed consent includes discussion about the quasi-absence of evidence on the use of COVID-19 vaccine in this population. 10 Society of Obstetricians and Gynaecologist of Canada, as well as American College of Obstetricians and Gynecologists, and Society for Maternal-Fetal Medicine supports offering COVID-19 vaccine to pregnant individuals.
Are there any specific contraindications or exceptions for pregnant people with heart disease?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 12 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. [13][14][15][16] Are there specific recommendations or considerations for safe and/or most effective administration?
Timing considerations for the administration of the COVID-19 vaccine relative to pregnancy care:
• There is no evidence for avoiding immunization at any point during pregnancy; there are no known teratogenic properties associated with the mRNA vaccines. 5 • Patient preference may include avoiding immunization during the first trimester (12 weeks).
As recommended by NACI 6 , as a matter of informed consent, people who are pregnant should be counselled about the lack of safety and efficacy data for the currently approved mRNA and adenovirus vaccines in people who are pregnant. However, they should also be reassured that expert consensus 5 is that benefits of immunization outweigh the risks. | None | None |
192bd928bcf619a46e21d6c24084c24793910ab8 | cma | None | This guideline outlines the recommendations for influenza immunization among adult and pediatric patients with cancer. For the most current Alberta Health Services information, clinical guidelines, and schedules on influenza immunization for the general population, please visit the Influenza Immunization Information for Health Professionals webpage. For information specific to COVID-19 immunization for Alberta cancer patients and families, please refer to COVID-19 and Cancer Treatment. For general COVID-19 immunization information, please refer to Health Professional 65 years of age and older# Background
Seasonal influenza is an important cause of morbidity and mortality in Canada. 1 An estimated 12,200 hospitalizations and 3,500 deaths can be attributed to influenza annually. 2 People at greatest risk of influenza-related complications are children 6 to 59 months of age, pregnant individuals, older adults (>65 years), residents of congregate living facilities and other chronic care facilities, Indigenous peoples and people with underlying medical conditions. 2 Adult and pediatric patients with cancer are considered immunosuppressed, either as a result of their underlying disease or secondary to their treatment, and are therefore included in this high risk group. Influenza infection not only causes primary illness but also can lead to severe secondary medical complications, including viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions. Guideline Questions 1. What are the recommendations for influenza immunization for adult and pediatric patients with solid tumours or hematologic cancers in Alberta? 2. What is the current evidence for response to the influenza vaccine among adult and pediatric patients with cancer receiving chemotherapy or other systemic therapy? 3. What is the best timing for administering the influenza vaccine in relation to the therapy cycle and other vaccines for adult and pediatric patients with cancer?
# Search Strategy
The PubMed database was searched according to the strategy outlined in Appendix B. The 2022 search yielded 111 citations, two of which met the criteria to be included in the evidence tables presented in a supporting document. A systematic search of grey literature included websites from the World Health Organization, Health Canada, the Public Health Agency of Canada, Alberta Health Services, Alberta Health, Centers for Disease Control and Prevention, and the American Academy of Pediatrics. A search for published clinical practice guidelines from within the oncology field yielded one result from the National Comprehensive Cancer Network. 3
# Target Population
The recommendations outlined in this guideline apply specifically to children and adults with solid tumours or hematologic malignancies.
# Recommendations
The following recommendations have been adapted from existing practice guidelines, policy documents, and consensus statements, including those from the Alberta Health Services Immunization Program Standards Manual, Alberta Influenza Immunization Policy, the National Advisory Committee on Immunization, 2 the Public Health Agency of Canada, 4 the Centers for Disease Control and Prevention 5 , and the American Academy of Pediatrics. 6 Evidence from the peer-reviewed literature was also reviewed and considered.
# Influenza Immunization: Adult Patients with Cancer
- Annual administration of the inactivated influenza vaccine is recommended for most adult patients with cancer. Patients considered to be the highest priority are those on active treatment. 2,5,10 Individuals with malignant solid tumours (and on immunosuppressive therapy) who are three months post-chemotherapy and the cancer is in remission are no longer considered immunocompromised. 11 Individuals with malignant hematologic disorders who are more than three years post therapy and no longer on immunosuppressive medications are considered healthy and should be assessed for immunizations as per the general population.
- Age, duration, type of systemic therapy (except for rituximab or other B-cell or T cell depleting antibodies), and curative versus palliative treatment intent do not appear to influence the response of adult patients with cancer to the influenza immunization. Adult patients with hematologic malignancies may have lower responses to immunization when compared to adult patients with solid tumours.
- Timing of inactivated influenza immunization in relation to the therapy cycle and other vaccines: a) The vaccine should ideally be given at least two weeks before commencing any immunesuppressing cancer treatment, including chemotherapy and ICI therapy, or delayed until at least three months after such treatment has stopped or is at the lowest possible level. 11 While administration of the vaccine at any time before, during or after immune-suppressing cancer treatment is safe, its efficacy may be reduced. b) Patients who are treated with rituximab (or other B-cell or T cell depleting antibodies), should have all their inactivated vaccines postponed until at least six months after the last dose of rituximab. A clearance letter is required before starting immunization. 12-15 c) Patients on high-dose systemic steroids (i.e., 20 mg/day or more of prednisone or its equivalent, for 14 days or more) should wait four weeks after discontinuation of therapy before the vaccine is administered. 11 d) For AHS employees, direction for co-administration of influenza and COVID-19 vaccines can be found on the internal website at Home Teams Communicable Disease Control Immunization Program Standards Manual Biological Product Information COVID-19. e) Patients on clinical trial protocols should continue to follow instructions based on their specific protocol.
- For adult patients undergoing hematopoietic stem cell transplant (HSCT) the recipient and donor immunization status pre-transplant both have an impact on post-transplant immunity. Immunity established prior to HSCT may increase immune response following transplant: 14,16,17 a) Recipient: the inactivated influenza vaccine should be administered at least two weeks prior to transplant conditioning or mobilization chemotherapy. Consult the attending transplant physician. Live influenza vaccine is contraindicated. b) Donor: the inactivated influenza vaccine should be administered at least two weeks before stem cell harvest. Consult the attending transplant physician. Live influenza vaccine is contraindicated. c) There is no difference in recommended schedules between autologous or allogeneic recipients. Although a current topic of research, the differences in immunity post-transplant for the two types of recipients are not enough to justify two separate schedules. d) Immune system recovery post-HSCT is variable and requires assessment by the transplant physician. The majority of HSCT recipients will have a detectable antibody response to the influenza vaccine at six months post-transplant which continues to increase over the next 12 to 24 months. Graft versus host disease (GVHD) may prolong the duration of immunosuppression. e) For HSCT recipients, inactivated influenza vaccine should ideally be administered six months post-transplant. Inactivated influenza vaccine can be given as early as three to four months post-transplant in outbreak situations at the discretion of the transplant physician.
In such case, two doses should be given, at least four weeks apart. f) For patients on post-transplant maintenance therapy, all immunizations should be postponed until at least six months after the last dose of chemotherapy. It is not known how new agents used for maintenance therapy (e.g., lenalinomide/revlimid) impact patients' ability to respond to vaccines; some physicians elect to have their patients immunized. A clearance letter is required before starting immunization. g) HSCT recipients who have started their post-HSCT vaccine series and then had the series interrupted by Chimeric Antigen Receptor T (CAR-T) cell therapy will need to restart their vaccine series. Inactivated influenza immunization can be restarted as early as three months post CAR-T cell therapy. h) Inactivated immunization should not be delayed due to GVHD/immunosuppressive therapy, unless due to high-dose steroids (see above). Live vaccines are contraindicated in patients with active GVHD. i) Household contacts and healthcare workers should be up to date for routine immunizations as per the Alberta Immunization Schedule, including annual influenza, to reduce the risk of disease transmission to transplant recipients. j) Individuals who have received the live nasal spray influenza vaccine (FluMist® Quadrivalent) should avoid close association with individuals with severe immunocompromising conditions (e.g., bone marrow transplant recipients requiring protective isolation) for at least two weeks following immunization. 14 The live nasal spray influenza vaccine (FluMist®) may be available for purchase in Alberta through community pharmacies.
- Annual influenza immunization of family members and hospital or clinic staff and volunteers who are in contact with adult patients with cancer is strongly recommended. In many cases, this may be more important than immunizing the patients themselves, as some patients may be less likely to respond to the vaccine. Transmission of influenza between infected healthcare workers and their vulnerable patients results in significant morbidity and mortality; therefore, healthcare workers should consider it their responsibility to provide the highest standard of care, which includes receiving the annual inactivated influenza vaccine. 2,18
- Contraindications for influenza immunization (standard or high-dose vaccine) in adult patients with cancer include: 2,9,19 - Known hypersensitivity to any component of the vaccine excluding eggs.
- Anaphylactic or other allergic reactions to a previous dose of influenza vaccine.
- Known history of severe oculorespiratory syndrome (ORS) symptoms that included lower respiratory symptoms within 23 hours of receiving influenza vaccine pending consultation with the Medical Officer of Health to review the risks and benefits of further influenza immunization. - Known history of Guillain Barré Syndrome (GBS) within six weeks of a previous dose of influenza vaccine. - Individuals presenting with a serious acute febrile illness o Recommendations should be provided for these individuals to be immunized when their symptoms have resolved. o Individuals with non-serious febrile illness may be immunized. 7. Precautions for influenza immunization (standard or high-dose vaccine) in adult patients with cancer include: 2,9,19 - Egg allergy is not considered a contraindication for inactivated influenza vaccine.
- Egg-allergic individuals may be safely immunized using inactivated influenza vaccine without a prior influenza vaccine skin test and with the full dose of vaccine, irrespective of a past severe reaction to egg. They can be immunized in any setting and should be kept under observation for 30 minutes following vaccine administration.
As with all vaccine administration, immunizers should have the necessary anaphylaxis equipment and protocols, and be prepared to always respond to a vaccine emergency. Vaccine recipients who have had an anaphylactic reaction to any agent should be kept under observation for at least 30 minutes post-immunization.
Individuals who report they have experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of a previous influenza immunization, had an apparent significant allergic reaction to the vaccine or any other symptoms (e.g., throat constriction or difficulty swallowing) should have a report sent to the Adverse Event Following Immunization Reporting | Alberta Health Services, please follow the reporting requirements laid out on this webpage. Follow up will then occur directly with the patient.
# Influenza Immunization: Pediatric Patients with Cancer
- Annual administration of the inactivated influenza vaccine is indicated for most pediatric patients with cancer who are six months of age and older. A standard dose quadrivalent influenza vaccine, Fluzone® or FluLaval® Tetra for children six months of age and older should be used. 2 The live attenuated influenza vaccine is not recommended for children with immunecompromising conditions. 2,5 Immunization with currently available influenza vaccines is not recommended for infants younger than six months of age. The recommended doses by age are as follows:
- Children nine years or older should receive one dose of influenza vaccine.
- Children previously unimmunized with influenza vaccine who are older than six months and less than nine years of age require two doses of influenza vaccine in the first year they are immunized, with a minimum interval of four weeks between doses. - Children six months to less than nine years of age who have been previously immunized with influenza vaccine in another season require only one dose of influenza vaccine. - A full dose (0.5 mL) of influenza vaccine should be used for all people who are receiving influenza immunization.
- Although the data is limited, age, duration, and type of systemic therapy (except for rituximab or other B-cell or T cell depleting antibodies) do not appear to influence the response of pediatric patients to influenza vaccine. Pediatric patients with hematologic malignancies may have lower responses to immunization when compared to pediatric patients with solid tumours. Patients who are treated with rituximab or other B-cell or T cell depleting antibodies should have all their inactivated vaccines postponed until at least six months after the last dose of rituximab. A clearance letter is required before starting immunization. 3. Timing of inactivated influenza immunization in relation to the therapy cycle and other vaccines: a) Influenza vaccine should ideally be given at least two weeks before the administration of any immune-suppressing cancer treatment, to allow the patient to develop a sufficient antibody response. If early immunization is not possible or feasible, administration of the inactivated vaccine less than two weeks before the start of immune-suppressing cancer treatment, or between treatment cycles has been reported to be safe and is recommended over not receiving the vaccine at all, although the efficacy of the vaccine may be reduced in this situation. b) For AHS employees, direction for co-administration of influenza and COVID-19 vaccines can be found on the internal website at Home Teams Communicable Disease Control Immunization Program Standards Manual Biological Product Information COVID-19.
- For pediatric patients undergoing hematopoietic stem cell transplant (HSCT) the recipient and donor immunization status pre-transplant both have an impact on post-transplant immunity.
Immunity established prior to HSCT may increase immune response following transplant: 11,14,20 a) Recipient: the inactivated influenza vaccine should be administered at least two weeks prior to transplant conditioning or mobilization chemotherapy. Consult the attending transplant physician. Live influenza vaccine is contraindicated. b) Donor: the inactivated influenza vaccine should be administered at least two weeks before stem cell harvest. Consult the attending transplant physician. Live influenza vaccine is contraindicated. c) There is no difference in recommended schedules between autologous or allogeneic recipients. Although a current topic of research, the differences in immunity post-transplant for the two types of recipients are not enough to justify two separate schedules. d) Immune system recovery post-HSCT is variable and requires assessment by the transplant physician. The majority of HSCT recipients will have a detectable antibody response to the influenza vaccine at six months post-transplant which continues to increase over the next 12 to 24 months. GVHD, may prolong the duration of immunosuppression. e) For HSCT recipients, inactivated influenza vaccine should ideally be administered six months post-HSCT but can be given as early as three to four months post-transplant in outbreak situations at the discretion of the transplant physician. In such case, two doses should be given, at least four weeks apart. k) For patients on post-transplant maintenance therapy all immunizations should be postponed until at least six months after the last dose of chemotherapy. It is not known how new agents used for maintenance therapy (e.g., lenalinomide/revlimid) impact patients' ability to respond to vaccines; some physicians elect to have their patients immunized. A clearance letter is required before starting immunization. l) HSCT recipients who have started their post-HSCT vaccine series and then had the series interrupted by Chimeric Antigen Receptor T (CAR-T) cell therapy will need to restart their vaccine series. Inactivated influenza immunization can be given as early as three months post CAR-T cell therapy. f) Inactivated immunization should not be delayed due to GVHD/immunosuppressive therapy, unless due to high-dose steroids (i.e., 2 mg/kg per day for children under 10 kg or 20 mg/day for children over 10 kg or more of prednisone or its equivalent, for 14 days or more). Live vaccines are contraindicated in patients with active GVHD. g) Household contacts and healthcare workers should be up to date for routine immunizations as per the Alberta Immunization Schedule, including annual influenza, to reduce the risk of disease transmission to pediatric transplant recipients. h) Individuals who have received the live nasal spray influenza vaccine (FluMist® Quadrivalent) should avoid close association with individuals with severe immunocompromising conditions (e.g., transplant recipients requiring protective isolation) for at least two weeks following immunization. 14 The live nasal spray influenza vaccine (FluMist®) may be available for purchase in Alberta through community pharmacies.
- Annual influenza immunization of family members, out-of-home caregivers, and hospital or clinic staff and volunteers in contact with pediatric patients with cancer is strongly recommended. In many cases, this may be more important than immunizing the patient themselves, as some patients may be less likely to respond to the vaccine. Transmission of influenza between infected healthcare workers and their vulnerable patients results in significant morbidity and mortality; therefore, healthcare workers should consider it their responsibility to provide the highest standard of care, which includes receiving the annual inactivated influenza vaccine. 2,18
- Contraindications for influenza immunization in pediatric patients with cancer include: 2,19
- Known hypersensitivity to any component of the vaccine excluding eggs.
- Anaphylactic or other allergic reactions to a previous dose of influenza vaccine.
- Known history of severe oculorespiratory syndrome (ORS) symptoms that included lower respiratory symptoms within 23 hours of receiving influenza vaccine pending consultation with the Medical Officer of Health to review the risks and benefits of further influenza immunization. - Known history of Guillain Barré Syndrome (GBS) within six weeks of a previous dose of influenza vaccine. - Individuals presenting with a serious acute febrile illness o Recommendations should be provided for these individuals to be immunized when their symptoms have resolved. o Individuals with non-serious febrile illness may be immunized.
# Precautions for influenza immunization in pediatric patients with cancer include: 2,19
- Egg allergy is not considered a contraindication for inactivated influenza vaccine.
- Egg-allergic individuals may be safely immunized using inactivated influenza vaccine without a prior influenza vaccine skin test and with the full dose of vaccine, irrespective of a past severe reaction to egg. They can be immunized in any setting and should be kept under observation for 30 minutes following vaccine administration.
As with all vaccine administration, immunizers should have the necessary anaphylaxis equipment and protocols, and be prepared to always respond to a vaccine emergency. Vaccine recipients who have had an anaphylactic reaction to any agent should be kept under observation for at least 30 minutes post-immunization.
Individuals who report they have experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of a previous influenza immunization, had an apparent significant allergic reaction to the vaccine or any other symptoms (e.g., throat constriction or difficulty swallowing) should have a report sent to the Adverse Event Following Immunization Reporting | Alberta Health Services, please follow the reporting requirements laid out on this webpage. Follow up will then occur directly with the patient.
# Discussion
# Influenza Immunization: Adult Patients with Cancer
Cancer treatments can produce acute and profound immunosuppression, although published literature suggests that the degree may differ according to the specific regimen, doses, and duration of treatment. Annual administration of the inactivated influenza vaccine is recommended for most adult patients with cancer.
Interpreting the results of influenza vaccine efficacy in adult patients with cancer is difficult because patient characteristics, cancer types, vaccine strains, and assessment of responses vary between published studies. In a review of 1,225 patients from the Surveillance, Epidemiology, and End Results (SEER) and Medicare databases, Earle et al. reported that among patients undergoing chemotherapy for stage IV colorectal cancer, those who had been immunized had lower rates of influenza and pneumonia than those who were not immunized (1.1% vs. 3.8%, p=0.004). 21 In addition, the immunized patients had significantly fewer interruptions in the chemotherapy cycles, showed a trend toward using fewer health care resources, and were more likely to survive to the next influenza season (HR for death=0.88, 95% CI 0.77-0.99). Similarly, a 2013 Cochrane review of four studies involving 2,124 adult patients with cancer receiving chemotherapy concluded that influenza immunization was associated with lower mortality and that infection rates were lower or similar in patients who were vaccinated versus those who were not. 22 Patients with cancer who develop influenza are at high risk for serious complications and death. In a review of 11 published studies involving adult patients undergoing chemotherapy treatment or hematopoietic stem cell transplantation (HSCT), Kunisaki et al. reported case fatality rates ranging from 11% to 33% for the studies involving chemotherapy. 23 Similarly, in a report of 168 critically ill patients admitted to Canadian intensive care units at the peak of the 2009-2010 H1N1 influenza outbreak, Kumar et al. reported that 8.2% of these patients had one or more major co-morbidities, including immunosuppression due to cancer or cancer therapies. 24 It is most beneficial to immunize patients with malignant solid tumours at least two weeks prior to beginning chemotherapy to allow for sufficient antibody production by the patient. 4, In a study involving patients with breast cancer, geometric mean titers were significantly lower among individuals immunized at day 16 of chemotherapy versus those immunized at day 4. 28 However, a pilot study of 18 patients with solid tumours immunized either one week before or on the first day of chemotherapy reported that all patients mounted an immune response to the vaccine, and there were no significant differences in seroconversion or seroprotection rates against the three influenza strains between the two groups of patients. 29 If early immunization is not possible, administration of the inactivated vaccine between chemotherapy cycles has been reported to be safe and is recommended over not receiving the vaccine at all, although the efficacy of the vaccine may be reduced in this situation. 21,25,30 In such situations, administration of the vaccine is preferable when therapy is at the lowest level possible. 4 There is a growing body of published data on the safety and efficacy of the influenza vaccine in patients with cancer treated with ICI therapies, including CTLA-4 inhibitors (e.g., ipilimumab) or PD-1 and PD-L1 inhibitors (e.g., nivolumab, pembrolizumab). One of the first studies on the safety of influenza vaccination in cancer patients receiving ICIs caused concern about an increased risk of severe immunological complications. 41 While data were based on a small number of lung cancer patients (n=23), because of this data many clinicians began to advise patients on ICIs against vaccination. A 2021 systematic review that included ten studies assessing the safety and eight assessing the efficacy of influenza vaccination in cancer patients receiving ICIs has since moderated these concerns. 38 The systematic review showed that in most subsequent and larger studies, the overall safety and efficacy of influenza immunization in cancer patients receiving ICIs is not markedly different from that observed in the general population. Therefore, it is the consensus of the Alberta Provincial Tumour Teams that patients receiving ICIs can receive the influenza vaccine at any time during therapy.
Adult patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT) are at significant risk for infections prior to immune regeneration. Preparation for both autologous and allogeneic HSCT involves intensive high-dose regimens of chemotherapy and/or radiotherapy, which leaves the patient acutely and profoundly immunocompromised for several months following transplantation. The impact of seasonal influenza on HSCT recipients can be devastating. Llungman et al. reported a case fatality rate of 23% among over 1,900 patients in Europe over three influenza seasons. 16 Kumar and colleagues reported the results of a multicentre prospective observational study of pediatric and adult solid organ transplant (SOT) and HSCT patients carried out across 20 sites from the United States, Canada, and Spain. They documented 616 patients with confirmed influenza (477 SOT; 139 HSCT) over a 5-year study period. The annual incidence of pneumonia ranged between 11.3-35.0% and ICU admission rates ranged between 8.1% to 14.3%. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia, and antiviral treatment within 48 hours was associated with improved outcomes. 42 No significant differences were noted between SOT and HSCT patients with regard to pneumonia and ICU care. However, HSCT patients had a higher 6month mortality (13.8% vs 4.8%, p<0.001) and viral load at disease onset (median viral load 1.04 × 105 copies/mL vs 8.04 × 103 copies/mL, p=0.001) compared to SOT patients.
There is variability in the efficacy of influenza immunization in HSCT patients reported in the literature. One study documented serologic responses ranging from 0% in allogeneic transplant patients to 32% in autologous transplant patients. Another study reported immune responses of 29% to 34% in patients who underwent HSCT, and 46% to 62% in a group of healthy matched controls. 43,44 In a study of 82 allogeneic HSCT recipients who received the 2009-2010 H1N1 vaccine, Issa et al. reported that seroprotective antibody titers were detected in 51% of patients, and this rate was not affected by the presence of chronic graft-versus-host disease or type of conditioning regimen. 45 Patients were more likely to have higher seroprotective titers the further away they were from the transplant (OR=1.79 per year, 95% CI 1.12-2.85), and rituximab administration prior to immunization was associated with lower seroprotective titers (OR=0.11, 95% CI 0.01-0.97). Bedognetti et al. reported the results of a study comparing response to the seasonal influenza vaccine in 31 patients with non-Hodgkin lymphoma in complete remission after treatment with rituximab-containing regimens to 34 age-matched healthy subjects. 46 They reported that CD27+ memory B-cells were significantly reduced in patients treated with rituximab-based chemotherapies, and this reduction correlated with lower responses to influenza immunization. Similarly, in a study of 67 patients with lymphoma who were treated with rituximab alone or in combination with chemotherapy, Yri et al. reported that only five patients had a measurable but non-protective antibody titer after immunization, and the remaining 62 patients had no detectable titers at all, giving a seroprotection rate of 0%. This is in comparison to the 82% seroprotection rate for the healthy control patients. The investigators suggest that the non-responsiveness was due to the B-cell depletion caused by rituximab therapy. 47 Similarly, Berglund and colleagues reported the results of a subgroup analysis of rituximab-treated patients among 96 adult outpatients with cancer who were undergoing treatment. Of the 13 patients treated with rituximab, only one responded to immunization against influenza A (H1N1) and none responded to immunization against seasonal influenza. 13 Patients who are treated with rituximab or other B-cell depleting antibodies should therefore have all immunizations postponed until at least six months after the last dose of rituximab or other B-cell depleting therapies. 47 Lower-respiratory tract infection (LRTI) is a complication of influenza infection that frequently leads to lung injury and death, and profound lymphopenia is one of the most significant risk factors for progression from upper-to lower-respiratory tract involvement. 48 Risk factors for progression of H1N1 influenza to LRTI in patients with hematologic malignancies are unknown at the present time.
It is recommended that both the recipient and donor (for allogeneic transplants) receive inactivated influenza immunization at least two weeks prior to the transplant. 4,16,49 While only 10% to 30% of HSCT recipients will have a detectable antibody response to the influenza vaccine at six to 24 months post-transplant, over 60% will have a detectable response at 24 months or more post-transplant. 50 Immune system recovery post-transplant is variable and requires individual assessment by the transplant physician. For example, patients treated with rituximab post-transplant will have a delay in their B-cell recovery by at least six months following the final dose. 16,46 In addition, adult transplant patients with chronic graft-versus-host disease may require up to 24 months or more post-transplant to recover CD4+ counts. It is recommended that HSCT patients receive annual seasonal inactivate influenza immunization beginning at six months post-transplant. 4,16,49 To reduce the risk of disease transmission, immunization of family members and hospital staff in contact with patients who are at high risk for severe or complicated seasonal influenza is strongly recommended. Influenza immunization rates of health care workers is associated with a reduction in influenza infections in cancer patients. 51 The Public Health Agency of Canada (PHAC) states that people who are potentially capable of spreading influenza to those who are at high risk should be immunized, regardless of whether the high-risk person has been immunized. 4 Immunization of family members and hospital staff who are in contact with HSCT recipients is also of particular importance, as these patients are severely immunocompromised. Family members and health care providers should receive the inactivated influenza vaccine beginning the season before the transplant and annually for 24 months or more post-transplant. 49 If the family member or healthcare worker will only accept the live nasal spray influenza vaccine, they should wait two weeks following immunization before continuing to provide care to severely immunocompromised individuals. 17
# Influenza Immunization: Pediatric Patients with Cancer
Pediatric patients with cancer are highly susceptible to influenza infections and have an increased rate of influenza infection compared to healthy children. 52 In addition, hospitalization rates due to influenza infection for children under the age of five years with chronic health conditions have been reported to be significantly higher than for healthy children in the same age group. 53 Annual administration of the inactivated influenza vaccine is indicated for all pediatric patients with cancer over the age of six months. Immunization with currently available influenza vaccines is not recommended for infants younger than six months of age.
Recommendations regarding influenza vaccine doses in healthy children state that those nine years of age and older should receive one dose of the vaccine annually. Children younger than nine years of age who have not previously received the trivalent or quadrivalent influenza vaccine require two doses of the vaccine in the first year they are immunized, with the second dose being administered four weeks or more after the first dose. The live vaccine is contraindicated in children with immune compromising conditions. 2
Like the literature regarding adult patients with cancer, interpreting the limited published results of influenza vaccine efficacy in pediatric patients with cancer is difficult because patient characteristics, cancer types, vaccine strains, and assessment of responses vary between published studies. In a meta-analysis of nine controlled clinical trials and one randomized controlled trial involving 770 children, Goossen et al. reported that immune responses to the seasonal influenza vaccine in children receiving chemotherapy were consistently weaker than in those children who had completed their chemotherapy regimen and in healthy controls. 54 Several studies have reported that pediatric patients with cancer who have completed their chemotherapy regimens have increased rates of seroconversion, suggesting that the timing of influenza immunization with regards to the chemotherapy cycle is an important factor in this population. 52,55 Seroconversion rates are also influenced by the type of cancer (solid tumour vs. hematologic malignancy) 56 and the type of chemotherapy. 57 Similar to the recommendations made for adults with cancer, it is likely most beneficial to immunize pediatric patients with cancer two weeks prior to beginning chemotherapy, to allow for sufficient antibody production by the patient. Shahgholi et al. assessed the immune response of 32 pediatric patients with acute lymphoblastic leukemia (ALL) and compared them to a control group of 30 healthy siblings. The trivalent influenza vaccine was well tolerated in the patients with ALL, and the immune responses were acceptable but limited. The percentage of ALL patients versus healthy controls with a fourfold increase in antibody titers were 56.2% versus 80% for H1N1 (p=0.04), 40.6% versus 53.3% for H3N2 (p=0.31), and 59.4% versus 83.3% for influenza B (p=0.038). 58 The recommendations for pediatric patients undergoing HSCT are like those for adult patients. 14,16,20,49 It is recommended that both the recipient and donor (for allogeneic transplants) receive the inactivated influenza vaccine two weeks prior to the transplant. Immune system recovery following transplant is variable and depends on factors such as the types of therapies administered and the presence of graft-versus-host disease; therefore, individual assessment is required by the transplant physician. Influenza vaccine should ideally be administered six months post-HSCT in pediatric patients. Inactivated influenza vaccine can be given as early as three to four months posttransplant in outbreak situations, at the discretion of the transplant physician. In such case, two doses should be given, at least four weeks apart. 59 Similar to the recommendations made for adult patients with cancer, immunization of family members, caregivers, and hospital staff in contact with pediatric patients who are at high risk for severe or complicated influenza is strongly recommended. 4 Immunization of family members and hospital staff who are in contact with pediatric HSCT recipients is also of particular importance, as these patients are severely immunocompromised and cannot be immunized themselves for at least four months post-transplant. In this situation, family members and health care providers should receive the inactivated influenza vaccine beginning the season before the transplant and annually for 24 months or more post-transplant. 20,49 If the family member or healthcare worker will only accept the live nasal spray influenza vaccine, they should wait two weeks following immunization before continuing to provide care to severely immunocompromised individuals. 20 | This guideline outlines the recommendations for influenza immunization among adult and pediatric patients with cancer. For the most current Alberta Health Services information, clinical guidelines, and schedules on influenza immunization for the general population, please visit the Influenza Immunization Information for Health Professionals webpage. For information specific to COVID-19 immunization for Alberta cancer patients and families, please refer to COVID-19 and Cancer Treatment. For general COVID-19 immunization information, please refer to Health Professional 65 years of age and older# Background
Seasonal influenza is an important cause of morbidity and mortality in Canada. 1 An estimated 12,200 hospitalizations and 3,500 deaths can be attributed to influenza annually. 2 People at greatest risk of influenza-related complications are children 6 to 59 months of age, pregnant individuals, older adults (>65 years), residents of congregate living facilities and other chronic care facilities, Indigenous peoples and people with underlying medical conditions. 2 Adult and pediatric patients with cancer are considered immunosuppressed, either as a result of their underlying disease or secondary to their treatment, and are therefore included in this high risk group. Influenza infection not only causes primary illness but also can lead to severe secondary medical complications, including viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions. Guideline Questions 1. What are the recommendations for influenza immunization for adult and pediatric patients with solid tumours or hematologic cancers in Alberta? 2. What is the current evidence for response to the influenza vaccine among adult and pediatric patients with cancer receiving chemotherapy or other systemic therapy? 3. What is the best timing for administering the influenza vaccine in relation to the therapy cycle and other vaccines for adult and pediatric patients with cancer?
# Search Strategy
The PubMed database was searched according to the strategy outlined in Appendix B. The 2022 search yielded 111 citations, two of which met the criteria to be included in the evidence tables presented in a supporting document. A systematic search of grey literature included websites from the World Health Organization, Health Canada, the Public Health Agency of Canada, Alberta Health Services, Alberta Health, Centers for Disease Control and Prevention, and the American Academy of Pediatrics. A search for published clinical practice guidelines from within the oncology field yielded one result from the National Comprehensive Cancer Network. 3
# Target Population
The recommendations outlined in this guideline apply specifically to children and adults with solid tumours or hematologic malignancies.
# Recommendations
The following recommendations have been adapted from existing practice guidelines, policy documents, and consensus statements, including those from the Alberta Health Services Immunization Program Standards Manual, Alberta Influenza Immunization Policy, the National Advisory Committee on Immunization, 2 the Public Health Agency of Canada, 4 the Centers for Disease Control and Prevention 5 , and the American Academy of Pediatrics. 6 Evidence from the peer-reviewed literature was also reviewed and considered.
# Influenza Immunization: Adult Patients with Cancer
1. Annual administration of the inactivated influenza vaccine is recommended for most adult patients with cancer. Patients considered to be the highest priority are those on active treatment. 2,5,10 Individuals with malignant solid tumours (and on immunosuppressive therapy) who are three months post-chemotherapy and the cancer is in remission are no longer considered immunocompromised. 11 Individuals with malignant hematologic disorders who are more than three years post therapy and no longer on immunosuppressive medications are considered healthy and should be assessed for immunizations as per the general population.
2. Age, duration, type of systemic therapy (except for rituximab or other B-cell or T cell depleting antibodies), and curative versus palliative treatment intent do not appear to influence the response of adult patients with cancer to the influenza immunization. Adult patients with hematologic malignancies may have lower responses to immunization when compared to adult patients with solid tumours.
3. Timing of inactivated influenza immunization in relation to the therapy cycle and other vaccines: a) The vaccine should ideally be given at least two weeks before commencing any immunesuppressing cancer treatment, including chemotherapy and ICI therapy, or delayed until at least three months after such treatment has stopped or is at the lowest possible level. 11 While administration of the vaccine at any time before, during or after immune-suppressing cancer treatment is safe, its efficacy may be reduced. b) Patients who are treated with rituximab (or other B-cell or T cell depleting antibodies), should have all their inactivated vaccines postponed until at least six months after the last dose of rituximab. A clearance letter is required before starting immunization. 12-15 c) Patients on high-dose systemic steroids (i.e., 20 mg/day or more of prednisone or its equivalent, for 14 days or more) should wait four weeks after discontinuation of therapy before the vaccine is administered. 11 d) For AHS employees, direction for co-administration of influenza and COVID-19 vaccines can be found on the internal website at Home Teams Communicable Disease Control Immunization Program Standards Manual Biological Product Information COVID-19. e) Patients on clinical trial protocols should continue to follow instructions based on their specific protocol.
4. For adult patients undergoing hematopoietic stem cell transplant (HSCT) the recipient and donor immunization status pre-transplant both have an impact on post-transplant immunity. Immunity established prior to HSCT may increase immune response following transplant: 14,16,17 a) Recipient: the inactivated influenza vaccine should be administered at least two weeks prior to transplant conditioning or mobilization chemotherapy. Consult the attending transplant physician. Live influenza vaccine is contraindicated. b) Donor: the inactivated influenza vaccine should be administered at least two weeks before stem cell harvest. Consult the attending transplant physician. Live influenza vaccine is contraindicated. c) There is no difference in recommended schedules between autologous or allogeneic recipients. Although a current topic of research, the differences in immunity post-transplant for the two types of recipients are not enough to justify two separate schedules. d) Immune system recovery post-HSCT is variable and requires assessment by the transplant physician. The majority of HSCT recipients will have a detectable antibody response to the influenza vaccine at six months post-transplant which continues to increase over the next 12 to 24 months. Graft versus host disease (GVHD) may prolong the duration of immunosuppression. e) For HSCT recipients, inactivated influenza vaccine should ideally be administered six months post-transplant. Inactivated influenza vaccine can be given as early as three to four months post-transplant in outbreak situations at the discretion of the transplant physician.
In such case, two doses should be given, at least four weeks apart. f) For patients on post-transplant maintenance therapy, all immunizations should be postponed until at least six months after the last dose of chemotherapy. It is not known how new agents used for maintenance therapy (e.g., lenalinomide/revlimid) impact patients' ability to respond to vaccines; some physicians elect to have their patients immunized. A clearance letter is required before starting immunization. g) HSCT recipients who have started their post-HSCT vaccine series and then had the series interrupted by Chimeric Antigen Receptor T (CAR-T) cell therapy will need to restart their vaccine series. Inactivated influenza immunization can be restarted as early as three months post CAR-T cell therapy. h) Inactivated immunization should not be delayed due to GVHD/immunosuppressive therapy, unless due to high-dose steroids (see above). Live vaccines are contraindicated in patients with active GVHD. i) Household contacts and healthcare workers should be up to date for routine immunizations as per the Alberta Immunization Schedule, including annual influenza, to reduce the risk of disease transmission to transplant recipients. j) Individuals who have received the live nasal spray influenza vaccine (FluMist® Quadrivalent) should avoid close association with individuals with severe immunocompromising conditions (e.g., bone marrow transplant recipients requiring protective isolation) for at least two weeks following immunization. 14 The live nasal spray influenza vaccine (FluMist®) may be available for purchase in Alberta through community pharmacies.
5. Annual influenza immunization of family members and hospital or clinic staff and volunteers who are in contact with adult patients with cancer is strongly recommended. In many cases, this may be more important than immunizing the patients themselves, as some patients may be less likely to respond to the vaccine. Transmission of influenza between infected healthcare workers and their vulnerable patients results in significant morbidity and mortality; therefore, healthcare workers should consider it their responsibility to provide the highest standard of care, which includes receiving the annual inactivated influenza vaccine. 2,18
6. Contraindications for influenza immunization (standard or high-dose vaccine) in adult patients with cancer include: 2,9,19 • Known hypersensitivity to any component of the vaccine excluding eggs.
• Anaphylactic or other allergic reactions to a previous dose of influenza vaccine.
• Known history of severe oculorespiratory syndrome (ORS) symptoms that included lower respiratory symptoms within 23 hours of receiving influenza vaccine pending consultation with the Medical Officer of Health to review the risks and benefits of further influenza immunization. • Known history of Guillain Barré Syndrome (GBS) within six weeks of a previous dose of influenza vaccine. • Individuals presenting with a serious acute febrile illness o Recommendations should be provided for these individuals to be immunized when their symptoms have resolved. o Individuals with non-serious febrile illness may be immunized. 7. Precautions for influenza immunization (standard or high-dose vaccine) in adult patients with cancer include: 2,9,19 • Egg allergy is not considered a contraindication for inactivated influenza vaccine.
• Egg-allergic individuals may be safely immunized using inactivated influenza vaccine without a prior influenza vaccine skin test and with the full dose of vaccine, irrespective of a past severe reaction to egg. They can be immunized in any setting and should be kept under observation for 30 minutes following vaccine administration.
As with all vaccine administration, immunizers should have the necessary anaphylaxis equipment and protocols, and be prepared to always respond to a vaccine emergency. Vaccine recipients who have had an anaphylactic reaction to any agent should be kept under observation for at least 30 minutes post-immunization.
Individuals who report they have experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of a previous influenza immunization, had an apparent significant allergic reaction to the vaccine or any other symptoms (e.g., throat constriction or difficulty swallowing) should have a report sent to the Adverse Event Following Immunization Reporting | Alberta Health Services, please follow the reporting requirements laid out on this webpage. Follow up will then occur directly with the patient.
# Influenza Immunization: Pediatric Patients with Cancer
1. Annual administration of the inactivated influenza vaccine is indicated for most pediatric patients with cancer who are six months of age and older. A standard dose quadrivalent influenza vaccine, Fluzone® or FluLaval® Tetra for children six months of age and older should be used. 2 The live attenuated influenza vaccine is not recommended for children with immunecompromising conditions. 2,5 Immunization with currently available influenza vaccines is not recommended for infants younger than six months of age. The recommended doses by age are as follows:
• Children nine years or older should receive one dose of influenza vaccine.
• Children previously unimmunized with influenza vaccine who are older than six months and less than nine years of age require two doses of influenza vaccine in the first year they are immunized, with a minimum interval of four weeks between doses. • Children six months to less than nine years of age who have been previously immunized with influenza vaccine in another season require only one dose of influenza vaccine. • A full dose (0.5 mL) of influenza vaccine should be used for all people who are receiving influenza immunization.
2. Although the data is limited, age, duration, and type of systemic therapy (except for rituximab or other B-cell or T cell depleting antibodies) do not appear to influence the response of pediatric patients to influenza vaccine. Pediatric patients with hematologic malignancies may have lower responses to immunization when compared to pediatric patients with solid tumours. Patients who are treated with rituximab or other B-cell or T cell depleting antibodies should have all their inactivated vaccines postponed until at least six months after the last dose of rituximab. A clearance letter is required before starting immunization. [12][13][14][15] 3. Timing of inactivated influenza immunization in relation to the therapy cycle and other vaccines: a) Influenza vaccine should ideally be given at least two weeks before the administration of any immune-suppressing cancer treatment, to allow the patient to develop a sufficient antibody response. If early immunization is not possible or feasible, administration of the inactivated vaccine less than two weeks before the start of immune-suppressing cancer treatment, or between treatment cycles has been reported to be safe and is recommended over not receiving the vaccine at all, although the efficacy of the vaccine may be reduced in this situation. b) For AHS employees, direction for co-administration of influenza and COVID-19 vaccines can be found on the internal website at Home Teams Communicable Disease Control Immunization Program Standards Manual Biological Product Information COVID-19.
4. For pediatric patients undergoing hematopoietic stem cell transplant (HSCT) the recipient and donor immunization status pre-transplant both have an impact on post-transplant immunity.
Immunity established prior to HSCT may increase immune response following transplant: 11,14,20 a) Recipient: the inactivated influenza vaccine should be administered at least two weeks prior to transplant conditioning or mobilization chemotherapy. Consult the attending transplant physician. Live influenza vaccine is contraindicated. b) Donor: the inactivated influenza vaccine should be administered at least two weeks before stem cell harvest. Consult the attending transplant physician. Live influenza vaccine is contraindicated. c) There is no difference in recommended schedules between autologous or allogeneic recipients. Although a current topic of research, the differences in immunity post-transplant for the two types of recipients are not enough to justify two separate schedules. d) Immune system recovery post-HSCT is variable and requires assessment by the transplant physician. The majority of HSCT recipients will have a detectable antibody response to the influenza vaccine at six months post-transplant which continues to increase over the next 12 to 24 months. GVHD, may prolong the duration of immunosuppression. e) For HSCT recipients, inactivated influenza vaccine should ideally be administered six months post-HSCT but can be given as early as three to four months post-transplant in outbreak situations at the discretion of the transplant physician. In such case, two doses should be given, at least four weeks apart. k) For patients on post-transplant maintenance therapy all immunizations should be postponed until at least six months after the last dose of chemotherapy. It is not known how new agents used for maintenance therapy (e.g., lenalinomide/revlimid) impact patients' ability to respond to vaccines; some physicians elect to have their patients immunized. A clearance letter is required before starting immunization. l) HSCT recipients who have started their post-HSCT vaccine series and then had the series interrupted by Chimeric Antigen Receptor T (CAR-T) cell therapy will need to restart their vaccine series. Inactivated influenza immunization can be given as early as three months post CAR-T cell therapy. f) Inactivated immunization should not be delayed due to GVHD/immunosuppressive therapy, unless due to high-dose steroids (i.e., 2 mg/kg per day for children under 10 kg or 20 mg/day for children over 10 kg or more of prednisone or its equivalent, for 14 days or more). Live vaccines are contraindicated in patients with active GVHD. g) Household contacts and healthcare workers should be up to date for routine immunizations as per the Alberta Immunization Schedule, including annual influenza, to reduce the risk of disease transmission to pediatric transplant recipients. h) Individuals who have received the live nasal spray influenza vaccine (FluMist® Quadrivalent) should avoid close association with individuals with severe immunocompromising conditions (e.g., transplant recipients requiring protective isolation) for at least two weeks following immunization. 14 The live nasal spray influenza vaccine (FluMist®) may be available for purchase in Alberta through community pharmacies.
5. Annual influenza immunization of family members, out-of-home caregivers, and hospital or clinic staff and volunteers in contact with pediatric patients with cancer is strongly recommended. In many cases, this may be more important than immunizing the patient themselves, as some patients may be less likely to respond to the vaccine. Transmission of influenza between infected healthcare workers and their vulnerable patients results in significant morbidity and mortality; therefore, healthcare workers should consider it their responsibility to provide the highest standard of care, which includes receiving the annual inactivated influenza vaccine. 2,18
6. Contraindications for influenza immunization in pediatric patients with cancer include: 2,19
• Known hypersensitivity to any component of the vaccine excluding eggs.
• Anaphylactic or other allergic reactions to a previous dose of influenza vaccine.
• Known history of severe oculorespiratory syndrome (ORS) symptoms that included lower respiratory symptoms within 23 hours of receiving influenza vaccine pending consultation with the Medical Officer of Health to review the risks and benefits of further influenza immunization. • Known history of Guillain Barré Syndrome (GBS) within six weeks of a previous dose of influenza vaccine. • Individuals presenting with a serious acute febrile illness o Recommendations should be provided for these individuals to be immunized when their symptoms have resolved. o Individuals with non-serious febrile illness may be immunized.
# Precautions for influenza immunization in pediatric patients with cancer include: 2,19
• Egg allergy is not considered a contraindication for inactivated influenza vaccine.
• Egg-allergic individuals may be safely immunized using inactivated influenza vaccine without a prior influenza vaccine skin test and with the full dose of vaccine, irrespective of a past severe reaction to egg. They can be immunized in any setting and should be kept under observation for 30 minutes following vaccine administration.
As with all vaccine administration, immunizers should have the necessary anaphylaxis equipment and protocols, and be prepared to always respond to a vaccine emergency. Vaccine recipients who have had an anaphylactic reaction to any agent should be kept under observation for at least 30 minutes post-immunization.
Individuals who report they have experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of a previous influenza immunization, had an apparent significant allergic reaction to the vaccine or any other symptoms (e.g., throat constriction or difficulty swallowing) should have a report sent to the Adverse Event Following Immunization Reporting | Alberta Health Services, please follow the reporting requirements laid out on this webpage. Follow up will then occur directly with the patient.
# Discussion
# Influenza Immunization: Adult Patients with Cancer
Cancer treatments can produce acute and profound immunosuppression, although published literature suggests that the degree may differ according to the specific regimen, doses, and duration of treatment. Annual administration of the inactivated influenza vaccine is recommended for most adult patients with cancer.
Interpreting the results of influenza vaccine efficacy in adult patients with cancer is difficult because patient characteristics, cancer types, vaccine strains, and assessment of responses vary between published studies. In a review of 1,225 patients from the Surveillance, Epidemiology, and End Results (SEER) and Medicare databases, Earle et al. reported that among patients undergoing chemotherapy for stage IV colorectal cancer, those who had been immunized had lower rates of influenza and pneumonia than those who were not immunized (1.1% vs. 3.8%, p=0.004). 21 In addition, the immunized patients had significantly fewer interruptions in the chemotherapy cycles, showed a trend toward using fewer health care resources, and were more likely to survive to the next influenza season (HR for death=0.88, 95% CI 0.77-0.99). Similarly, a 2013 Cochrane review of four studies involving 2,124 adult patients with cancer receiving chemotherapy concluded that influenza immunization was associated with lower mortality and that infection rates were lower or similar in patients who were vaccinated versus those who were not. 22 Patients with cancer who develop influenza are at high risk for serious complications and death. In a review of 11 published studies involving adult patients undergoing chemotherapy treatment or hematopoietic stem cell transplantation (HSCT), Kunisaki et al. reported case fatality rates ranging from 11% to 33% for the studies involving chemotherapy. 23 Similarly, in a report of 168 critically ill patients admitted to Canadian intensive care units at the peak of the 2009-2010 H1N1 influenza outbreak, Kumar et al. reported that 8.2% of these patients had one or more major co-morbidities, including immunosuppression due to cancer or cancer therapies. 24 It is most beneficial to immunize patients with malignant solid tumours at least two weeks prior to beginning chemotherapy to allow for sufficient antibody production by the patient. 4, [25][26][27] In a study involving patients with breast cancer, geometric mean titers were significantly lower among individuals immunized at day 16 of chemotherapy versus those immunized at day 4. 28 However, a pilot study of 18 patients with solid tumours immunized either one week before or on the first day of chemotherapy reported that all patients mounted an immune response to the vaccine, and there were no significant differences in seroconversion or seroprotection rates against the three influenza strains between the two groups of patients. 29 If early immunization is not possible, administration of the inactivated vaccine between chemotherapy cycles has been reported to be safe and is recommended over not receiving the vaccine at all, although the efficacy of the vaccine may be reduced in this situation. 21,25,30 In such situations, administration of the vaccine is preferable when therapy is at the lowest level possible. 4 There is a growing body of published data on the safety and efficacy of the influenza vaccine in patients with cancer treated with ICI therapies, including CTLA-4 inhibitors (e.g., ipilimumab) or PD-1 and PD-L1 inhibitors (e.g., nivolumab, pembrolizumab). [31][32][33][34][35][36][37][38][39][40] One of the first studies on the safety of influenza vaccination in cancer patients receiving ICIs caused concern about an increased risk of severe immunological complications. 41 While data were based on a small number of lung cancer patients (n=23), because of this data many clinicians began to advise patients on ICIs against vaccination. A 2021 systematic review that included ten studies assessing the safety and eight assessing the efficacy of influenza vaccination in cancer patients receiving ICIs has since moderated these concerns. 38 The systematic review showed that in most subsequent and larger studies, the overall safety and efficacy of influenza immunization in cancer patients receiving ICIs is not markedly different from that observed in the general population. Therefore, it is the consensus of the Alberta Provincial Tumour Teams that patients receiving ICIs can receive the influenza vaccine at any time during therapy.
Adult patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT) are at significant risk for infections prior to immune regeneration. Preparation for both autologous and allogeneic HSCT involves intensive high-dose regimens of chemotherapy and/or radiotherapy, which leaves the patient acutely and profoundly immunocompromised for several months following transplantation. The impact of seasonal influenza on HSCT recipients can be devastating. Llungman et al. reported a case fatality rate of 23% among over 1,900 patients in Europe over three influenza seasons. 16 Kumar and colleagues reported the results of a multicentre prospective observational study of pediatric and adult solid organ transplant (SOT) and HSCT patients carried out across 20 sites from the United States, Canada, and Spain. They documented 616 patients with confirmed influenza (477 SOT; 139 HSCT) over a 5-year study period. The annual incidence of pneumonia ranged between 11.3-35.0% and ICU admission rates ranged between 8.1% to 14.3%. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia, and antiviral treatment within 48 hours was associated with improved outcomes. 42 No significant differences were noted between SOT and HSCT patients with regard to pneumonia and ICU care. However, HSCT patients had a higher 6month mortality (13.8% vs 4.8%, p<0.001) and viral load at disease onset (median viral load 1.04 × 105 copies/mL vs 8.04 × 103 copies/mL, p=0.001) compared to SOT patients.
There is variability in the efficacy of influenza immunization in HSCT patients reported in the literature. One study documented serologic responses ranging from 0% in allogeneic transplant patients to 32% in autologous transplant patients. Another study reported immune responses of 29% to 34% in patients who underwent HSCT, and 46% to 62% in a group of healthy matched controls. 43,44 In a study of 82 allogeneic HSCT recipients who received the 2009-2010 H1N1 vaccine, Issa et al. reported that seroprotective antibody titers were detected in 51% of patients, and this rate was not affected by the presence of chronic graft-versus-host disease or type of conditioning regimen. 45 Patients were more likely to have higher seroprotective titers the further away they were from the transplant (OR=1.79 per year, 95% CI 1.12-2.85), and rituximab administration prior to immunization was associated with lower seroprotective titers (OR=0.11, 95% CI 0.01-0.97). Bedognetti et al. reported the results of a study comparing response to the seasonal influenza vaccine in 31 patients with non-Hodgkin lymphoma in complete remission after treatment with rituximab-containing regimens to 34 age-matched healthy subjects. 46 They reported that CD27+ memory B-cells were significantly reduced in patients treated with rituximab-based chemotherapies, and this reduction correlated with lower responses to influenza immunization. Similarly, in a study of 67 patients with lymphoma who were treated with rituximab alone or in combination with chemotherapy, Yri et al. reported that only five patients had a measurable but non-protective antibody titer after immunization, and the remaining 62 patients had no detectable titers at all, giving a seroprotection rate of 0%. This is in comparison to the 82% seroprotection rate for the healthy control patients. The investigators suggest that the non-responsiveness was due to the B-cell depletion caused by rituximab therapy. 47 Similarly, Berglund and colleagues reported the results of a subgroup analysis of rituximab-treated patients among 96 adult outpatients with cancer who were undergoing treatment. Of the 13 patients treated with rituximab, only one responded to immunization against influenza A (H1N1) and none responded to immunization against seasonal influenza. 13 Patients who are treated with rituximab or other B-cell depleting antibodies should therefore have all immunizations postponed until at least six months after the last dose of rituximab or other B-cell depleting therapies. [12][13][14]47 Lower-respiratory tract infection (LRTI) is a complication of influenza infection that frequently leads to lung injury and death, and profound lymphopenia is one of the most significant risk factors for progression from upper-to lower-respiratory tract involvement. 48 Risk factors for progression of H1N1 influenza to LRTI in patients with hematologic malignancies are unknown at the present time.
It is recommended that both the recipient and donor (for allogeneic transplants) receive inactivated influenza immunization at least two weeks prior to the transplant. 4,16,49 While only 10% to 30% of HSCT recipients will have a detectable antibody response to the influenza vaccine at six to 24 months post-transplant, over 60% will have a detectable response at 24 months or more post-transplant. 50 Immune system recovery post-transplant is variable and requires individual assessment by the transplant physician. For example, patients treated with rituximab post-transplant will have a delay in their B-cell recovery by at least six months following the final dose. 16,46 In addition, adult transplant patients with chronic graft-versus-host disease may require up to 24 months or more post-transplant to recover CD4+ counts. It is recommended that HSCT patients receive annual seasonal inactivate influenza immunization beginning at six months post-transplant. 4,16,49 To reduce the risk of disease transmission, immunization of family members and hospital staff in contact with patients who are at high risk for severe or complicated seasonal influenza is strongly recommended. Influenza immunization rates of health care workers is associated with a reduction in influenza infections in cancer patients. 51 The Public Health Agency of Canada (PHAC) states that people who are potentially capable of spreading influenza to those who are at high risk should be immunized, regardless of whether the high-risk person has been immunized. 4 Immunization of family members and hospital staff who are in contact with HSCT recipients is also of particular importance, as these patients are severely immunocompromised. Family members and health care providers should receive the inactivated influenza vaccine beginning the season before the transplant and annually for 24 months or more post-transplant. 49 If the family member or healthcare worker will only accept the live nasal spray influenza vaccine, they should wait two weeks following immunization before continuing to provide care to severely immunocompromised individuals. 17
# Influenza Immunization: Pediatric Patients with Cancer
Pediatric patients with cancer are highly susceptible to influenza infections and have an increased rate of influenza infection compared to healthy children. 52 In addition, hospitalization rates due to influenza infection for children under the age of five years with chronic health conditions have been reported to be significantly higher than for healthy children in the same age group. 53 Annual administration of the inactivated influenza vaccine is indicated for all pediatric patients with cancer over the age of six months. Immunization with currently available influenza vaccines is not recommended for infants younger than six months of age.
Recommendations regarding influenza vaccine doses in healthy children state that those nine years of age and older should receive one dose of the vaccine annually. Children younger than nine years of age who have not previously received the trivalent or quadrivalent influenza vaccine require two doses of the vaccine in the first year they are immunized, with the second dose being administered four weeks or more after the first dose. The live vaccine is contraindicated in children with immune compromising conditions. 2
Like the literature regarding adult patients with cancer, interpreting the limited published results of influenza vaccine efficacy in pediatric patients with cancer is difficult because patient characteristics, cancer types, vaccine strains, and assessment of responses vary between published studies. In a meta-analysis of nine controlled clinical trials and one randomized controlled trial involving 770 children, Goossen et al. reported that immune responses to the seasonal influenza vaccine in children receiving chemotherapy were consistently weaker than in those children who had completed their chemotherapy regimen and in healthy controls. 54 Several studies have reported that pediatric patients with cancer who have completed their chemotherapy regimens have increased rates of seroconversion, suggesting that the timing of influenza immunization with regards to the chemotherapy cycle is an important factor in this population. 52,55 Seroconversion rates are also influenced by the type of cancer (solid tumour vs. hematologic malignancy) 56 and the type of chemotherapy. 57 Similar to the recommendations made for adults with cancer, it is likely most beneficial to immunize pediatric patients with cancer two weeks prior to beginning chemotherapy, to allow for sufficient antibody production by the patient. Shahgholi et al. assessed the immune response of 32 pediatric patients with acute lymphoblastic leukemia (ALL) and compared them to a control group of 30 healthy siblings. The trivalent influenza vaccine was well tolerated in the patients with ALL, and the immune responses were acceptable but limited. The percentage of ALL patients versus healthy controls with a fourfold increase in antibody titers were 56.2% versus 80% for H1N1 (p=0.04), 40.6% versus 53.3% for H3N2 (p=0.31), and 59.4% versus 83.3% for influenza B (p=0.038). 58 The recommendations for pediatric patients undergoing HSCT are like those for adult patients. 14,16,20,49 It is recommended that both the recipient and donor (for allogeneic transplants) receive the inactivated influenza vaccine two weeks prior to the transplant. Immune system recovery following transplant is variable and depends on factors such as the types of therapies administered and the presence of graft-versus-host disease; therefore, individual assessment is required by the transplant physician. Influenza vaccine should ideally be administered six months post-HSCT in pediatric patients. Inactivated influenza vaccine can be given as early as three to four months posttransplant in outbreak situations, at the discretion of the transplant physician. In such case, two doses should be given, at least four weeks apart. 59 Similar to the recommendations made for adult patients with cancer, immunization of family members, caregivers, and hospital staff in contact with pediatric patients who are at high risk for severe or complicated influenza is strongly recommended. 4 Immunization of family members and hospital staff who are in contact with pediatric HSCT recipients is also of particular importance, as these patients are severely immunocompromised and cannot be immunized themselves for at least four months post-transplant. In this situation, family members and health care providers should receive the inactivated influenza vaccine beginning the season before the transplant and annually for 24 months or more post-transplant. 20,49 If the family member or healthcare worker will only accept the live nasal spray influenza vaccine, they should wait two weeks following immunization before continuing to provide care to severely immunocompromised individuals. 20 | None | None |
6237d32bc5ca578bb37c8e8bf78b9bbef7666fd3 | cma | None | - We present updated, temporary recommendations for gestational diabetes (GDM) screening options during the coronavirus disease 2019 (COVID-19) pandemic. 2. After the COVID-19 pandemic is over, screening should revert to the previous guidelines outlined in the 2018 Diabetes Canada Clinical Practice Guidelines on Diabetes and pregnancy (1).1. There are no changes to screening for overt diabetes (diabetes present before conception) in early pregnancy. This can be done in high-risk women with a hemoglobin A1c (A1c) or fasting plasma glucose if an A1c is unreliable. 2. This update suggests an option for GDM screening using an A1c and random plasma glucose. The use of this option should be based on each institution's clinical capacity and/or an individual's willingness to undergo screening during COVID-19. 3. We continue to reinforce the importance of healthy lifestyle for all women throughout pregnancy (see resources below). 4. Postpartum screening for maternal dysglycemia should be deferred until after the COVID-19 pandemic is over. We do not recommend bringing women to an in-person healthcare appointment solely for an oral glucose tolerance test (OGTT) postpartum. 5. Whenever possible and using clinical judgement, clinicians should use telehealth devices (video or phone calls) to care for patients in order to reduce potential COVID-19 exposure to women and healthcare providers.# Introduction
The COVID-19 pandemic has already had a profound effect on both pregnant women and our interprofessional diabetes and pregnancy teams. Given this, we present GDM screening options to try to minimize exposure to pregnant women and limit healthcare resource utilization while still providing quality care. The risk of exposure to COVID-19 must be weighed against the benefit of widespread glucose screening and treatment of GDM. These guideline updates are temporary in nature and designed with the goal of preventing excess maternal and fetal morbidity rather than the current approach which is much more sensitive in detecting GDM cases. Once the COVID-19 pandemic has subsided, GDM screening should revert to recommendations in the 2018 Diabetes Canada Clinical Practice Guidelines (1).
We have developed an alternate screening option which includes a provision for disruption to the OGTT, which may occur due to decrease laboratory staffing or locations, public health recommendations, or due to patient concern about COVID exposure during this test.
# EARLY SCREENING
We recommend no changes to screening for overt diabetes early in pregnancy. This should be done only in women who are at risk of overt diabetes. A complete list of risk factors can be found in the 2018 Diabetes Canada guidelines (2). The test of choice continues to be an A1c or a fasting plasma glucose if an A1c is unreliable. All women screened in early pregnancy with negative testing should be re-screened at 24-28 weeks gestation.
# REGULAR (24-28 WEEKS) SCREENING
Anticipating that the COVID-19 pandemic may substantially reduce access to, capacity for, and safety of attending for laboratory testing in different regions at different times, we recommend an alternative screening strategy for GDM outside 2018 Diabetes Canada Clinical Practice Guidelines (1). We recommend that the decision to shift to using this alternative screening strategy be made at an institutional (or district / regional level, as applicable) rather than by individual clinicians.
# Current GDM screening, as per 2018 CPG (1) may continue if there are only minimal disruptions to capacity for lab testing or treatment of GDM.
- These recommend screening all pregnant women without pre-existing diabetes using a 50 g glucose challenge followed by a 75 g OGTT in those with a 1-hour glucose of 7.8-11.0 mmol/L (1).
This ALTERNATIVE SCREENING STRATEGY should be used if the COVID-19 pandemic causes severe disruptions to laboratory testing and treatment, and/or patient refusal.:
- All pregnant women without pre-existing diabetes will be SCREENED WITH AN A1c & NON-FASTING, RANDOM PLASMA GLUCOSE
- Women with an A1c of < 5.7% and a random plasma glucose < 11.1 mmol/L require no further testing or treatment.
- Those with an A1c of 5.7% or a random plasma glucose of 11.1 mmol/L are identified as having GDM and should be referred to the interprofessional diabetes and pregnancy healthcare team.
# Rationale:
Of all the available screening tests, we chose an A1c and a random plasma glucose as they are easy, widely accessible, do not require fasting, and require minimal laboratory resources compared to other screening tests. Non-fasting labwork provides flexibility for women to attend for testing and may reduce the burden on laboratories, while potentially increasing the sensitivity of the glucose test. We recognize that this alternative screening option will miss many women with GDM as an A1c of 5.7% has high specificity (96% ) but low sensitivity (25% ) (3). This strategy is aimed at identifying only the highest risk women. A random plasma glucose of ≥ 11.1 mmol/l was chosen by consensus in order to avoid missing a woman with quite elevated glucose levels but in whom an A1c is unreliable (for example because of a hemoglobinopathy) (4). Testing can be repeated if previously negative at any time if there is a high clinical suspicion of diabetes.
The alternative screening strategy is displayed in Figure 1.
# POSTPARTUM SCREENING FOR TYPE 2 DIABETES
Postpartum screening for maternal dysglycemia should be deferred until after the COVID-19 pandemic has ended. We do not recommend bringing women back solely for an OGTT.
# VIRTUAL MANAGEMENT OF WOMEN WITH GESTATIONAL DIABETES
We suggest that, whenever possible and using clinical judgement, clinicians use telehealth devices (video or phone calls) to care for individuals in order to reduce exposure to women and healthcare providers. This can include initial and follow-up visits. When in-person visits are conducted as part of routine obstetric care, every effort should be made to share key clinical data (eg weight, blood pressure) obtained with subspecialty teams including the interprofessional diabetes and pregnancy teams.
Clinicians may find it helpful to prepare for virtual visits by asking individuals to email blood glucose testing records in prior to the visit and uploading these on their clinical platform when available. Interprofessional diabetes and pregnancy teams can also consider the use of video conference platforms to host virtual GDM classes and teach insulin injections.
Resources: Diabetes Canada and SOGC websites have helpful online resources:
- www.diabetes.ca - Information regarding healthy lifestyle can be found here:
- /. Additional resources for patients and providers:
Pregnant women between 24 and 28 weeks' gestation - www.diabetes-pregnancy.ca | 1. We present updated, temporary recommendations for gestational diabetes (GDM) screening options during the coronavirus disease 2019 (COVID-19) pandemic. 2. After the COVID-19 pandemic is over, screening should revert to the previous guidelines outlined in the 2018 Diabetes Canada Clinical Practice Guidelines on Diabetes and pregnancy (1).1. There are no changes to screening for overt diabetes (diabetes present before conception) in early pregnancy. This can be done in high-risk women with a hemoglobin A1c (A1c) or fasting plasma glucose if an A1c is unreliable. 2. This update suggests an option for GDM screening using an A1c and random plasma glucose. The use of this option should be based on each institution's clinical capacity and/or an individual's willingness to undergo screening during COVID-19. 3. We continue to reinforce the importance of healthy lifestyle for all women throughout pregnancy (see resources below). 4. Postpartum screening for maternal dysglycemia should be deferred until after the COVID-19 pandemic is over. We do not recommend bringing women to an in-person healthcare appointment solely for an oral glucose tolerance test (OGTT) postpartum. 5. Whenever possible and using clinical judgement, clinicians should use telehealth devices (video or phone calls) to care for patients in order to reduce potential COVID-19 exposure to women and healthcare providers.# Introduction
The COVID-19 pandemic has already had a profound effect on both pregnant women and our interprofessional diabetes and pregnancy teams. Given this, we present GDM screening options to try to minimize exposure to pregnant women and limit healthcare resource utilization while still providing quality care. The risk of exposure to COVID-19 must be weighed against the benefit of widespread glucose screening and treatment of GDM. These guideline updates are temporary in nature and designed with the goal of preventing excess maternal and fetal morbidity rather than the current approach which is much more sensitive in detecting GDM cases. Once the COVID-19 pandemic has subsided, GDM screening should revert to recommendations in the 2018 Diabetes Canada Clinical Practice Guidelines (1).
We have developed an alternate screening option which includes a provision for disruption to the OGTT, which may occur due to decrease laboratory staffing or locations, public health recommendations, or due to patient concern about COVID exposure during this test.
# EARLY SCREENING
We recommend no changes to screening for overt diabetes early in pregnancy. This should be done only in women who are at risk of overt diabetes. A complete list of risk factors can be found in the 2018 Diabetes Canada guidelines (2). The test of choice continues to be an A1c or a fasting plasma glucose if an A1c is unreliable. All women screened in early pregnancy with negative testing should be re-screened at 24-28 weeks gestation.
# REGULAR (24-28 WEEKS) SCREENING
Anticipating that the COVID-19 pandemic may substantially reduce access to, capacity for, and safety of attending for laboratory testing in different regions at different times, we recommend an alternative screening strategy for GDM outside 2018 Diabetes Canada Clinical Practice Guidelines (1). We recommend that the decision to shift to using this alternative screening strategy be made at an institutional (or district / regional level, as applicable) rather than by individual clinicians.
# Current GDM screening, as per 2018 CPG (1) may continue if there are only minimal disruptions to capacity for lab testing or treatment of GDM.
• These recommend screening all pregnant women without pre-existing diabetes using a 50 g glucose challenge followed by a 75 g OGTT in those with a 1-hour glucose of 7.8-11.0 mmol/L (1).
This ALTERNATIVE SCREENING STRATEGY should be used if the COVID-19 pandemic causes severe disruptions to laboratory testing and treatment, and/or patient refusal.:
• All pregnant women without pre-existing diabetes will be SCREENED WITH AN A1c & NON-FASTING, RANDOM PLASMA GLUCOSE
• Women with an A1c of < 5.7% and a random plasma glucose < 11.1 mmol/L require no further testing or treatment.
• Those with an A1c of 5.7% or a random plasma glucose of 11.1 mmol/L are identified as having GDM and should be referred to the interprofessional diabetes and pregnancy healthcare team.
# Rationale:
Of all the available screening tests, we chose an A1c and a random plasma glucose as they are easy, widely accessible, do not require fasting, and require minimal laboratory resources compared to other screening tests. Non-fasting labwork provides flexibility for women to attend for testing and may reduce the burden on laboratories, while potentially increasing the sensitivity of the glucose test. We recognize that this alternative screening option will miss many women with GDM as an A1c of 5.7% has high specificity (96% [95% confidence interval 86, 99%]) but low sensitivity (25% [95% confidence interval 10, 49%]) (3). This strategy is aimed at identifying only the highest risk women. A random plasma glucose of ≥ 11.1 mmol/l was chosen by consensus in order to avoid missing a woman with quite elevated glucose levels but in whom an A1c is unreliable (for example because of a hemoglobinopathy) (4). Testing can be repeated if previously negative at any time if there is a high clinical suspicion of diabetes.
The alternative screening strategy is displayed in Figure 1.
# POSTPARTUM SCREENING FOR TYPE 2 DIABETES
Postpartum screening for maternal dysglycemia should be deferred until after the COVID-19 pandemic has ended. We do not recommend bringing women back solely for an OGTT.
# VIRTUAL MANAGEMENT OF WOMEN WITH GESTATIONAL DIABETES
We suggest that, whenever possible and using clinical judgement, clinicians use telehealth devices (video or phone calls) to care for individuals in order to reduce exposure to women and healthcare providers. This can include initial and follow-up visits. When in-person visits are conducted as part of routine obstetric care, every effort should be made to share key clinical data (eg weight, blood pressure) obtained with subspecialty teams including the interprofessional diabetes and pregnancy teams.
Clinicians may find it helpful to prepare for virtual visits by asking individuals to email blood glucose testing records in prior to the visit and uploading these on their clinical platform when available. Interprofessional diabetes and pregnancy teams can also consider the use of video conference platforms to host virtual GDM classes and teach insulin injections.
Resources: Diabetes Canada and SOGC websites have helpful online resources:
• www.diabetes.ca • https://sogc.org Information regarding healthy lifestyle can be found here:
• https://www.pregnancyinfo.ca/your-pregnancy/healthy-pregnancy/healthy-eating/. Additional resources for patients and providers:
Pregnant women between 24 and 28 weeks' gestation • www.diabetes-pregnancy.ca
# Acknowledgments
The authors and steering committee wish to express their gratitude to Dr Edmond Ryan for his comments on the initial drafts of this temporary update. | None | None |
351a89dec7db6a713265fbbbb8062796af448ff7 | cma | None | # Legal Disclaimer
While the individuals and groups involved in the production of this document have made every effort to ensure the accuracy of the information contained in this treatment guideline, please note that the information is provided "as is" and that CIHR and CRISM make no representation or warranty of any kind, either expressed or implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest extent possible under applicable law, CIHR and CRISM disclaim and will not be bound by any express, implied, or statutory representation or warranty (including, without limitation, representations or warranties of title or non-infringement).
This guideline is intended to give an understanding of a clinical problem and outline one or more preferred approaches to the management of the problem. This guideline is not intended as a substitute for the advice or professional judgment of a health care professional, nor is it intended to be the only approach to the management of a clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medication conditions. If you need medical advice, please contact a local health care professional. 1.0 INTRODUCTION ............................................................................................................................................
# TABLE OF CONTENTS
EXECUTIVE
# Executive Summary
Opioid use disorder (OUD) is one of the most challenging forms of substance use disorder facing the health care system in Canada and a major driver of the recent increase in overdose deaths across the country. In 2018, at least 4,460 Canadians died from an opioid overdose, with 94% determined to be unintentional (accidental) overdoses. This represents a 48% increase in overdose deaths from 2016 and a 9% increase from 2017. The recent emergence of street fentanyl, carfentanil, and other highly potent synthetic opioids increasingly cut into heroin and other street drugs is a pressing public health concern that has contributed significantly to the overdose emergency. Fentanyl and other synthetic analogues were implicated in 73% of opioid-related deaths in Canada in 2018, compared to 67% in 2017 and 50% in 2016. Although pan-Canadian opioid-related deaths were not tracked prior to 2016, it is known that there were at least 655 deaths in which fentanyl was determined to be a cause or contributing cause between 2009 and 2014, compared to an estimated 3,256 deaths involving fentanyl or fentanyl analogues in 2018 alone. This unprecedented public health emergency underscores the importance of developing comprehensive, collaborative, compassionate, and evidence-based health services to address the harms related to untreated OUD. Injectable opioid agonist treatment (iOAT) is an evidence-based, high intensity, costeffective treatment option for OUD for those patients who have not benefitted from other treatments and those whose individual situations and needs indicate they may benefit from injectable opioid agonist treatment.
When OUD is treated effectively, the benefits are not only to the individual (e.g., reduction in morbidity and mortality) but also to the community (e.g., reduced activity in the criminal justice system). Along these lines, the primary aim of iOAT is to improve the health of the individual, by reducing overdose risk and other imminent health and social harms associated with ongoing injection drug use. The second aim of iOAT is to engage individuals in addiction treatment who have not benefited from less-intensive treatments or who have been otherwise unable to access other forms of treatment. Patients may not benefit from oral medications such as buprenorphine/naloxone, methadone, and slow-release oral morphine (SROM) for a variety of reasons, including side effects, cravings persisting despite optimal oral opioid agonist treatment (OAT) dosing or being unable to reach a therapeutic dose. Repeated oral treatment attempts without significant benefit for these patients may result in increased risk of poor health and social outcomes, including fatal and non-fatal overdose(s).
This guideline recommends that iOAT should be considered for individuals with severe, treatment refractory opioid use disorder and ongoing illicit injection opioid use; that both diacetylmorphine and hydromorphone may be appropriate treatment options; and that iOAT should be provided as an open-ended treatment, with decisions to transition to oral OAT made in collaboration with the patient.
The Canadian Research Initiative in Substance Misuse (CRISM), a Canadian Institutes of Health Research (CIHR)-funded research network, assembled an expert interdisciplinary committee composed of 30 individuals, including representation from physicians, nurses, pharmacists, people with lived experience, researchers, and front-line staff. This clinical guideline was developed to provide three key clinical recommendations as well as clinical guidance on the provision of iOAT. Recommendations and clinical guidance are based on a structured literature review and clinical expertise. Its partner document, National Injectable Opioid Agonist Treatment for Opioid Use Disorder Operational Guidance, provides guidance on the implementation, operation, and evaluation of iOAT programs.
# Introduction
This document provides a brief overview of the rationale for and evidence supporting the use of injectable opioid agonist treatment (iOAT) for the management of opioid use disorder (OUD) followed by in-depth clinical guidance for the provision of iOAT. Considerations from the literature and clinical experience in Canada and other jurisdictions are provided, offering a framework for how to build a clinical practice of iOAT. However, the unique nature of each person's situation requires clinical judgement in order to determine the best course of treatment.
National Injectable Opioid Agonist Treatment for Opioid Use Disorder Operational Guidance (iOAT Operational Guidance), a partner guideline to this clinically-focused document, provides guidance on implementing an iOAT program and operational considerations.
# BRIEF OVERVIEW OF iOAT RATIONALE AND EVIDENCE
In 2018, at least 4,034 Canadians died from an opioid overdose, with 94% determined to be unintentional (accidental) overdoses. a This represents a 48% increase in overdose deaths from 2016 and a 9% increase from 2017. 1 The recent emergence of street fentanyl, carfentanil, and other highly potent synthetic opioids increasingly cut into heroin and other street drugs, including cocaine and methamphetamine, is a pressing public health concern that has contributed significantly to the overdose emergency. Contamination of street drugs is ongoing and progressive, with new agents such as benzodiazepine analogues being found in substances sold as opioids. Fentanyl and other synthetic analogues were implicated in 73% of opioid-related deaths in Canada in 2018, compared to 67% in 2017 and 50% in 2016. 1 Although pan-Canadian opioid-related deaths were not tracked prior to 2016, it is known that there were at least 655 deaths in which fentanyl was determined to be a cause or contributing cause between 2009 and 2014, 2 compared to an estimated 3,256 deaths involving fentanyl or fentanyl analogues in 2018 alone. 1 a Epidemiological data and research literature often use the term "overdose" or "accidental overdose" to refer to fatal and non-fatal dose intolerances to both prescription and illicit opioids. In the context of the drug supply being contaminated with fentanyl and other highly potent synthetic opioids, fatal and non-fatal overdoses may be reasonably considered "poisonings", as the adulteration of the drug supply makes it difficult if not impossible to determine a safe dose without knowing the composition and strength of illicit opioids and other substances which may also contain highly potent synthetic opioids.
This unprecedented public health emergency underscores the importance of developing comprehensive, collaborative, compassionate, and evidence-based health services to address the harms related to untreated OUD. Opioid agonist treatment (OAT) has proven to be the most effective approach to reducing all-cause mortality in individuals with opioid use disorder 3 and harms associated with illicit opioid use, including morbidity and mortality. Individuals with severe opioid use disorder who inject opioids may not adequately benefit from oral OAT medications for a variety of reasons, including cravings persisting despite optimal OAT dosing, patients being unable to reach a therapeutic dose, insufficient improvements in health, social function, or quality of life, or opting not to initiate oral OAT (e.g., previous experience with oral OAT including intolerable reactions to specific medication b or insufficient reduction in craving and illegal drug use). Individuals who inadequately benefit from first-line medications, or whose circumstances and risks otherwise indicate that they may benefit from iOAT, like other individuals using illicit opioids, face significant risks, including premature death, non-fatal overdose, blood-borne infectious diseases (e.g., HIV and hepatitis C), violence, and arrest. 9,10 Meta-analyses have shown that, among individuals who are treatment refractory c to methadone, prescription injectable diacetylmorphine-administered under the supervision of trained health professionals in a clinic setting-is beneficial in terms of reducing illicit opioid use, premature treatment discontinuation (or "treatment drop-out"), criminal activity, incarceration, and mortality as well as improving overall health and social functioning. In response to regulatory barriers limiting the provision of diacetylmorphine for the treatment of OUD in Canada, the SALOME (Study to Assess Longer-term Opioid Medication Effectiveness) trial compared injectable hydromorphone to injectable diacetylmorphine and found both medications, delivered in identical conditions, showed positive outcomes such as high retention rates (over 77% intention to treat ; over 92% per protocol analysis), reduction of street opioid use (from daily to a few days per month), and reduction in illegal activities. 13 A more in-depth review of evidence supporting iOAT for the treatment of OUD is available in Appendix 1.
In jurisdictions where diacetylmorphine is currently not available, or in patients where it is contraindicated or unsuccessful, hydromorphone provides an effective, licensed alternative. 13 b Although side effects for opioids are a class effect, individuals may have different experiences on different opioid medications.
c It should be noted that there has been an intentional shift away from the use of "treatment refractory," as it may inadvertently perpetuate stigma against individuals with opioid use disorder. This document uses this term, when necessary, to reflect its use in the scientific literature. However, substance use disorders are known to be chronic, relapsing conditions which may require multiple treatment approaches across the lifespan, thus rendering such a term and concept otherwise moot.
# DEVELOPMENT PROCESS
See Appendix 2 for details of the development process and review process.
# 1.2.i Intended Audience
The target audience of this document is iOAT prescribers, pharmacists, and nurses, however, there is clinical utility for other members of iOAT care teams, including psychologists, social workers, peer workers, addiction counsellors, case managers, team leaders, program managers, other health care providers, and organizations that provide substance use disorder and addictions treatment and care. Clinical and operational leads may find this document useful in informing the implementation of iOAT. Although this document is primarily written for clinicians and other health care providers, individuals with lived experience of opioid use disorder may wish to read all or part of the document to inform their understanding of treatment options. Additional materials intended for people who use drugs and materials for the general public are available on the CRISM website.
# PURPOSE AND SCOPE
This guideline was created to provide a framework to assist with the clinical practice of iOAT. This includes recommended eligibility considerations; prescription of iOAT; titration, stabilization, and transitions off iOAT; conversion to alternate OAT; supervision of injection; and referral to ancillary services. This guideline does not include guidance on program implementation and other operational issues. Its partner document, iOAT Operations Guidance, provides an overview of potential models of care for this treatment and guidance on selecting the most appropriate model for each site; recommendations on prescriber and staff competencies; guidance on obtaining and preparing injectable medications; and guidance on implementing evaluation of iOAT programs.
This document should be understood as a living document, which will be updated by the National iOAT Clinical Guideline Committee regularly to reflect changes in evidence, policy, and practice.
As the implementation and expansion of iOAT progresses, regulatory and training frameworks will emerge and be added to this and its partner guideline.
# Clinical Recommendations
This clinical guideline makes three key recommendations regarding the provision of injectable opioid agonist treatment. These recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework, which was developed to provide a transparent and systematic approach for making clinical practice recommendations. 15 These three key recommendations are based on the existing literature on iOAT, including two systematic reviews and meta-analyses. The rest of the guidance in this guideline can be understood as clinical guidance informed by the existing literature and reached by consensus of the experts on the National Injectable Opioid Agonist Treatment for Opioid Use Disorder Clinical Guideline Subcommittee.
The GRADE approach rates evidence quality as high, moderate, low, or very low. Evidence quality can also be understood as certainty of evidence or confidence in the estimated effect size.
Recommendations can be rated as either strong or conditional. More information on the GRADE system can be found in Appendix 2; the full recommendations and accompanying evidence summaries can be found in Appendix 3.
# Recommendation
# Quality of Evidence
# Strength of Recommendation
# Clinical Practice Guidance
# Summary of Clinical Practice Guidance
# General considerations
Individuals with severe opioid use disorder who inject opioids and have continued to experience significant health/and or social consequences who have not benefitted from previous attempts at oral opioid agonist treatment, or other circumstances and risks that indicate they may benefit from iOAT.
# p. 21
# Eligibility
Recommended considerations for eligibility in concert with clinical judgment and precautions p. 21
# Medication selection
Both hydromorphone and diacetylmorphine are reasonable choices, based on availability, patient choice, and prescriber judgment p. 30
# Titration process
The titration protocol should be followed.
# Administration of injectable medications
Generally, up to 3 visits per day are recommended.
Individuals should self-administer under supervision of a qualified health professional.
Patients may inject intravenously, intramuscularly, or subcutaneously.
Intravenous injection is recommended in upper extremities only. Lower extremity injection should be discussed and risks identified for those who cannot find an appropriate site in their upper extremities or who otherwise prefer intravenous injection in their legs or feet.
Intramuscular sites should be identified by a qualified health professional and rotated according to established practice standards.
# p. 32
# Post-intake assessment
Performed by a qualified health professional or other trained staff member supervised by a health professional to ensure safety and attend to dose intolerance or other adverse event.
p. 31, Appendix (p. 73)
# Co-prescription of oral OAT
Consider co-prescription of slow release oral morphine or methadone to prevent withdrawal and cravings between iOAT doses, particularly overnight.
# p. 34
# Missed doses
The short-acting nature of iOAT medications requires adequate supervision for missed doses. Refer to missed doses protocol.
# p. 36
# Ongoing substance use
Ongoing substance use while on iOAT may be an indication to intensify treatment, which may include dose increases, transferring to a more intensive model of care, and/or increasing psychosocial and other supports. See Ongoing Substance Use for substance-specific guidance.
p. 42
# GENERAL CONSIDERATIONS
Injectable opioid agonist treatment is generally considered for individuals d with severe OUD who inject opioids and have continued to experience significant health and/or social consequences related to their OUD despite past experience or attempts with appropriately dosed oral OAT e (per CRISM's National Guideline for the Clinical Management of Opioid Use Disorder), previous attempts at oral OAT without being able to achieve a therapeutic dose, or other circumstances and risks that indicate the patient may benefit from iOAT. It is important that all health care providers maintain thorough documentation of treatment offers, treatment attempts, overdoses, and patient outcomes in order to ensure that individuals are appropriately transitioned through the continuum of treatment and care, and to document the need for iOAT, when appropriate. Rather than specific doses and dates, the context of the person's life should guide clinician judgment and patients should be adequately counselled on treatment options across the spectrum of care.
The following eligibility considerations are based on published primary literature and experience from existing clinical programs. However, these clinical programs were developed prior to the illicit drug supply in many parts of Canada being contaminated with highly potent synthetic opioids such as fentanyl and carfentanil. Given the high risk of fatal and non-fatal overdose for individuals using illicit opioids in markets where the drug supply has been contaminated, eligibility considerations should address the clinical context. The following eligibility considerations were compiled with the clinical determination, based on decades of clinical and research experience with OAT and iOAT, that pharmaceutical grade opioids prescribed under supervision with sterile injection supplies are safer than illicit opioids.
# PATIENT POPULATION AND ELIGIBILITY
# 3.2.i Eligibility Considerations
As individual situations vary, considerations for eligibility are presented below, with the recognition that individual patients may not meet all of the listed criteria, while other criteria not listed could make a compelling case for program admission. Prescribers f are advised to use these considerd In line with other clinical guidelines, this document primarily refers to recipients of iOAT as patients, however, where appropriate, other terms such as "individuals", "clients", and "service users" are used to reflect the collaborative and non-hierarchical relationship providers and service users should develop. When working with individuals, their preferred terminology should be sought and mirrored.
e For the sake of simplicity, both oral (methadone and slow-release oral morphine) and sublingual (buprenorphine/naloxone, trade name Suboxone) opioid agonist treatments are referred to as oral OAT in this document.
f This term denotes physicians and nurse practitioners authorized to prescribe iOAT.
ations to guide clinical judgment and collaborative decision-making in determining, with the individual, which treatments have the highest likelihood of ensuring the goals of care, which should include survival, reduction in the harms related to drug use, increased quality of life, and any other patient-defined goals based on their context and needs. It should be noted that these eligibility considerations were informed by inclusion and exclusion criteria in randomized trials and modified according to expert consensus.
# Minimum Required Criteria
The assessment and confirmation of these minimum criteria for iOAT are required:
- Confirmed and documented history of injection drug use with opioids and severe opioid use disorder (see DSM-5 criteria in Appendix 4); and
- Current opioid injection drug use confirmed by patient report, signs of injection drug use (e.g., fresh puncture wounds or "track" marks), and documented opioid-positive urine drug tests; and
- Capacity to consent to the treatment (see Capacity to Consent in this document for those under 18), including the ability to understand:
-Level of intensity of treatment -Alternate treatment options -Potential risks and side effects of iOAT -Requirements of inclusion in the program.
Additional eligibility considerations for injectable opioid agonist treatment for those who meet the minimum required criteria include:
- Ability to attend clinic or pharmacy or (where offered) receive home nurse visits up to three times daily; g g Some programs may provide more than three doses per day, such as in jurisdictions where high potency (≥50mg/mL) hydromorphone is not covered, to ensure that patients can receive their needed dose, whereas others may only provide twice-daily doses. Clinical experience in British Columbia has shown that many individuals do well on two doses per day.
- Able to self-administer (i.e., inject via intravenous, intramuscular, or subcutaneous route) medication under supervision or willing to learn, or depending on jurisdiction, model of care, and staffing model, willing to receive health care provider or peer injection (see Appendix 6 in this document for more information on health care provider administration of injectable medications);
- Previous experience with therapeutic dose of oral OAT (per CRISM's National Guideline for the Clinical Management of Opioid Use Disorder) while continuing to experience significant health and social consequences related to their OUD and continued regular injection opioid use, previous attempts at oral OAT without being able to achieve a therapeutic dose, or other circumstances and risks that indicate the individual may benefit from iOAT; and
- Significant risk of medical consequences of injection opioid use that would likely benefit from increased health system involvement and engagement in care, or existing significant medical and/ or psychiatric comorbidities (e.g., HIV-positive and antiretroviral non-adherence, acute hepatitis, cardiopulmonary disease, severe mental health disorders, history of multiple overdoses).
In addition to the above considerations, the iOAT prescriber, with their patient's consent, should consult members of that person's extended care network (e.g., addiction counsellor, outreach worker, supervised consumption site staff, mental health worker) in order to gain a robust understanding of each patient's individual circumstances. For example, an outreach worker may have important information about the health needs of an individual, such as the circumstances of a recent overdose event.
Those same health and service providers should, in partnership with the patient, formulate biopsychosocial treatment goals in the same manner as for oral OAT. Prior to admission, individuals identified as likely to benefit from iOAT should go through an admission process that involves full informed consent and a recommended peer orientation to ensure program regulations, time commitments, and other requirements are fully understood.
The appropriateness of iOAT should be determined by the patient in concert with their primary care provider and the iOAT prescriber (if different from their primary care provider). As such, the decision of starting treatment with iOAT relies not simply on a list of criteria, but on the prescriber-patient relationship, patient experience, input from the patient's network of care providers (who may have relevant information, for example, knowledge of overdoses), and clinical judgement. Clinical judgment and patient preference should balance the benefits and risks of iOAT (which include risk of overdose, seizure, and soft tissue infection) as well as the potential patient burden of up to three visits per day. If the patient is currently receiving oral OAT, the iOAT prescriber should consult with the oral OAT prescriber as part of the assessment process. Additionally, a two-prescriber review for iOAT eligibility may be considered where feasible, and is especially recommended in situations where an individual has not previously been trialed at least once on appropriately dosed oral OAT. While the above criteria are not exhaustive, they reflect current best practices in multiple jurisdictions for determining iOAT eligibility.
# 3.2.ii Precautions and Cautions
# Eligibility Precautions
Caution should be exercised when prescribing iOAT in:
- Youth (under 25 years; see Youth in this document) and older adults, h in whom oral OAT or other forms of treatment may be more appropriate.
- Pregnant people or people who become pregnant while receiving iOAT (see Pregnancy in this document).
- Individuals with active moderate or severe alcohol use disorder, due to increased overdose risk.
Patients should be treated concurrently for both OUD and alcohol use disorder.
- Individuals with active moderate or severe benzodiazepine use disorder and those prescribed benzodiazepines or z-drugs (e.g., zopiclone, zolpidem). While not necessarily an absolute contraindication, given that concurrent use of benzodiazepines and opioids increases the risk of respiratory depression, overdose, and death, caution is warranted. Completing a benzodiazepine taper prior to initiation of iOAT is recommended as the preferred approach. i
- Individuals with chronic medical conditions such as respiratory, hepatic or renal disease, acute conditions, or a history of recent head injury.
- Individuals with renal failure. There is evidence indicating that the hydromorphone-3-glucoronide metabolite accumulates in renal failure. 21 Hydromorphone should be used carefully in this setting, although hydromorphone has been used in renal failure patients with no adverse effects. Nephrology consultation is recommended in patients with:
-GFR 30mg/mmol -Acute kidney injury in absence of readily reversible cause.
h Rather than a specific age range for older adults, determinations should be made based on function, frailty, and specific needs (e.g., living independently, needing extra support, or residing in long-term care facilities). Frailty can be assessed using the Clinical Frailty Scale. 16 In addition, forthcoming guidelines on treating opioid use disorder in seniors should be consulted when appropriate.
i In line with a recent report from the FDA in the US encouraging prescribers to provide OAT for people with OUD even in the context of active benzodiazepine use due to the high risk of overdose from untreated or undertreated opioid use disorder, 20 and in the absence of data regarding risks associated with iOAT and benzodiazepine use, concurrent benzodiazepine use disorder is considered a strong precaution but one that may be handled in more intensive models of care and according to clinical judgment. In those cases, a concurrent benzodiazepine taper should be initiated with iOAT treatment.
- The risk of opioid toxicity inherent in using short-acting medication as is prescribed in iOAT should be individually considered in each case.
# General Cautions for Treatment
- Long-term opioid use, including both illicit opioid use and opioid agonist treatment, may lead to abnormalities in the endocrine system, mainly affecting the gonadal axis and leading to hypogonadism. 22,23 In line with this, low testosterone levels and erectile dysfunction have been associated with long-term opioid use (including oral OAT) in males 24 and menstrual disturbances in females. 22 Osteoporosis and reduced bone mineral density can also result from hypogonadism. Clinicians should discuss the potential hormonal changes from chronic opioid use before initiating iOAT and should monitor for its impacts as part of routine care.
- Prescribers should carefully consult the pharmacist associated with their iOAT program regarding drug-drug interactions, j including psychotropic medications with sedative effects (e.g., gabapentinoids, 25,26 antipsychotics).
- Individuals with coagulation disorders should be preferentially prescribed oral OAT, due to potential increased risk of bleeding or venous clotting following injection.
# 3.2.iii Hospitalization
Individuals on iOAT may have comorbidities which put them at increased risk for hospitalization, whether for acute or chronic health conditions. Hospitalization, whether for an acute event or longerterm, should not be understood as an absolute contraindication for iOAT eligibility. Injectable opioid agonist treatment inductions (see Medication Induction) can be performed in a hospital setting with adequate hospital policies and procedures in place. When hospital inductions are performed, the patient should be clinically stable and a physician with expertise in iOAT should assess the patient in hospital. Individuals with existing injection-related infection should be considered medically stable prior to iOAT initiation (e.g., not admitted to ICU, already on appropriate antibiotic therapy, stable vital signs, afebrile) and should receive closer supervision and education around sterile injection techniques. In addition, hospital-based inductions must be done in coordination with an outpatient prescriber and/or program who agrees to receive the patient into care following discharge. See Hospitalization and Acute Pain Events in this document for more information on treating patients on iOAT in hospital.
j Prescribers may also consult the Canadian Pharmacists Association's RxTx tool, available as a subscription both online and in a mobile app, or other subscription-based drug interaction tools.
# 3.2.iv Youth
The research to date on iOAT has not included participants younger than 18 years old (19 in British Columbia). Thus, the research evidence presented here has been extrapolated from studies conducted in adult populations, with the recognition that prescribers may encounter adolescent (aged 12-17 years) and young adult (aged 18-25 years) populations with severe OUD who do meet some or all of the considerations for eligibility for iOAT in their practice. While it is outside the scope of this guideline to make specific recommendations for the treatment of adolescents and young adults, physicians and nurse practitioners should use all available information and their best judgment when considering treatment options for any individual who is at high risk of overdose death, including use of available and evidence-based pharmacotherapy where indicated and appropriate and with the support of appropriate agencies such as local health authorities, youth-oriented programs, and the ministry charged with the protection of children in each province. Treatment decisions for youth (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) should be made by or with consultation from health care professionals with experience in treatment of adolescents and young adults with substance use disorders. If administration of pharmacotherapy to this population is beyond scope of practice, expertise, or experience, care providers should refer such patients to a health care professional with experience in treatment of adolescents and young adults with substance use disorders. For additional guidance in treating youth with opioid use disorder, see the BC Centre on Substance Use's Treatment of Opioid Use Disorder for Youth-Guideline Supplement.
# Capacity to Consent
As with any treatment, youth under the legal age of majority in Canada do not necessarily need parental consent in order to receive treatment. Capacity to consent for these youth is determined based on the capacity to fully understand the treatment and possible consequences of treatment, except in Quebec, where the age of consent is 14 years and older, 27 and New Brunswick, where the age of consent is 16 unless two medical practitioners are in agreement that the individual is capable of consenting and that the medical procedure in question is in the patient's best interest. 28 A patient under the legal age of majority seeking treatment who is determined able to understand the treatment and give consent should not require parental permission or notification. Informed consent and discussion of rationale for treatment should be documented, and the limits of confidentiality should be discussed (for example, duty to report). For more information on determining capacity to provide consent in those under the age of majority, refer to guidance from the Canadian Medical Protective Association 27 and Royal College of Physicians and Surgeons of Canada. 28
# Youth-Centered Environment and Approach
Several studies have found that youth (adolescents and young adults) experience the adult-oriented environment of most treatment services as a barrier to accessing and continuing treatment. It should be noted, however, that the evidence base is for substance use disorder treatment more generally, and oral OAT where specified, rather than iOAT. Injectable opioid agonist treatment programs serving youth should ensure that they are relevant, engaging, and accessible in order to engage patients in care. 31 While, generally, the elements that improve retention in adults also apply to youth (e.g., staff who are well-trained, clear policies, and low staff turnover), 32 several youth-specific factors have been identified. These include confidentiality of services, 33 inclusion of family members, the opportunity to develop close relationships with staff, use of pharmacological treatments when appropriate, a combination of pharmacological treatments and psychosocial treatment interventions and supports, and ensuring treatment is provided without a pre-determined end date. 29 Youth receiving opioid agonist treatment in the United States identified several factors that impact youth engagement in treatment, including a reluctance to access treatment in locations populated by older patients who appeared to have more experience with substance use, as well as the relatability of language and environment. 29 Inclusion of peer navigators and peer support may also support a youth-centered approach, for example, by helping youth who may be ambivalent about receiving care from adult professionals who have not experienced OUD feel more comfortable accessing treatment. Peer support staff, with their own lived experience of OUD, can offer hope, model problem-solving skills, and offer an example of the benefits of participating in OUD treatment. 34 Where feasible, OAT programs for youth may include iOAT provision. Where youth-specific programs are not feasible, considering the age range of clients and staff when referring youth may prove beneficial for patient retention and the success of the treatment. This consideration should be extended to pharmacy services for youth receiving OAT.
# 3.2.v Pregnancy and People of Child-Bearing Capacity
To date, published evidence on the feasibility and safety of iOAT during pregnancy is limited to two European case reports, both of which attribute positive pregnancy outcomes to the continuation of treatment with diacetylmorphine in the case of women with severe opioid use disorder and multiple comorbidities. 35,36 In view of the paucity of evidence supporting the safety of iOAT for this population, oral treatment options should always be offered before contemplating the initiation or continuation of iOAT. For transition from iOAT to oral OAT, methadone or slow-release oral morphine may be preferable to buprenorphine/naloxone as it does not require a period of opioid abstinence prior to induction.
However, the potential harms of initiating iOAT should be weighed against the considerable risk of morbidity and mortality associated with untreated opioid use disorder in the case of individuals with severe opioid use disorder who have been unable to stabilize with other options. Similarly, for individuals who are stable on iOAT prior to pregnancy, the likelihood of relapse to non-medical opioid use and associated harms should be carefully assessed when considering treatment de-intensification. In addition to the published case reports, there have been a small number of cases of successful iOAT continuation through pregnancy provided by services across Europe (M. Vogel, MD, Written communication, November 22, 2017). Decisions concerning the initiation and continuation of iOAT should be made with caution and in consultation with an addiction specialist. The patient's informed consent should be obtained and documented prior to initiating this treatment.
All patients of childbearing capacity starting iOAT should be offered screening for pregnancy at intake, with contraceptive counselling and prescriptions offered as appropriate, and ongoing sexual health and pregnancy planning provided (as is standard in primary care). This is in consideration of the fact that the majority of pregnancies among individuals with substance use disorders are unplanned. 37 In addition, pregnant individuals with substance use disorders may present for prenatal care relatively late in their term due to various social and personal barriers such as fear of losing custody of their children. Family planning services and treatment should also be offered to patients who are currently pregnant in order to reduce the likelihood of a subsequent unplanned pregnancy as short intervals between pregnancies may disrupt ongoing treatment and amplify potential risks to recovery and long-term health. 37
# PRESCRIBING INJECTABLE MEDICATIONS
# 3.3.i Initial Considerations
This document is intended to provide guidance on the clinical practice of iOAT provision. Detailed guidance regarding iOAT practice implementation is outside the scope of this document (see iOAT Operations Guidance); however, there are certain minimum requirements which must be considered and addressed at the outset. These include:
- Determining who may prescribe iOAT in each jurisdiction-this may include both physicians and nurse practitioners and will be determined by the appropriate authorities and regulatory bodies in each jurisdiction. See iOAT Operations Guidance.
- Appropriate prescriber training:
-Each jurisdiction will have its own expectations for training, as determined by ministries of health, regional health authorities, and/or regulatory colleges.
-At minimum, previous training and experience with both methadone-and buprenorphine/ naloxone-based oral OAT prescribing, completion of iOAT-specific training, and a preceptorship (which could be completed remotely through telehealth) are recommended.
-The BC Centre on Substance Use provides online training on iOAT prescribing through the Provincial Opioid Addiction Treatment Support Program.
- Clinical supervision with a consultant or team leader - Support of a local pharmacy for medication procurement
- Capacity to provide methadone and/or SROM along with iOAT
- Colocation of psychosocial services, primary care, other medical care (e.g., hepatitis C treatment, wound care, HIV/AIDS treatment), psychiatric care, or well-developed referral pathways
- Consultation on local regulatory framework for provision of hydromorphone and diacetylmorphine (see iOAT Operations Guidance)
- Patient orientation-goals of iOAT, policies and procedures, as well as patient rights and responsibilities should be included in patient orientation. This may include a checklist discussed between staff and patient, peer orientation, and/or other approaches.
k Toward the Heart has multiple resources on reducing stigma, including training modules and guidance on respectful language.
# 3.3.ii Medication Selection and Preparation
Both hydromorphone and diacetylmorphine can be considered a reasonable choice, however, selection of medication will be subject to availability of diacetylmorphine (see iOAT Operations Guidance for more information).
The SALOME trial, a non-inferiority trial, found that hydromorphone is non-inferior to diacetylmorphine. 13 However, while diacetylmorphine has significantly more evidence supporting its efficacy in treating OUD, it may pose an increased risk of adverse events (e.g., seizures, oversedation) compared to injectable hydromorphone. 13,38 See Appendix 11 for a table of serious side effects for both medications. For these reasons, either medication is a reasonable choice, based on availability, patient choice, and prescriber judgement. If the individual is not benefitting sufficiently or is experiencing unacceptable side effects, they should be given the option to transition to the other medication. See iOAT Operations Guidance for information on availability of diacetylmorphine.
# Preparing and Dispensing Hydromorphone
Hydromorphone may be prepared at point of care for immediate use or in advance if appropriate infrastructure and procedures are in place. Beyond use dating is dependent upon several factors, including equipment and infrastructure. Injectable opioid agonist treatment programs should refer to the National Association of Pharmacy Regulatory Authorities (NAPRA) sterile compounding standards 39 and bylaws of each province's regulatory body for pharmacies. Please see the relevant regulatory body's website for more information on bylaws. Health authorities should be involved in providing the service or contracting for pharmacy services within their area. The decision of which format is to be utilized will vary based on the number of individuals for whom the medication is needed in a particular setting as well as available infrastructure and resources. Advanced compounding is recommended, when possible, to prevent drug wastage and potential for diversion; however, the lack of an embedded pharmacy to provide this service should not preclude consideration of offering this treatment to patients who would benefit.
# Dispensing and Preparing Diacetylmorphine
Currently, diacetylmorphine is available in 100mL (100mg/mL) vials. In the future, as access to diacetylmorphine expands, and if a Canadian supplier is secured, diacetylmorphine may be prepared at point of care for immediate use or in advance if appropriate infrastructure and procedures are in place. Beyond use dating is dependent upon several factors, including equipment and infrastructure.
Injectable opioid agonist treatment programs should refer to the National Association of Pharmacy Regulatory Authorities (NAPRA) sterile compounding standards 39 and bylaws of each province's regulatory body for pharmacies. Please see the relevant regulatory body's website for more information on bylaws. Health authorities should be involved in providing this medication or contracting for pharmacy services within their area. It is important to note that the procurement mechanisms for access to diacetylmorphine are evolving rapidly, and while this document will be updated regularly, the CRISM website will provide the most up-to-date information.
# 3.3.iii Medication Provision
# Supervision of Injections
Service users self-administer under supervision of a qualified staff member. Any appropriately trained unregulated health care worker may supervise injection as long as a regulated health professional is also in the room and can attend to any issues that may arise. Training for staff members involves orientation to an existing supervised injection program, along with training on conducting pre-and post-injection assessments, responding to dose intolerances, and aftercare.
Supervision of self-administered injection involves completing a pre-injection assessment, direct observation of the injection and disposal of equipment, and a post-injection assessment (see following section for more information on pre-and post-injection assessments). Each visit, including pre-injection assessment, administration of medication, and post-injection assessment, takes between 30 and 45 minutes.
# Pre-and Post-Injection Assessment
The purpose of the pre-injection assessment, completed by a qualified health professional or other trained staff if supervised by a health professional (physician, nurse practitioner, nurse or pharmacist), is to ensure that the patient is not intoxicated, including by centrally-acting sedatives and/or stimulants, or in any other acute clinical condition that would increase the risk of an adverse event with the use of iOAT. Cautions could include intoxication due to the use of stimulants resulting in the participant being actively psychotic or agitated in a way that would pose an immediate safety risk to themselves, staff, or other service users. Appropriate actions in response to these cautions may include holding the dose, reducing the dose, and/or delaying the dose. Prior to iOAT initiation, preand post-dose injection assessment procedures should be discussed with the service user and agreed upon as a requirement of the program.
In line with appropriate local regulatory body and nursing standards, any qualified health professional or other trained staff supervised by a health professional can conduct the post-injection assessments; however, any doubts or uncertainties must be reported to a regulated health professional (e.g., physician, nurse practitioner, nurse, or pharmacist) who will complete the post-injection assessment.
Patients can leave the premises when they are deemed fit to do so after the minimum 15-minute observation period post-dose. l The post-injection assessment time period should be extended if any of the following are present and are not part of the patient's usual disposition: drowsiness, slow response, or slurring. The post-injection observation period may be an ideal time to engage service users in psychosocial services and other medical care, although some individuals may not wish to engage after receiving their dose.
Clinical experience shows that some individuals experience a histaminergic reaction (e.g. swelling, itching) after injecting hydromorphone or diacetylmorphine; this can be managed through dose adjustments and/or provision of oral diphenhydramine or other antihistamines.
The pre-and post-injection assessment protocols can be found in Appendix 5.
# Administration of Injectable Medications
It is recommended that patients have access to the iOAT program up to three times per day, however, some programs may provide additional doses per day when feasible and required. m Patients selfadminister their prepared dose under the supervision of a qualified health professional. Patients may inject intravenously, intramuscularly, or subcutaneously. For safety reasons and to promote sustainable injection processes, it is recommended that intravenous injection be encouraged only in the upper extremities (hands or arms, no jugular or femoral vein use permitted), while intramuscular injections can be allowed in deltoid, ventrogluteal, or dorsogluteal muscles. However, for individuals who cannot find appropriate sites in their upper extremities or who otherwise prefer intravenous injection in their legs, the risks of intravenous injection should be discussed and an informed decision may be made to inject in legs or feet. Subcutaneous injection or short-term transition to oral OAT is also an option for those patients who need to give their veins a rest to heal venous damage.
More guidance on operational considerations is covered in iOAT Operations Guidance, however, each program must ensure the necessary supplies for safe injection are available, including tourniquets, Steri-Wipes, and needles of various gauges. Patients should also receive education on safer injection practices. Vancouver Coastal Health, CATIE, and Here to Help all have useful patient-facing materials on safer injection.
Injection sites should be identified in consultation with a physician, nurse practitioner, Registered Nurse, Registered Psychiatric Nurse, Registered Practical Nurse, or pharmacist (in jurisdictions where pharmacists are permitted to administer medications intramuscularly) and rotated, with the total volume of medication for injection taken into consideration for the most appropriate site, according to l Each program should create a policy on post-dose observation periods, depending on the context and patient population, which prioritizes patient safety.
m See footnote g, p. 22.
established practice standards (i.e., a large volume should be injected into a large muscle). When clinically indicated and feasible given the particular model of care and jurisdiction (see iOAT Operations Guidance), a physician, nurse practitioner, Registered Nurse, Registered Psychiatric Nurse, Licensed or Registered Practical Nurse, or pharmacist (hereafter referred to as health care provider) can administer the medication intramuscularly or subcutaneously. Nurses with phlebotomy or IV insertion certification may be able to provide IV injection when requested by the patient and determined appropriate. See Appendix 6 for more information on health care provider administration of injectable medication.
It should be noted that route of administration may impact tolerance, and patients should be observed more closely when they switch route of administration (e.g., switching from IM to IV). Some clients may choose to inject some of their dose intravenously and then inject the rest intramuscularly. In these cases, the needle tip should be changed to accommodate each route of administration.
# 3.3.iv Medication Induction
# Selection of Dose
Due to high inter-individual variability, each individual's dose must be carefully determined. There are no fixed doses for optimal stable dosing of hydromorphone or diacetylmorphine for individuals with an opioid use disorder. The upward titration at the start of therapy should begin with a safe dose and follow the protocol outlined in Appendix 7.
Dose increases need to be tolerated in order to continue at that dose. Doses that are not tolerated, as per assessment during the pre-or post-injection assessment periods, should be reduced. Doses should be titrated to clinical effect (i.e., reduction or cessation of illicit opioid use and opioid cravings) and avoidance of side effects (e.g., sedation, narcotic bowel, opioid-induced hyperalgesia).
# Hydromorphone
Maximum hydromorphone dosages are based on a 2:1 potency ratio of hydromorphone to diacetylmorphine, which was observed in the SALOME study and is supported by clinical experience at Providence Health Care's Crosstown Clinic. 40 Maximum recommended daily doses of hydromorphone can be found in Table 1 below, however, clinical experience in British Columbia shows that there may be clinical exceptions for those who continue to experience cravings and/or withdrawal symptoms. These exceptions should be made according to clinical judgment, with the reason for the exception documented.
# Diacetylmorphine
Maximum diacetylmorphine dosages are based on the Swiss clinical studies and were adopted by all of the other settings. 40 Maximum recommended daily doses of diacetylmorphine can be found in Table 1 above, however, clinical experience in British Columbia shows that there may be clinical exceptions for those who continue to experience cravings and/or withdrawal symptoms. These exceptions should be made according to clinical judgment, with the reason for the exception documented.
# Titration Process
The initial adjustment of the medication dose should be done over a two-to five-day titration period.
A three-day titration period has been shown to be safe, 41 however, clinical practice may vary due to specific patient needs and operational considerations. At any time during the titration period, prescribers can lower a patient's dose or suggest a more gradual titration based on the patient's response and safety concerns. Doses must be titrated specifically for each individual in order to achieve a safe and effective dose for each person. A lower starting dose or a slower titration process can be followed, per the patient's medical history or clinical experience, under the direction of the prescribing physician or nurse practitioner. Patients, in consultation with and under the guidance of their prescriber, can adjust the dose and frequency of daily injection sessions (up to three). Such adjustments can be considered after a visit between the prescriber and the patient, review of the dose received history and, if appropriate, consulting with at least one nurse (or other health care provider) who has been directly involved in pre-and post-assessment and supervision of current dosing schedule for that patient. A recommended titration process can be found in Appendix 7.
# Co-Prescribed Oral Opioid Agonist Treatments
Oral OAT is frequently co-prescribed with iOAT in order to prevent withdrawal and cravings between iOAT doses, particularly overnight during the longest between-dose period, as the injectable medications are relatively short-acting. In this way, co-prescription of oral OAT helps provide greater clinical n See footnote g, p. 22.
stability. Another potential benefit of co-prescription of oral OAT may be the facilitation of transitions to oral OAT alone. Clinical trials have included co-prescribed methadone, however, SROM may also be considered. o Buprenorphine/naloxone is not an appropriate co-prescription; due to its high affinity for the opioid receptor, it preferentially binds to the receptor and displaces other opioids if they are present, which can cause precipitated withdrawal.
# Dosing Recommendations
Induction of co-prescribed methadone should follow the process outlined in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. Guidance on induction of SROM can be found in the BCCSU's A Guideline for the Clinical Management of Opioid Use Disorder. Oral OAT may be started in advance if practical matters require waiting to start iOAT, at the same time as iOAT induction, or after a patient has been titrated onto iOAT.
Co-prescribed oral OAT doses can be given at any time of day. However, it is recommended that SROM be given at a similar time each day to avoid withdrawal, as the preparation is slow-release over 24 hours only, so the effect will not extend beyond 24 hours. Generally, supplemental oral OAT doses should be witnessed, however, prescribers may follow CRISM's National Guideline for the Clinical Management of Opioid Use Disorder's guidance on take-home dosing or provincial standards, when appropriate.
Because of prior experiences receiving only oral OAT with insufficient reduction of cravings and withdrawal symptoms, some individuals may prefer to try iOAT with no co-prescribed oral OAT, on the assumption that oral OAT does not benefit them. Some patients will find a sufficient reduction in cravings and withdrawal symptoms from iOAT alone. For those who are continuing to experience cravings, withdrawal symptoms, or other negative symptoms like disrupted sleep, consider recommending co-prescription of oral OAT to aid their sleep and help provide a baseline level of physical comfort and well-being.
# Stable Range of Co-Prescribed Oral Opioid Agonist Treatments
Similar to iOAT doses, co-prescribed oral OAT doses must be determined individually for each patient and will depend, in part, on the patient's goals and circumstances. Doses should be titrated to a dose where there are no withdrawal symptoms between iOAT doses, but may be titrated further in accordance with CRISM's National Guideline for the Clinical Management of Opioid Use Disorder or provincial standards.
- See Appendix 10 for more information on SROM and iOAT including co-prescription and transition from iOAT to SROM. See CRISM's National Guideline for the Clinical Management of Opioid Use Disorder for a review of evidence supporting the use of slow-release oral morphine more broadly for opioid use disorder.
# MEDICATION STABILIZATION
# 3.4.i Stable Dose Ranges
Stable doses must be determined individually for each patient and will depend, in part, on the patient's goals and circumstances. A therapeutic dose range has not been established with iOAT, and it is not possible to predict the dose an individual will need based on their history of illicit drug use or previous OAT dosing. Doses should be titrated to a dose where there are no withdrawal symptoms between iOAT doses. While stable doses must be individually determined, mean daily doses from randomized controlled trials on iOAT may be instructive (diacetylmorphine: 443mg; 11 hydromorphone: 244mg 11,13 ).
Some patients may wish to further adjust their dose as they achieve psychosocial stabilization and integrate new activities into their lives, for example, once they start working or re-connect with family.
In addition to overall wellbeing and a lack of cravings, sleep quality and duration may also indicate when the right dose for a patient has been reached.
For patients wishing to increase their dose, it is recommended that each dose be increased by 10mg (to a maximum of 30mg per day) for hydromorphone and 20mg (to a maximum of 60mg per day) for diacetylmorphine, as long as each dose increase is well tolerated, until their symptoms resolve and they are comfortable, or they reach the recommended dose maximums (200mg/dose and 500mg/ day for hydromorphone; 400mg/dose and 1000mg/day for diacetylmorphine).
# 3.4.ii Missed Doses
All iOAT programs should have a missed dose protocol in place which lowers the dose immediately and requires re-titration. When considering the most appropriate missed dose schedule, clinicians should consider opioid tolerance and prioritize safety, with more conservative re-titration approaches used when doses have been missed and tolerance is expected to have been lowered (for example, a patient who has been in a custodial setting without continued illicit opioid use or access to oral OAT).
The following missed dose protocol is based on expert consensus and may be modified based on clinical judgment and considerations about safety and tolerance.
- If a new, not-yet stabilized patient misses 3 consecutive doses or 1 day (whichever is first), they should restart the titration process following the titration protocol in Appendix 7.
- If a stabilized patient misses 6 consecutive doses or 2 days (whichever is first), their reason for missing doses should be discussed, their best estimate of the amount and frequency of illicit opioid use should be recorded and, according to clinical judgment, they may receive their usual or a reduced dose provided they meet the pre-dose assessment requirements. See Appendix 8 for an example dose reduction protocol.
- If a stabilized patient misses 9 consecutive doses or 3 days (whichever is first), their reason for missed doses should be discussed, and they should be re-titrated entirely following the titration protocol in Appendix 7.
Unlike the long-acting oral OAT formulations, iOAT medications are short-acting. As such, toxicity effects are more likely to emerge shortly after dose administration, allowing them to be quickly identified within the post-dose observation period in a clinical setting. This may allow for necessary dose adjustments to be made prior to each subsequent dose during the re-titration period to ensure tolerability.
If a client misses a dose or a day, a staff member should follow up with them to ensure their safety and support them in continuing treatment and address any barriers that are interfering with their adherence to treatment. If the client chooses to reduce the frequency with which they receive doses, it should be documented in their chart. In the event that a dose is held due to intoxication found in the pre-dose assessment, it should be considered a missed dose.
The missed dose protocol should be discussed with the patient prior to initiation and agreed to as a requirement of the program.
# CONTINUING CARE
As with any chronic condition, individuals on iOAT should receive comprehensive and continuing care. This should include ongoing review and assessment of adequacy of dosage, side effects, drugdrug interactions, patient goals, physical and mental health, and psychosocial domains including housing, relationships, and finances. Both daily program visits and prescriber appointments can be used for building therapeutic relationships, providing education about harm reduction and safe injection practices, offering supports and referrals to appropriate services, and promoting health and healthy behaviours.
Urine drug testing (UDT) can be used to help guide patient care, to ensure patients are aware of which substances they are ingesting if using illicit substances, and to start a conversation on harm reduction and safety. Unlike with oral OAT, where regular and random UDT are considered standard of care, regular and mandatory call-back UDT are not considered standard care for iOAT, due to both the low risk of diversion and the high frequency of contact with care providers. See Appendix 12 for more information on UDT.
# TREATMENT TRANSITIONS
This document recommends that iOAT should be provided as an open-ended treatment, given two post-randomized controlled trial observational studies that have found a loss of treatment benefit when prescription diacetylmorphine treatment was discontinued at a predetermined end date (see Appendix 3). 42,43 This document also recommends the use of a stepped and integrated continuum of care model for treatment of OUD, where treatment intensity is continually adjusted to match individual patient needs and circumstances over time and recognizes that many individuals may benefit from the ability to move between treatments. This includes intensification (e.g., initiating iOAT when oral OAT approaches have not been met with success) as well as routine strategies to de-intensify treatment (e.g., transitioning from iOAT to oral OAT) when patients achieve successful outcomes and wish to transition to lower intensity treatments. It is further recommended that iOAT prescribers support appropriate movement along the continuum of care for patients by being comfortable with prescribing both iOAT and all forms of OAT and routinely discussing treatment goals with patients (and families, when appropriate), including plans for medically supported transition to oral OAT. Discussion of de-intensification of treatment should not involve pressuring patients into moving to other treatment options, but rather outline treatment options and their potential risks and benefits.
As individuals stabilize, they may be ready to move to lower intensity treatments (including oral OAT) or move from an acute care setting to a community-or pharmacy-based iOAT program (see Models of Care in iOAT Operations Guidance). Any decisions to de-intensify care from iOAT to oral OAT should be made between patient (and their family, if included in their care), iOAT prescriber, and any other relevant health care providers. This decision should be made with the understanding that treatment modalities across the continuum of care for OUD that were previously insufficient may be appropriate and effective at different times in a person's life, depending upon health and general life circumstances.
Patients should not have their treatment discontinued without consent. If, for example, a patient's prescriber retires or moves, the patient should have the choice to be transferred to another iOAT prescriber, be slowly titrated off of iOAT, or transitioned to oral OAT.
As with intensification of treatment, de-intensification of treatment should not be understood as necessarily a permanent change. If a patient is not benefitting sufficiently from oral OAT, they should be offered the opportunity to immediately reinitiate iOAT. Patients should have the opportunity to trial transitioning to oral OAT and to transition from iOAT to oral OAT and back as many times as necessary in order to maintain their safety and meet their needs and goals.
More information on strategies for de-intensifying treatment can be found in Appendix 10.
# 3.6.i Dosage Equivalence with Oral Methadone and Slow-Release Oral Morphine
In order to maintain an average degree of saturation of the opiate receptors by opioids to prevent withdrawal symptoms and avoid over-dosage, for those receiving a daily supplemental dose of oral methadone or SROM, it is critical to establish a conversion factor for switching between methadone or SROM and hydromorphone or diacetylmorphine.
The opioid bioavailability of the individual pharmaceutical agents must be considered when converting dosages. A 100% bioavailability of injectable medication is assumed, irrespective of whether it is administered intravenously, subcutaneously, or intramuscularly. The calculation is always based on the intended effective opioid dose.
The conversion should be based on doses received, not prescribed. See the conversion table in Appendix 9.
# 3.6.ii Hospitalization and Acute Pain Events
Individuals on iOAT may have comorbidities which put them at increased risk for hospitalization, whether for acute or chronic physical or mental health conditions. For example, in the North American Opiate Medication Initiative (NAOMI) trial, 53.4% of participants had a chronic medical problem, 62.9% were hepatitis C positive, and 9.6% were HIV positive. 14 For this reason, planning for management of hospitalization and/or acute pain events must be included when initiating community-based treatment.
The following components are recommended in order to support continuity of care:
- Protocol in place for acute care prescribers and addiction medicine consult services to contact the community prescriber;
- Protocol in place for the community prescriber to contact the in-hospital most responsible provider (MRP) to inform them that the patient is on iOAT and, thus, will have a high opioid tolerance; p p Provincial electronic medical records or prescription monitoring programs are ideal, however, in jurisdictions lacking these systems, programs should provide patients with documents (for example, a wallet card) that can be given to acute care providers.
- Protocol in place for community prescriber to contact addiction medicine consult team (AMCT) in hospitals where these services exist. In the absence of these services, the community provider should be consulted to support in-patient care.
- Protocol in place for the hospital team providing care to access date and size of last dose received by patient (for example, uploaded to provincial electronic health record or prescription monitoring program, where possible); and
- Contact information for all iOAT programs, including ability to contact program outside of program hours. Program contact information, including on-call phone number should be included in provincial electronic health record or prescription monitoring program, where possible.
Patients experiencing acute pain events will likely require non-opioid analgesics as well as additional opioids to manage acute pain. Like with oral OAT, the baseline opioid dose will not address acute pain; patients will require higher and more frequent opioid dosing if they have an acute pain event.
In addition, when continued in hospital, the iOAT dose may need to be adjusted due to the medications being prescribed for management of acute pain.
In hospital settings where appropriate protocols and procedures are in place, iOAT may be continued (with self-administration or nurse-provided IM or subcutaneous doses). Expert consultation is important for these patients, as doses may need to increase (e.g. acute pain) or decrease (e.g., acute illness leading to an inability to tolerate regular outpatient dose). In hospital settings where iOAT is not feasible or available, alternative oral opioids (for example, oral hydromorphone or SROM) should be provided, with expert consultation to ensure adequate dose and tolerability is instituted.
# 3.6.iii Considerations for Transitioning Off of iOAT
Once they have reached stability, some individuals may request to transition to an alternative treatment.
In other situations, the care team may identify one or more of the following signs that transitioning to oral OAT may be appropriate or necessary and should be discussed with the patient:
- Patient request to transition to less intensive treatment;
- Patient not attending for all doses (Note: this may indicate a need for adjustment of the treatment schedule or dose);
- After an adequate trial of iOAT, patients not deriving benefit from treatment (e.g., escalating substance use-including non-opioid substances, repeated episodes of toxicity despite dose adjustments, no reduction in illicit opioid use or related harms);
- Any situation that jeopardizes staff or other patient safety or security and cannot be resolved through other means;
- Cognitive and/or physical health decline resulting in inability to consent to treatment or selfadminister medication; or
- New or evolving physical health conditions that exclude use of high-dose opioid treatment or could be worsened by high-dose opioid treatment (e.g., severe respiratory disease requiring long-term oxygen, renal failure, hepatic failure).
Whenever possible, the decision to transition off of iOAT should be made collaboratively with the patient, with an understanding that the benefits of iOAT may vary between patients and should be based, in part, on patient goals. Examples of benefits include reduced illicit substance use, increased stability, fewer overdoses, less money spent on drugs, and less criminal involvement. If a patient has been stable and meeting their goals on iOAT, they should be offered the opportunity to transition to oral OAT in a non-coercive manner that respects the long-term goals of the patient, which, for some individuals, may include an opioid-free life. Treatment decisions should be made collaboratively and be guided by patient goals, needs, and safety.
# 3.6.iv Short-term Transition to Oral Treatment for Travel
If individuals receiving iOAT need to travel, they may receive prescriptions for methadone or SROM. Generally, for a single-day trip, patients would be provided with a prescription for witnessed ingestion of SROM, due to its superior safety profile compared to methadone. 44 For longer absences, daily witnessed ingestion of SROM at a community pharmacy is recommended. Conversely, a slow transition (over 7 to 14 days) to methadone is possible. If the pharmacy is located outside of the patient's province of residence, the prescriber should call the pharmacy to ensure daily witnessed ingestion of SROM or methadone is possible. Note: Prescriptions filled outside of the province of residence may not be reimbursed by the patient's provincial drug plan.
For conversions to oral OAT for travel, because of the potential variability in bioequivalency when switching opioids, standard opioid conversions should be used in concert with clinical judgment. All SROM doses should be witnessed ingestion at the dispensing pharmacy. Any missed doses should be reported to the prescriber. See Appendix 9 for more details on conversion.
# 3.6.v Transition to Oral Treatment Due to Incarceration
Incarceration should not result in inadequate treatment for OUD, and best efforts should be made to provide the best standard of care for OUD regardless of setting. However, at this point in time, iOAT is not provided to individuals in correctional facilities in Canada. It should be noted, however, that there are two prison-based iOAT programs currently in operation in Switzerland. 45 In addition, a 2018 case study reported on the successful integration of iOAT into a drug court treatment program in Vancouver, BC, with positive health and social outcomes reported for the individual. 46 Patients who have been convicted of a crime and face a period of incarceration must be transitioned to a suitable oral OAT option prior to, or as quickly as possible following, their entry into the correctional system. Detailed recommendations for managing this transition can be found in Appendix 10 of this document.
When an individual receiving iOAT enters a correctional facility, the treatment plan should include the following components:
- Protocol in place for MRP in correctional facility to contact the community prescriber;
- Protocol in place for community prescriber to contact MRP in correctional facility to inform them that patient is on iOAT and, thus, will have a high opioid tolerance; q
- Protocol in place for community prescriber to communicate and make recommendations for management should a patient be subjected to a custodial environment while on iOAT;
- Protocol in place for the care team in the correctional setting providing care to access date and size of last dose received by patient (for example, uploaded to provincial electronic health record or prescription monitoring program, where possible); and
- Contact information for all iOAT programs, including ability to contact program outside of program hours. Program contact information, including on-call phone number should be included in provincial electronic health record or prescription monitoring program, where possible.
# 3.6.vi Continuity of Care
Regardless of which decisions are made regarding transition from iOAT to oral OAT, individuals should have continued access to the ancillary services offered as part of the iOAT program (for example, social workers, housing workers, psychosocial supports) to ensure that continuity is maintained and patients continue to receive a high quality of care.
# ONGOING SUBSTANCE USE
Ongoing substance use while on iOAT may be an indication to intensify treatment, which may include dose increases, transferring to a more intensive model of care, or increasing psychosocial and other q Provincial electronic medical records or prescription monitoring programs are ideal, however, in jurisdictions lacking these systems, programs should provide patients with documents (for example, a wallet card) that can be given to corrections staff.
supports. If a patient is found to be intoxicated during the pre-assessment, their dose should be postponed or withheld to ensure safety (see Appendix 5). Repeated findings of intoxication in the pre-assessment should be discussed with the patient and should be addressed in a substance-specific manner as outlined below. As described in Harm Reduction-Oriented Care, patients should be advised of the risk of overdose due to contamination of the illicit drug supply with fentanyl and other highly potent synthetic opioids (including non-opioid substances such as benzodiazepines and stimulants), receive education and, where possible, access to a variety of harm reduction strategies, including takehome naloxone, drug-checking facilities, and fentanyl test strips. It should be noted, however, that drug-checking and fentanyl test strips are not well validated and are not available in all jurisdictions.
# 3.7.i Non-prescribed Opioids
Continued use of illicit (non-prescribed) opioids, ascertained by self-report or urine drug test (see Urine Drug Testing in this document), while on iOAT should be considered an indication to discuss intensification of treatment. Ongoing use at the same intensity as pre-iOAT should be understood as an indication to intensify treatment, however, illicit opioid use in and of itself should not be considered an absolute indication. Some individuals' goals may not include absolute cessation of illicit opioid use.
In those cases, harm reduction and overdose prevention should be discussed and reinforced. In situations where intensification of treatment is indicated, clinical judgment should be used in determining what intensification is appropriate. Intensification of treatment may include adding a daily dose of oral OAT (i.e., SROM or methadone), increasing an existing evening dose of oral OAT, increasing the iOAT dose, transferring to a more intensive model of care (for example, moving from a community health clinic to a comprehensive and dedicated iOAT model), or increasing evidence-based psychosocial treatment interventions and supports. If a patient is continuing to use illicit opioids at the same intensity despite intensification of treatment, clinical judgment should be used to determine appropriate follow up. Reduction from daily illicit injection opioid use may be considered a significant treatment benefit in many cases, however, if the patient is continuing to use illicit opioids or continuing to inject other substances and receiving no benefits from iOAT after intensification and optimization of treatment, treatment cessation may be considered. When considering transition to another treatment approach such as oral OAT, continuity of ancillary services (e.g., mental health care, trauma therapy, primary care) should be ensured. Treatment decisions should be made with the recognition that connection to health care and community are important outcomes of treatment engagement and access to services, and that patients may experience significant benefits from engagement in care, including maintaining housing, connection with family and friends, and decreased crime.
# 3.7.ii Stimulants
If patients are using stimulants (e.g., cocaine or methamphetamine) while receiving iOAT, the risks and benefits of iOAT should be evaluated to ensure that the person is benefiting from the treatment. Injectable opioid agonist treatment is not a treatment for stimulant use disorder and withholding of doses should be based on patient safety, not used to penalize stimulant use. Clinical judgment should be used in determining if intensification of treatment is appropriate. Intensification of treatment may include increasing psychosocial and other supports, such as implementing contingency management. 47 Preliminary evidence from a single-centre RCT in a European HAT program suggests sustained-release dexamphetamine may be effective for concurrent treatment-refractory cocaine use in iOAT patients, however, more research is needed. 48
# 3.7.iii Sedatives (Alcohol and Benzodiazepines)
Ongoing sedative use may indicate a need to intensify treatment. However, due to the additive effect on respiratory depression of both benzodiazepines and alcohol, patients using alcohol and/ or benzodiazepines may require a more intensive model of care to ensure adequate management of the co-occurring substance use and patient safety (see iOAT Operations Guidance). Clinical judgment should be used to determine which interventions are appropriate for each patient.
# Alcohol
Individuals who present for their iOAT dose intoxicated on alcohol should have their dose withheld due to the increased risk for respiratory depression and overdose. These individuals should be screened for alcohol use disorder and brief intervention should be performed. Clinician-delivered brief intervention, including motivational interviewing, has been shown to reduce alcohol consumption in individuals receiving OAT to treat OUD who had problematic alcohol use but did not meet diagnostic criteria for concurrent alcohol use disorder, however, this was specifically in individuals receiving methadone-based OAT. Due to the high risk of respiratory depression, patients who continue to present for their iOAT dose intoxicated on alcohol should be started on a medication for relapse prevention and agree to ongoing breathalyzer testing before each dose, with doses postponed or withheld if the patient's blood alcohol level exceeds 0.05%. Acamprosate has an established evidence base for safety and efficacy for the treatment of alcohol use disorder. For individuals receiving iOAT, acamprosate should be considered along with evidence-based psychosocial treatment interventions and supports for treating concurrent alcohol use disorder, 52,53 and may be dispensed on site. In jurisdictions where acamprosate is not covered by provincial drug plans, an addiction medicine expert should be consulted to discuss other medication options (e.g., topiramate, gabapentin, disulfiram). Due to its effects on opioid receptors, oral naltrexone cannot be used to treat alcohol use disorder in patients who are on opioid agonist treatment.
Although gabapentin has a growing evidence base supporting its use for withdrawal management and preliminary evidence supporting its use in relapse prevention for alcohol use disorder, there are specific concerns for individuals with opioid use disorder. This includes the possibility of high doses of gabapentin being combined with opioids to potentiate euphoric effects and the additive effects on respiratory suppression, which can increase risk of overdose. 25 A 2017 Canadian study found that concomitant use of opioid medications and gabapentin increased the risk of fatal overdose by 49%, with moderate and high daily doses increasing fatal opioid overdose risk by 60% compared to those with no concomitant gabapentin use. 26
# Benzodiazepines
Given the known severe risks associated with concomitant use of opioids and benzodiazepines, patients with OUD who were using benzodiazepines and illicit (non-medical and/or illegal) opioids concurrently should, ideally, have completed a benzodiazepine taper prior to iOAT initiation. Management of concurrent benzodiazepine use will depend on clinical judgment and model of care, with patient safety prioritized. Prescribers are encouraged to engage a second opinion as needed.
Patients who begin using benzodiazepines while receiving iOAT should have the risks of concurrent use discussed with them and initiate a benzodiazepine taper. An increase in treatment intensity, including a more intensive model of care, or increasing evidence-based psychosocial treatment interventions and supports may be required.
# 3.7.iv Tobacco
Mortality in smokers is almost three times higher than in non-smokers, 64 and is causally linked to significant morbidity including pulmonary disease, coronary heart disease, chronic obstructive pulmonary disease, diabetes mellitus, and multiple cancers including lung, esophageal, and stomach. 65 A 2018 population-based study found that 39% of deaths in individuals with opioid use disorder were due to smoking-related conditions. 66 Disproportionately high rates of tobacco use have been found in individuals receiving treatment for opioid use disorder compared to general population prevalence rates. Looking specifically at individuals receiving iOAT, 94% of participants in the SALOME trial reported tobacco smoking at baseline, with a similar percentage reporting smoking at 6 months. 71 Although tobacco use disorder is commonly undertreated in addictions treatment, 72 a 2016 Cochrane systematic review found a consistent association between tobacco cessation interventions-both pharmacotherapy and counselling combined with pharmacotherapy-and tobacco abstinence in individuals in treatment and recovery for substance use disorders, with no evidence showing an effect on abstinence from alcohol and other drugs. 73 Despite common assumptions to the contrary, 44-80% of individuals receiving substance use disorder treatment are interested in tobacco cessation. 74 Evidence-based treatments for tobacco use disorder, including nicotine replacement therapy, varenicline, and bupropion, should be integrated into iOAT care and delivered onsite when possible.
# 3.7.v Cannabis
Ongoing cannabis use is not an indication to discontinue iOAT. Patients who are using cannabis recreationally may benefit from a discussion of the recommendations made in the Lower-Risk Cannabis Use Guidelines. 75 Patients who are using medical cannabis should be monitored by their iOAT prescriber to ensure the benefits they receive outweigh the potential harms.
# FAMILY AND SOCIAL CIRCLE INVOLVEMENT IN CARE
This document emphasizes the important role of families-as defined by patients, which may include romantic partners, close friends, and other people of significance who may or may not be legally recognized as family-as partners in patient care when appropriate, and recommends the inclusion of family members in decision-making processes and care at all levels when deemed appropriate by the adult patient and their care team. Patients should not be pressured to include family members and should be given full discretion on the decision to include family, if at all. Family members wanting support should be referred to external services and supports, to avoid overlap of service providers, which may impact client trust and create concerns about confidentiality or perceived conflicts of interest.
In the case of youth, parental participation in the treatment of youth should be actively encouraged, if appropriate, and family members should be supported with sufficient information and training.
Offering or referring out to group or individual sessions for parents and/or caregivers (e.g., parent guidance sessions) is recommended. In addition to providing emotional support, family members can also function as caregivers and may help ensure that patients regularly attend for their doses and keep appointments. 76 A family history should be taken, when possible, to identify and treat any mental health or substance use issues requiring treatment in the youth's family. It should also be noted that not all youth have healthy or positive relationships with their family members and decisions to include family members in care should be guided by an understanding of the family dynamic and the patient's wishes.
If the patient determines family involvement would be a positive element in their treatment plan, care providers are encouraged to educate family members about available options and resources and provide as much patient-specific information as possible within the boundaries set by each province's privacy legislations. The care team must have current and complete knowledge of consent protocols for releasing information. In the context of this document, the term 'family' encompasses all relations that are important to the patient, including significant others who are not legally recognized as family.
# PATIENT-CENTRED CARE
Research suggests that incorporating patient-centred approaches into the clinical management of substance use disorders can improve retention in care, treatment satisfaction, and health outcomes. In addition to recognizing the unique needs, values, and preferences of each patient, patient-centred care aims to engage and empower patients as experts in their own care, including acting as the primary agent for reducing harms related to substance use, setting individualized treatment goals that are realistic and meaningful, and selecting treatment options or interventions that will best support achieving their individual goals. 80 From this foundation of inclusion and encouraging personal agency, providers can build on the therapeutic relationship, while keeping patients safe from the harms associated with street opioid use and reducing the risks associated with iOAT.
As is the standard of care for management of any complex or chronic medical condition, all iOAT prescribers should provide patient-centred medical management including general support and unstructured counselling to patients receiving iOAT, regardless of the model of iOAT care employed. In this context, medical management is defined as medically-focused, informal counselling that includes, but is not limited to, performing health and mental wellness checks, offering non-judgmental support and advice, assessing motivation and exploring barriers to change, developing a holistic treatment plan, promoting alternative strategies for managing stress, and providing referrals to health and social services when requested or appropriate. Establishing a trusting, respectful, and collaborative therapeutic relationship with patients remains a cornerstone of treating substance use disorders in clinical practice.
# 3.9.i Motivational Approach
Motivational interviewing (MI) is a counselling approach that empowers the patient to develop motivation to change, and creates a therapeutic alliance that is predominantly a partnership, rather than an expert/patient dynamic. 81 Motivational interviewing techniques have been adapted for use in primary care settings to support behavioural change and improve self-management for a range of health conditions including HIV/AIDS, diabetes, cardiovascular disease, and substance use disorders. Motivational interviewing-based counselling does not require professional specialization and can be delivered by primary care physicians, nurse practitioners, nurses, pharmacists, and other health professionals who have completed education and training in its delivery. 85 In practice, clinicians engage patients in guided discussion about health behaviours while adhering to the general principles of MI, which are to: 1) express empathy, 2) support self-efficacy, 3) avoid arguing or power struggles, 4) roll with resistance, and 5) develop understanding of discrepancy. 86 The intended outcome is to bring awareness to any discrepancies between current behaviours and future goals.
A 2011 systematic review of MI for treatment of substance use disorders (59 RCTs, n=13,342) found that MI significantly reduced substance use in comparison to no treatment. 85 Further, review results indicated that MI was as effective as other active psychosocial modalities (e.g., cognitive behavioural therapy) as well as assessment and feedback in reducing substance use, although overall the effects were modest in scale. 85 The strongest treatment effects were observed immediately post-intervention, with progressively weaker effects observed at each consecutive follow-up, such that no significant effects were observed more than 12 months post intervention. 85 Additional systematic reviews have reported that MI appears to be most effective when delivered in an individual format rather than group settings, and in combination with assessment and feedback. 82 It should be noted that there is limited evidence supporting MI for OUD specifically 87,88 and a lack of evidence examining MI in the provision of iOAT, however, motivational interviewing is a common general approach to addiction care across substances.
# 3.9.ii Trauma-informed Care
Due to the higher prevalence of histories of trauma and comorbid post-traumatic stress disorder among individuals with substance use disorders compared to the general population, 89 prescribers should be familiar with the principles of trauma-informed practice (e.g., trauma awareness; safety and trustworthiness; choice, collaboration, and connection; strengths-based approaches and skill building). There are several useful resources for learning about and integrating trauma-informed practice. These include the
# 3.9.iii Providing Care to Groups at Risk of Marginalizing Experiences
The social determinants of health can be understood as "the social and economic factors that influence people's health." 90 They include income, housing, social exclusion, gender, aboriginal status, race, and disability status, among others, 90 which impact health along a social gradient, with those at the lowest socioeconomic levels experiencing the worst health outcomes. 91 Clinicians providing care to groups at risk of marginalizing experiences in addition to being an injection drug user (includingbut not limited to-Indigenous peoples, racialized people, gender and sexual minorities, women, and people living in poverty) should be sensitive to the ways that these social locations are subject to unequal distribution of power, economic opportunity, and resources, 91 and aware of the fact that a person's multiple social locations (e.g., gender, race, and sexuality) interact with and impact each other, 92 and should endeavour to remove barriers to accessing care patients may experience.
Health care providers should be sensitive to the power differentials inherent in the provider-patient relationship and the ways that the social locations of each (including, but not limited to, race, gender, and class) can further those differentials, as well as the likelihood of previous, concurrent, and future negative experiences in the health care system due to discrimination. EQUIP Health Care provides several resources as well as a Health Equity Toolkit to support health care providers to implement equity-oriented care into primary health care practice.
Each patient will have their own needs, which must be addressed, depending on the social location(s) they inhabit. Examples may include a translator for individuals with limited English or French (depending on provider), connection to immigrant and/or refugee services, and/or referral to gender affirming care for transgender individuals. Safety should be prioritized for all patients, including emotional and cultural safety. Patients belonging to groups at risk of marginalizing experiences may also benefit from patient advocacy, for example, to secure housing, apply for disability assistance, or access psychosocial services, and all patients will benefit from health care providers working to prevent and mitigate stigma by avoiding and rejecting stigmatizing language, labels, and behaviour.
# Cultural Safety and Humility When Working with Indigenous Peoples
Health care providers hold social and institutional power, which is amplified when non-Indigenous health care providers treat Indigenous patients. Internalized negative attitudes about Indigenous peoples inform patient-provider relationships and can thus impact the quality of care provided and the client health care experience. 93 The provider-patient relationship is also impacted by health care providers' knowledge of Indigenous cultures, health care providers' understandings of Indigenous health disparities without historical and social context, and the history of colonization in Canada. 93 Structural violence, which can be understood as systemic exclusion, disadvantage, and discrimination, shapes the health of Indigenous peoples in Canada and globally. 94 It is well documented that Indigenous peoples in Canada are at increased risk of premature morbidity and mortality compared to non-Indigenous populations, 95 and multiple factors are believed to shape these social and health inequalities. Factors that impact health inequalities in all populations, such as environment, access to preventive and primary healthcare, and social determinants of health are believed to have a role, as do factors that are unique to the experiences of Indigenous peoples in Canada, including the impacts of colonization, intergenerational trauma, cultural deprivation, forced assimilation, and systemic racism and discrimination. 96,97 Research that shows that Indigenous peoples are at increased risk of substance-related harms 95,98 should be interpreted within this context. More specifically, it should be understood that Indigenous peoples are not, by definition, "high-risk" populations; rather, factors such as trauma, discrimination, and systemic racism faced by Indigenous peoples have likely created conditions and experiences of marginalization that, in turn, have led to increased use of opioids and other substances in some individuals as a means of coping with historical and cultural trauma exacerbated by stresses such as racism, violence, poverty, and systemic discrimination in their daily lives. 99,100 Specific approaches and understandings have been identified as necessary to provide culturally competent care to Indigenous peoples, 101 these include:
- Understanding the importance of local history and the lasting and multigenerational impacts of colonization and the residential school system;
- Examining, understanding, and acknowledging how health care providers' own values impact the healthcare environment and healthcare encounters;
- Understanding health as encompassing physical, intellectual, emotional, and spiritual wellbeing;
- Understanding the impacts of disparities in the social determinants of health;
- Respecting local traditions, traditional beliefs, and healing practices;
- Recognizing and respecting differences in communication styles, which may be influenced by power imbalances as well as cultural behaviours; r
- Understanding that whole communities may be impacted by what happens to one community member, that the family unit may be a large, extended family, and that hostile healthcare experiences can influence entire communities healthcare seeking attitudes;
- Understanding that cultural healing practices may require that families be involved in the care of clients;
- Approaching patient relationships with respectful curiosity;
- Challenging personal assumptions, being flexible, and being open to changing how things are commonly done; and r For example, less eye contact, long silences, and not answering direct questions or replying with a story or longer narrative response may be the norm for some Indigenous peoples compared to non-Indigenous populations.
- Recognizing and accommodating the need for a translator for those whose primary language is not English or French.
For an understanding of how the dominant healthcare system is frequently hostile and culturally unsafe for Indigenous peoples, and how health care providers may lack insight into how their approaches, behaviours, and programs create barriers to Indigenous community members, this document strongly recommends that non-Indigenous prescribers and staff undertake cultural safety and humility training to improve their ability to establish positive partnerships with Indigenous clients seeking care for substance use and related harms. Cultural safety can be understood as an outcome in which people feel safe when receiving care in an environment free from racism and discrimination, which results from respectful engagement that seeks to address power imbalances inherent in the healthcare system. Cultural humility is a process undertaken to understand, through self-reflection, personal and systemic biases, and to develop and maintain respectful processes and relationships based on mutual trust; it requires humbly acknowledging oneself as a learner when attempting to understand another person's experience. s
# 2SLGBTQ+ Populations
Two-Spirit, lesbian, gay, bisexual, trans, queer, and other gender and sexually diverse individuals (2SLGBTQ+) face unique challenges that should be addressed when providing care to 2SLGBTQ+ patients with substance use disorders. 2SLGBTQ+ individuals report disproportionate rates of substance use, and enter treatment with greater severity of substance use problems. 105 Suggested explanations for these disproportionate rates include the stress of being in a minority group, dealing with social prejudice and discrimination, internalized stigma, and lack of cultural competence in the health care system. 105,106 Data on OUD specifically in 2SLGBTQ+ individuals is lacking, however, given the high s Definitions borrowed and lightly adapted from the First Nation's Health Authority.
rates of substance use in 2SLGBTQ+ individuals, OUD treatment should be culturally sensitive and include an awareness of the issues that 2SLGBTQ+ individuals are likely to face.
Strategies for working with 2SLGBTQ+ individuals include actively communicating that services are available for 2SLGBTQ+ patients, building relationships with organizations serving diverse marginalized communities, and using inclusive language in forms and clinical materials and during appointments. 105 Although substance use disorder treatment for 2SLGBTQ+ individuals is similar to that for other populations, additional factors must be considered, including acknowledging and affirming the patient's feelings about their sexual and gender identities and the impacts of stigma and discrimination in their lives. 107 Other strategies include respecting that identities are fluid and tailoring care accordingly; mirroring the language that your patients use (e.g., to refer to themselves, their relationships, and their bodies); not assuming sexual activity levels or motives for substance use; and being affirmative-recognizing the ways that individuals successfully practice harm reduction in their lives. 2SLGBTQ+ individuals may also have experienced discrimination in the health care system and thus require extra sensitivity from health care providers in order to build trust. 107 Prescribers should make themselves aware of local support groups and resources for 2SLGBTQ+ individuals. Additional information and guidance can be found in the Substance Abuse and Mental Health Services Administration's publication, A Provider's Introduction to Substance Abuse Treatment for Lesbian, Gay, Bisexual, and Transgender Individuals.
A non-judgmental attitude, active demonstration of awareness of and sensitivity toward trans issues, and a reinforcement of confidentiality can help trans people feel safe approaching care providers. 108 Other ways to demonstrate transgender awareness and sensitivity include placing trans inclusive brochures and posters in waiting rooms, asking about gender identity on intake forms (and avoiding conflating gender and sex t ), 108 and using open-ended questions about sexuality and gender. 107 Additional strategies include being reflexive and acknowledging personal biases; recognizing an individual's intersecting identities (e.g., race, disability, gender, sexuality) and how they may compound and impact patients' experiences of health care; making gender neutral bathrooms available; and respecting that identities and pronouns are fluid and can change. More information on working with trans, Two-Spirit, and gender diverse patients can be found in Trans Care BC's Gender-affirming Care for Trans, Two-Spirit, and Gender Diverse Patients in BC: A Primary Care Toolkit. Additional resources include the Trans Care Program in British Columbia, Rainbow Health Ontario, "Je m'engage"-a guide for Quebec health and social service providers, and the Canadian Professional Association for Transgender Health.
t Sex generally refers to the classification of a person as male, female, or intersex at birth, usually based on the appearance of their external anatomy, whereas gender refers to one's internal, deeply held sense of their gender, which may or may not align with the sex they were assigned at birth. A person's sex should not be assumed to match their gender; for example, that a person will have specific genitalia or reproductive anatomy based on their gender identity.
Two-Spirit u is term used by some North American Indigenous societies to describe people with diverse gender identities, gender expressions, gender roles, and sexual orientations. Dual-gendered, or 'Two-Spirited' people have been and are viewed differently in different Indigenous communities. Additional information on Two-Spirit individuals can be found on the Two Spirit Journal website.
# 3.9.iv Wellness and Self-Defined Progress
One of the goals of treatment across the continuum of care for OUD should be wellness, with an understanding that wellness looks different for each person, with many different possible paths. For some individuals, this may include a concept of recovery, which can be understood as "A process of change through which individuals improve their health and wellness, live a self-directed life, and strive to reach their full potential," 109 while others may have other personal definitions of wellness and progress.
Those seeking wellness require understanding, support, and referral to appropriate services to achieve their goals. Injectable opioid agonist treatment care teams are encouraged to incorporate and use language that promotes wellness in their practice. This includes ensuring respect of the patient's autonomy and individuality, emphasizing skills and strengths, and avoiding reinforcement of paternalistic models of care provision. 110 Additionally, and as appropriate, iOAT prescribers and care teams are encouraged to work collaboratively with patients to develop long-term, personalized, strengths-based wellness plans regardless of the severity, complexity, and duration of their substance use. The importance of peer navigators and peer support should also be recognized across the continuum of care for opioid use disorders. For wellness planning, iOAT providers should consider incorporating peer navigators to support long term, patient-centered treatment goals.
# 3.9.v Role of peers
The vital importance of peer navigators and peer support should be recognized across the continuum of care for opioid use disorders, including individual peer/patient navigation and advocacy as well as the work of drug user organizations, including the Canadian Association of People Who Use Drugs (CAPUD) and the Vancouver Area Network of Drug Users (VANDU), in advocating for expansion of iOAT and the need for it to be low-barrier, especially in the current context of criminalization creating a toxic drug supply contaminated with fentanyl and other highly potent synthetic opioids.
"Nothing About Us Without Us": Greater, Meaningful Involvement of People Who Use Drugs: A Public Health, Ethical, and Human Rights Imperative identifies several important benefits to peer involvement especially relevant for the provision of iOAT. These include more patient "buy-in" to the u Term borrowed and lightly adapted from Qmunity's "Queer Terminology from A to Q " program; the ability for patients' needs to be recognized and addressed; service delivery that meets the needs of patients by being realistic, low-barrier, and useful; and providing a sense of ownership for peers. 111 A qualitative study of a peer-run overdose response program in emergency shelters identified several factors that lead to increased feelings of safety from peer workers compared to non-peer paid staff, including social safety due to shared experiences, an absence of uneven power dynamics, and a perception of being cared for that contrasted with their everyday experiences. 112 Peer workers working at VANDU have identified several significant benefits to their work, including decreased risks associated with sex work, drug dealing, or theft as well as increased social contact, social recognition, structure, collective purpose, and an acknowledgment of their work. 113
# Peer Orientation and Education
Prior to admission, individuals identified as likely to benefit from iOAT should go through an admission process that involves full informed consent and a recommended peer orientation, to ensure program regulations, time commitments, and other requirements are fully understood. Some patients starting iOAT have not previously been engaged in care in the health system; these patients may benefit from peer support in navigating the system and advocacy as needed.
Peers should also be included in educational efforts for potential patients and the larger community.
Working with peers to create clear messaging about the expectations, benefits, and requirements of iOAT will help ensure that new patients have realistic expectations for the treatment.
# 3.9.vi Harm Reduction-oriented Care
Broadly defined, harm reduction refers to policies, programs, and practices that aim to reduce the adverse health, social, and economic consequences of licit and illicit substance use. 114 Across Canada, established harm reduction initiatives include needle/syringe distribution programs, overdose prevention with take-home naloxone, and supervised injection or consumption services. Including these harm reduction approaches within the continuum of addiction care provides additional mechanisms for promoting health and safety in diverse patient populations, including individuals who have difficulties achieving abstinence or who relapse to non-medical opioid use. There is substantial evidence that uptake of harm reduction services is associated with significant decreases in substance-related harms, including risky behaviours, HIV and hepatitis C infection, and overdose deaths. In addition, research has shown that participation in harm reduction services can promote entry into addiction treatment. For these reasons, if a patient is at risk of opioid-related harms, providing information and referrals to harm reduction services is a reasonable and appropriate clinical decision, particularly in the current environment of heightened overdose risk. Beyond specific harm reduction interventions, programs should take a non-punitive approach to treatment that utilizes a strengthsbased approach and meets patients where they are.
There are a number of actions clinicians can take to increase awareness of harm reduction services among patients. These include patient education about harm reduction and safer injection practices, including drug-checking services (where available) and take-home fentanyl testing, with a discussion of the limitations of these interventions. In order to provide informed referrals, clinicians should also be aware of harm reduction programs available in the local area and services provided. Additional information on harm reduction principles and available harm reduction services across Canada can be found in the iOAT Operations Guidance.
# 3.9.vii Naloxone
Where possible, all iOAT patients should receive overdose prevention education and a take-home naloxone kit at the start of injectable opioid agonist treatment and have ongoing and continuous access to harm reduction services and supplies. Families, colleagues, friends, and other loved ones should also be engaged to receive overdose response and prevention education and naloxone training. See Appendix 13 for guidance on responding to dose intolerances.
# 3.9.viii Mental Health Care
Mental health and substance use disorders frequently co-occur. Twelve-month prevalence rates for adults in the US with a substance use disorder and any concurrent mental health disorder were 43.3% in 2016, 127 while over 50% of individuals with a severe mental illness are estimated to have problematic substance use. 128 Looking specifically at opioid use disorder, an observational study of individuals receiving methadone-based OAT in Ontario found that 78.5% met diagnostic criteria for at least one comorbid psychiatric disorder, with anxiety disorders most common. 129 A 2017 meta-analysis examining the treatment of mood and anxiety disorders in individuals receiving OAT found psychotherapy and tricyclic anti-depressants most effective. Selective serotonin reuptake inhibitors (SSRIs) were not significantly better than placebo. 130 Patients who present with opioid use disorder should be screened for concurrent mental health disorders, and those who screen positive should receive evidence-based treatment for both. Generally, OUD and any comorbid mental health disorders should be treated concurrently, however, with severe OUD, stabilization-including initiation of iOAT-may be prioritized initially, with concurrent treatment once stability has been achieved.
# 3.9.ix Referral Pathways
As part of their practice, iOAT service providers should establish fully functioning referral pathways to addiction, recovery, and substance use treatment programs in their local area, to ensure access to services meant to improve quality of life and address social determinants of health. Some programs may co-locate or partner with community organizations which provide psychosocial services, others may offer some services on-site (e.g., counselling, housing workers) and refer out to other community services, and others will utilize referral pathways to ensure service users can access the psychosocial services they need and will benefit from. These referral pathways may include outpatient, inpatient, and residential treatment programs; recovery-oriented services including peer-support programs; supportive recovery housing; psychosocial treatment interventions and supports; chronic pain management; primary care; addiction medicine specialist consultation; trauma therapy; and specialized services where appropriate, for example, for women, youth, immigrants and refugees, and Indigenous peoples.
# 3.9.x Treatment Plan
Prescribers should work collaboratively with patients and their care teams to create and continuously revisit treatment plans based on each patient's goals, health, and circumstances. Treatment plans should use a comprehensive approach that includes assessment and treatment of any mental health or other comorbidities, psychosocial treatment interventions including cognitive behavioural therapy and motivational enhancement therapy, psychosocial supports (e.g., housing, education, and employment support), recovery services, and, when appropriate, family involvement in care; however, the creation of a comprehensive treatment plan should not be considered a pre-requisite to initiating iOAT and may be expanded as patients stabilize and their needs and goals change. Treatment plans should factor in age, gender, substance use history and trajectory, any experiences of violence, exploitation, trauma, and other factors that may support or negatively impact treatment adherence, including romantic partners, gender identity, sexual orientation, and family history.
Patients and care teams may also benefit from filling out a client safety care plan or behaviour agreement. This may include identifying triggers or irritants, calming strategies, and an agreement for how staff will respond if a patient is upset. In addition to building this plan or agreement together, the conversation that accompanies this agreement can represent an important relationship-building opportunity. A sample client safety care plan is available on the CRISM website.
# 3.9.xi Cost and Coverage
See iOAT Operations Guidance for information on cost and coverage of iOAT.
# Appendices APPENDIX 1: EVIDENCE SUPPORTING INJECTABLE OPIOID AGONIST TREATMENT FOR OPIOID USE DISORDER Injectable Opioid Agonist Treatment in Other Jurisdictions
The United Kingdom has provided unsupervised prescription injectable diacetylmorphine for the treatment of OUD for over a century. 131 Supervised prescription diacetylmorphine treatment has been available in Switzerland starting with a national clinical study in 1994, 132 and as a standard drug treatment since 1999. In 2008, as part of a national referendum, 68% of Swiss voters supported the permanent institution of a legalized prescription diacetylmorphine program funded by national health insurance. 133 More recently, Germany, Denmark, and the Netherlands have also adopted supervised prescription diacetylmorphine treatment for those with severe, treatment-refractory OUD. 134 In these countries, diacetylmorphine is used for <1% to 12% of all patients engaged in treatment for OUD. The Comprehensive and Dedicated Injectable Opioid Agonist Treatment Program model has been widely applied in European jurisdictions, v wherein patients receive comprehensive addictions care, with the aim of meeting as many of the patients' health and psychosocial needs as possible on-site. There are both stand-alone clinics and clinics co-located with (or very close to) other addictions and psychosocial services. 134
# Evidence Summary
Two meta-analyses of clinical trials involving patients with long-term, refractory heroin addiction have demonstrated the efficacy of diacetylmorphine in comparison to methadone in terms of reducing illicit heroin use, criminal activity, and involvement in sex work, as well as improving overall health and social functioning. 11,12 These meta-analyses include a 2011 Cochrane Review which examined eight randomized controlled trials and found that supervised injection of diacetylmorphine, paired with flexible doses of methadone, was superior to oral methadone alone in retaining treatment refractory patients in treatment while helping reduce the use of illicit drugs. 11 The authors of the Cochrane review concluded that there is value in co-prescribing diacetylmorphine with flexible doses v Switzerland, Germany, Denmark, and the Netherlands use this model. The UK's unsupervised take-home model and Spain's limited weekday clinics are exceptions.
-f methadone and that, due to the higher risk of adverse events, treatment with diacetylmorphine should be considered for those who have not benefited from oral opioid agonist treatment. 11 In 2015, the lead investigators of iOAT treatment trials conducted a systematic review and meta-analysis on the efficacy of injectable diacetylmorphine to complement the Cochrane Review. 12 Six randomized controlled trials (in Switzerland, the Netherlands, Spain, Germany, Canada, and England) were identified and included in the analysis, which found greater reductions in illicit heroin use among individuals who received supervised injectable diacetylmorphine compared to those who received oral methadone treatment only. 12 Further supporting the use of iOAT for those who have not benefitted from oral OAT, a 2017 evidence review undertaken and released by Public Health Ontario concluded that the available literature on iOAT demonstrates efficacy for iOAT over methadone in terms of treatment retention, reduction in illicit drug use, and reduction in criminal activities. 137 Although treatment with diacetylmorphine is a standard of care in a number of countries, 134 it is considered an emerging treatment in Canada and, currently, can only be accessed through Health Canada's Special Access Programme or inclusion in Health Canada's List of Drugs for an Urgent Public Health Need. Due to the restrictions on accessing diacetylmorphine, the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME), a phase 3, double-blind randomized controlled trial conducted in Vancouver, BC, compared diacetylmorphine with injectable hydromorphone in a population of individuals with long-term, treatment-refractory OUD. 13 After six months of treatment, researchers found that injectable hydromorphone was not inferior w to injectable diacetylmorphine for long-term injection street opioid users not currently benefitting from available treatments. x Both medications, delivered in identical conditions, have been shown to have positive outcomes such as high retention rates (over 77% ITT; over 92% PP), reduction of street opioid use (from daily to a few days per month) and illegal activities. 13 Thus, in jurisdictions where diacetylmorphine is currently not available, or in patients where it is contraindicated or unsuccessful, hydromorphone provides an effective, licensed alternative. 13
# Treatment Duration
To date, two studies have found a loss of treatment benefit-that is, an increase in street heroin use post-treatment to levels comparable to that of the control group-when prescription diacetylmorphine treatment was discontinued at a predetermined end date (12 months). 42,43 Thus, the authors of the Treatment Assisted by DAM (diacetylmorphine) study in Belgium, in line with World Health Organization recommendations for other opioid agonist treatments, recommend that supervised injection of diacetylmorphine be provided as an open-ended treatment. 42,138 w This study was a non-inferiority trial, which is a study design based on the assumption that a finding of non-inferiority indicates that the trial medication would prove superior to placebo in a placebo-controlled trial.
x Given that the results of the trial showed non-inferiority to diacetylmorphine, the assumption is made that hydromorphone would show the same (that is, non-inferior) effectiveness as diacetylmorphine. 13
# Expanded Eligibility
The majority of clinical trials evaluating iOAT have restricted participation to individuals who have previously undergone oral OAT treatment; thus, the evidence base can be understood as being supportive of iOAT for the treatment of patients who have not benefited from oral OAT. However, one large randomized trial comparing injectable diacetylmorphine with oral methadone included a subset of participants (n=107 of 1,015 total) with severe OUD but no previous experience with oral OAT. 139,140 Study authors found that outcomes of diacetylmorphine treatment were similar whether individuals had prior oral OAT experience or not, and within the subset of participants with no prior OAT experience, diacetylmorphine was superior to methadone in reducing nonmedical heroin use and criminal involvement, and as effective as methadone in improving overall health and retaining individuals in treatment. 139 Clinical practice in British Columbia has also shifted to broader eligibility considerations, which includes past experience with appropriately dosed oral OAT while continuing to experience significant health and social consequences related to their OUD; multiple attempts at oral OAT without being able to achieve a therapeutic dose; or other circumstances and risks that indicate the individual may benefit from iOAT. In addition, some European jurisdictions have expanded their eligibility criteria beyond those who have tried and not benefitted sufficiently from oral OAT.
# Safety
Optimizing patient safety has been an important factor in the designation of iOAT as an alternative intervention when oral OAT has not been successful (in jurisdictions where iOAT is available), and in requiring doses to be administered in structured, supervised clinical settings. Any frequently administered injectable treatment is associated with higher risks of cutaneous and infectious complications compared to its equivalent oral formulation. In the context of iOAT, the more rapid onset of action and shorter duration to reach peak effects (including respiratory depression) achieved with injection rather than oral ingestion of high-dose, full agonist opioid medications must also be considered. For this reason, and as emphasized throughout this document, iOAT should only be administered in designated clinical settings, with sterile supplies, in clean and safe conditions, and under supervision of qualified staff trained to intervene in the event of an adverse event or emergency. Further, while injectable treatment may confer higher risks of adverse effects than oral treatment, it is important to note that risks of injecting street drugs are considered to be significantly higher than injecting prescribed iOAT.
Studies in Europe and Canada have reported instances of significant respiratory depression events in people receiving injectable opioids, at an overall rate of about 1 in every 6000 injections, which is significantly lower than the risk present when injecting street heroin. 12 Each of these incidents was safely managed with appropriate resuscitation measures, which speaks to the necessity of injection being supervised by trained staff. 12 It should be noted that hydromorphone had significantly fewer adverse events and serious adverse events (SAEs) in the SALOME trial, 13 and thus diacetylmorphine may pose an increased risk of other adverse events (e.g., histamine reactions, seizures, and overdose) compared to injectable hydromorphone 13 and oral methadone. 11,12 The majority of SAEs occur within a few minutes of receiving an injection, 140 therefore, the recommended post-injection supervision period of 15 minutes, which would be required regardless of program type or treatment setting, is sufficient to recognize and resolve the majority of SAEs. Additionally, the combination of prescription diacetylmorphine and flexible doses of oral methadone may have a protective effect against overdose from illicit opioid use not in the treatment setting, as demonstrated by a non-statistically significant reduced mortality risk compared to oral methadone alone. 11,12 An additional concern with ongoing injection-based opioid agonist treatment is heightened risk of infectious complications such as sepsis, osteomyelitis, cellulitis, and abscesses. When the skin is punctured (even with a sterile needle in a clinical setting), it provides a potential port of entry for bacteria or other microorganisms, particularly when the injections are being given multiple times per day (as is the case with diacetylmorphine and hydromorphone). With that said, the risk of infection and infectious sequelae in a sterile and supervised setting is only a fraction of the risk for those injecting illicit drugs. For example, in the 12-month NAOMI trial, two SAEs involving sepsis or other infections were reported, while three SAEs involving abscesses or cellulitis were reported, across a total of 89,924 injections. 141 In the SALOME trial, over the 180-day treatment period, 18 adverse events involving infectious complications were reported (14 cellulitis, 4 subcutaneous abscesses) over a total of 85,451 injections, which translates to 3.4% and 4.8% of all adverse events deemed related to injectable hydromorphone and diacetylmorphine treatment, respectively. 38 Although difficult to compare and more data is needed, this is compared to 6-12 month prevalence rates of skin and soft tissue infections in people who inject illicit drugs, which range from 6.9% to 37.3%. 142 Additionally, the risk of contracting a blood-borne illness (e.g., HIV or hepatitis C) is eliminated with the use of sterile equipment in a supervised setting.
In the majority of the studies on prescribed diacetylmorphine, nurses supervised patients' selfadministration of medication and closely monitored patients to ensure their safety both before (e.g., no signs of intoxication) and after (e.g., no signs of oversedation or respiratory depression) treatment was administered. If an overdose occurred after injection of the medication, supervision allowed for immediate onsite treatment, ensuring the safety of the patient; it is for this reason that supervised administration of iOAT is recommended rather than take-home dosing. 11,12,38 Provision of injectable opioids under supervision also ensures the safety of the community by, for example, preventing diversion of a prescribed injectable opioid into the street for illicit use. While concern has been expressed over security, public safety, and potential for diversion from sites offering prescribed injectable opioids, findings thus far suggest no negative effects for public safety. 12
# Cost Effectiveness
Studies in both Europe and Canada have found injectable diacetylmorphine treatment to be more cost-effective than oral methadone treatment, due to significant reductions in criminal activity and the costs associated. Similarly, hydromorphone has been found to be more effective and less costly than oral methadone treatment, due to significant reductions in criminal activity and hospitalization and the associated costs. 146 It should be noted that these cost savings rely on the effective negotiation of hydromorphone prices. In addition to cost effectiveness, data from British Columbia shows that individuals receiving injectable hydromorphone and diacetylmorphine gain more qualityadjusted life years (QALYs) than individuals receiving methadone (8.4 ) and ( 8
# APPENDIX 2-DEVELOPMENT PROCESS
# Content Development
The medical writer and committee co-chairs, on behalf of CRISM, developed this national guideline using a structured literature review approach. Relevant search terms and structured search strategies were used to search PubMed, the Cochrane Library databases, and reference lists (up to August 1, 2019) using a hierarchical approach, whereby meta-analyses and systematic reviews were given the most weight, followed by individual randomized controlled trials (RCTs), quasi-experimental studies, observational studies, and, lastly, expert opinion. The medical writer manually reviewed titles, abstracts, and full text of identified citations, selected evidence for inclusion, and compiled narrative evidence reviews, including cost effectiveness data, for the guideline co-chairs and the guideline review panel. Grey literature searches were also conducted for any other existing iOAT guidelines and international researchers and other experts in the field were engaged to determine whether iOAT guidelines exist anywhere in the world. While some individual clinics have various protocols and manuals, this process determined that the BC Centre on Substance Use's 2017 provincial Guidance Document for Injectable Opioid Agonist Treatment for Opioid Use Disorder is the only clinical guidance document in existence, to date. Any questions or uncertainties in the literature search, evidence review, and synthesis processes were brought to the chairs for clarity and consensus.
# Review Process
The National iOAT Clinical Guideline was written by the National iOAT Clinical Guideline Review Committee. Once finalized, the clinical guideline was reviewed by the National iOAT Operational Guidance Review Committee, followed by external review by people with lived experience, experts in the subject matter, and a family member impacted by opioid use disorder.
# Composition of Guideline Review Committee
The CRISM National iOAT Steering Committee was assembled to coordinate guideline preparation activities including recruiting the committee, with representation sought from each of the four CRISM nodes (BC, Prairies, Ontario, and Quebec-Atlantic). The Steering Committee included representation from BC, Alberta, Ontario, and Quebec; each member had relevant expertise, including injectable opioid agonist treatment prescribing, research, and service planning. The Steering Committee decided to create two complementary documents: A clinical guideline and an operational guidance document. To that end, the Steering Committee assembled expert committees for each document. Each member of the Steering Committee was invited to nominate relevant experts from their own province and across the country. As committee members accepted the invitation to join, they were encouraged to nominate additional members to ensure a diverse committee representing a range of experience and expertise. Final committee composition was determined by co-chair consensus. The National iOAT Clinical Guideline Review committee was composed of 30 individuals, including the two co-chairs, which included physicians, nurses and nurse practitioners, pharmacists, people with lived experience, researchers, treatment providers, and front-line staff.
# Development of Recommendations
Recommendations were developed and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool through an iterative consensus process. Draft recommendations were developed by the committee co-chairs and medical writer, then revised by the full committee in two consecutive rounds of review, as described below. Following each round of review, the medical writer revised the recommendations, incorporating all feedback received from committee members. Recommendations were agreed upon by committee consensus. External reviewers did not provide input on the three key recommendations. The committee co-chairs then reviewed and approved the final version of recommendations (more detailed explanation of the evidence underlying each recommendation and score is available in Appendix 3).
# GRADE Approach and Interpretation of Grading
The GRADE approach to rating quality of evidence starts with a simplified categorization of study types (meta-analyses and randomized controlled trials (RCT), quasi-experimental studies, observational studies, and expert opinion), accompanied by initial estimated levels of confidence (high, moderate, low, or very low) in the estimate of a treatment effect. The rating scheme allows for factors that would raise or lower a level of confidence. Factors that would lower confidence in evidence include risk of bias, inconsistency across the RCTs, indirectness, and publication bias; factors that would increase confidence include large effect size and an observed dose-response effect. The final quality ratings are reflective of the confidence in the estimated effect in context of bias and limitations that have been identified, as described below:
- High: We are very confident that the true effect lies close to that of the estimate of the effect.
- Moderate: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
- Low: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
- Very low: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
The GRADE approach uses a binary system to classify strength of recommendations as either strong or weak/conditional. For this guideline, "conditional" was used rather than "weak." It is important to note that, although quality of evidence is an important factor when classifying strength of recommendations, "strong" or "conditional" in this case does not refer exclusively to the quality of evidence underlying a given recommendation. Except for cost and resource allocation, the recommended GRADE factors to classify strength of recommendations were considered:
- Balance between desirable and undesirable effects: The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a conditional recommendation is warranted.
- Quality of evidence: The higher the quality of evidence, the higher the likelihood that a strong recommendation is warranted.
- Values and preferences: The more values and preferences vary, or the greater the uncertainty in values and preferences, the higher the likelihood that a conditional recommendation is warranted.
# Interpretation of Strength of Recommendations
Examples of how a strong versus conditional recommendation could be interpreted by selected audience or user groups are listed below.
A strong recommendation indicates the following:
- For patients: Most people in your situation would want the recommended course of action and only a small proportion would not; you should request discussion with your care provider if the intervention is not offered.
- For clinicians: Most patients should receive the recommended course of action. As an example, in this scenario, an algorithm or decision-making tool would not be necessary-the benefits of the recommended course of action would clearly outweigh any advantages of alternative interventions.
- For health care administrators: The recommendation can be adopted as a policy in most situations.
A conditional recommendation indicates the following:
- For patients: Most people in your situation would want the recommended course of action, but many would not.
- For clinicians: You should recognize that different choices will be appropriate for different patients and that you must help each patient to arrive at a management decision consistent with her or his values and preferences. In this scenario, an algorithm or decision-making tool would be advantageous to determine the best course of action.
- For health care administrators: Policy-making will require substantial debate and involvement of many stakeholders.
# Review of Recommendations
The review process consisted of one round of revisions of the draft guideline recommendations and evidence review by the pan-Canadian review committee. The medical writer and committee co-chairs consolidated guideline revisions as needed to address committee feedback. Differences in opinion or interpretation with regard to the guideline recommendations or the evidence review were resolved through facilitated discussions in a committee teleconference or direct communication. A final decision was reached for all cases without the need for arbitration.
# Management of Competing Interests
This guideline was entirely funded through the CIHR-funded CRISM network and without pharmaceutical industry support. Competing interests were assessed using the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts in Guidelines. 151 No current or ongoing direct competing interests were disclosed by the 30 members of the clinical sub-committee on screening for participation in the review committee. No individual reported a history of employment (either self or family member); consulting or advising; honoraria or fees for training, speaking, or panel discussions; investment interests; grants-in-aid for research, non-monetary research or program support (e.g., equipment, travel, staff salary, facilities); or intellectual property holdings with industry or any commercial entity that could potentially benefit from guideline recommendations. In terms of indirect sources of potential interest or bias, overall, 21 individuals disclosed special interests in relation to the guideline content. These pertained to specific expertise and/or clinical experience (e.g., addiction medicine clinician, academic addictions expert), involvement with provincial OAT or iOAT programs and committees, or research interests and publications. No individual reported that his/her clinical revenue would be influenced by the guideline recommendations. Upon review by the committee co-chairs, none of the potential direct or indirect conflicts of interest or bias disclosed by committee members were deemed to be of sufficient relevance or weight to warrant the members' exclusion from the committee.
All 30 committee members participated in multiple rounds of review and revision of the draft and granted final approval of the guideline contents and clinical recommendations.
# External Review Process
This guideline was reviewed by the National Injectable Opioid Agonist Treatment Operational Guidance Review Committee, which was responsible for the development of its partner document. Following this review, it underwent external review by people with lived experience, experts in the subject matter, and a family member impacted by opioid use disorder.
# Update Schedule/Process
In line with AGREE II criteria, 152 every two years a structured literature search from the last date update will be conducted and the National iOAT Clinical Guideline Committee will be reconvened to determine which updates from research evidence and expert consensus should be added.
# APPENDIX 3-RECOMMENDATIONS AND EVIDENCE SUMMARIES
The GRADE approach rates quality of evidence and strength of recommendation. More information on the GRADE approach is available in Appendix 2. A brief overview of the rating system precedes the recommendations and evidence summaries.
# Quality of Evidence
# High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
# Very low
We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
# Strength of Recommendation
# Strong Conditional
# For patients
Most people in your situation would want the recommended course of action and only a small proportion would not; you should request discussion with your care provider if the intervention is not offered.
Most people in your situation would want the recommended course of action, but many would not.
# For clinicians
Most patients should receive the recommended course of action. As an example, in this scenario, an algorithm or decision-making tool would not be necessary-the benefits of the recommended course of action would clearly outweigh any advantages of alternative interventions.
You should recognize that different choices will be appropriate for different patients and that you must help each patient to arrive at a management decision consistent with her or his values and preferences. In this scenario, an algorithm or decision-making tool would be advantageous to determine the best course of action.
# For health care administrators
The recommendation can be adopted as a policy in most situations.
Policy-making will require substantial debate and involvement of many stakeholders.
# Recommendation 1
Injectable opioid agonist treatment should be considered for individuals with severe, treatment-refractory opioid use disorder and ongoing illicit injection opioid use.
# Quality of Evidence: Moderate
Strength of Recommendation: Conditional
# Remarks:
The rapid onset of action and shorter time to reach peak effects (including respiratory depression) that is achieved with injection rather than oral ingestion of high-dose, full agonist opioid medications necessitate that iOAT be administered in clinical settings, with sterile supplies and in clean and safe conditions, and under supervision of qualified staff trained to intervene in the event of an adverse event or emergency.
The majority of clinical trials evaluating iOAT have restricted participation to individuals who have previously undergone, but not benefited from, oral OAT treatment; thus, the evidence base is supportive of iOAT for the treatment of patients who have not benefited from oral OAT. However, one large randomized trial comparing injectable diacetylmorphine with oral methadone included a subset of participants (n=107 of 1,015 total) with severe OUD but no previous experience with oral OAT. 139,140 Study authors found that outcomes of diacetylmorphine treatment were similar whether individuals had prior oral OAT experience or not, and within the subset of participants with no prior OAT experience, diacetylmorphine was superior to methadone in reducing nonmedical heroin use and criminal involvement, and as effective as methadone in improving overall health and retaining individuals in treatment. 139 Clinical practice in British Columbia has also shifted to broader eligibility considerations, which includes past experience with appropriately dosed oral OAT while continuing to experience significant health and social consequences related to their OUD; multiple attempts at oral OAT without being able to achieve a therapeutic dose; or other circumstances and risks that indicate the individual may benefit from iOAT based on clinical judgment.
This treatment should be offered to and discussed with all those patients who may benefit from it.
It was decided that this recommendation should be conditional due to the high intensity of treatment requiring (in most cases) multiple trips to the clinic or pharmacy per day, which may be experienced as overly onerous for some patients; the increased risk of adverse events compared to oral OAT; 11,12 the potential for other treatment approaches being collaboratively decided as the best option by clinician and patient; and the likelihood that policy-making will require substantial debate and involvement of many stakeholders.
To date, there has not been research conducted specifically looking at iOAT provision in youth. Specific considerations for youth (adolescent-aged 12-17 years; and young adult-aged 18-25 years) populations with severe OUD who do meet some or all of the considerations for eligibility for iOAT in their practice are outlined in this clinical guideline.
# Evidence Summary:
Two systematic reviews, which included meta-analyses, of clinical trials involving patients with longterm, refractory heroin addiction have demonstrated the efficacy of diacetylmorphine in comparison to methadone in terms of reducing illicit heroin use, criminal activity, and involvement in sex work, as well as improving overall health and social functioning. 11,12 These meta-analyses include a 2011 Cochrane Review which found that supervised injection of diacetylmorphine, paired with flexible doses of methadone, was superior to oral methadone alone in retaining treatment refractory patients in treatment (4 RCTs; n=1388, Relative Risk (RR) 1.44 ) 11 and a 2015 systematic review and meta-analysis which found supervised injectable heroin treatment to be superior to methadone in treating treatment refractory opioid use disorder (4 RCTs; n=1377, RR 1.37 ). 12 Both systematic reviews also reported greater reductions in illicit drug use (both heroin and other illicit substances), however, due to heterogeneity in reporting, these were reported narratively rather than included in the meta-analyses.
In response to restrictions on accessing diacetylmorphine in Canada, the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) compared diacetylmorphine with injectable hydromorphone in a population of patients (n=202) with long-term, treatment-refractory OUD. 13 Both per protocol (PP) and intention to treat (ITT) analyses found that injectable hydromorphone was not inferior to injectable diacetylmorphine for long-term injection street opioid users not currently benefitting from oral opioid agonist treatment, in terms of retention rates (≥92% PP; ≥ 77% ITT), reduction of any street opioid use (-0. 13 Thus, in jurisdictions where diacetylmorphine is currently not available, or in patients where it is contraindicated or unsuccessful, hydromorphone provides an effective, licensed alternative. 13 Recommendation 2
For patients who are determined to be likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone are acceptable treatment options.
# Quality of Evidence: Low
Strength of Recommendation: Strong
# Remarks:
Both hydromorphone and diacetylmorphine are approved for the treatment of opioid use disorder in Canada. However, diacetylmorphine must be applied for through the Special Access Programme for individual patients or added to the List of Drugs for an Urgent Public Health Need for a given jurisdiction.
Either medication may be considered a reasonable choice, based on availability, patient choice, and prescriber judgement. If the individual is not benefitting sufficiently or is experiencing unacceptable side effects, they should be given the option to transition to the other medication.
The quality of evidence is rated low due to the discrepancy in evidence supporting each medication, with two systematic reviews supporting the use of diacetylmorphine, and only a single study supporting the use of hydromorphone. The recommendation is rated as strong based on expert consensus, significant clinical experience in British Columbia, reduced risk of adverse events for hydromorphone compared to diacetylmorphine, and the lack of regulatory and supply barriers impacting access to hydromorphone.
# Evidence Summary:
As outlined above, two systematic reviews support the recommendation of diacetylmorphine for the treatment of severe opioid use disorder. 11,12 Due to regulatory barriers which limited access to diacetylmorphine in Canada, the SALOME trial compared injectable hydromorphone to injectable diacetylmorphine in a non-inferiority trial and found no evidence indicating that hydromorphone is inferior to diacetylmorphine. 13,28 Both per protocol and intention to treat analysis found that injectable hydromorphone was not inferior to injectable diacetylmorphine for long-term injection street opioid users not currently benefitting from oral opioid agonist treatment, in terms of retention rates (≥ 92% PP; ≥ 77% ITT), reduction of any street opioid use (-0. While diacetylmorphine has significantly more evidence supporting its efficacy in treating OUD, it may pose an increased risk of adverse events (e.g., seizures, and overdose) compared to injectable hydromorphone. Hydromorphone was associated with a significantly lower risk of both adverse events (0.60 ) and serious adverse events (0.21 [95% CI 0.06 to 0.69) compared to diacetylmorphine. 13 For these reasons, either medication can be considered a reasonable choice, based on availability, patient choice, and prescriber judgement.
# Recommendation 3
Injectable opioid agonist treatment should be provided as an open-ended treatment, with decisions to transition to oral OAT made collaboratively with the patient.
# Quality of Evidence: Low
# Strength of Recommendation: Strong
Remarks:
The quality of evidence is rated low due to the low number of studies evaluating the impact of pre-determined treatment end dates. It was decided that this recommendation should be strong despite the low quality of evidence, due to the risk associated with fentanyl-contaminated illicit opioid use and its alignment with a recommendation from the World Health Organization that opioid agonist treatment be provided as an open-ended treatment. 153 Evidence Summary:
A loss of treatment benefit when prescription diacetylmorphine treatment was discontinued at a predetermined end date has been found in two post-randomized controlled trial observational cohorts. 42,43 Both of these studies found an increase in street heroin use post treatment end to levels comparable to that of the control group. One study found a rapid deterioration in 82% (94/115) of responders in the diacetylmorphine group two months after treatment discontinuation, with mean scores on the constituent scales of the multi-domain outcome index returning to pre-treatment levels, 43 while the other showed a significant increase of street heroin use in the diacetylmorphine group three months after treatment discontinuation (p=0.005, mean number of days of heroin use in past month=8 days at 12 months, mean=14 days at 15 months). 42 Another study compared individuals who voluntarily transitioned from injectable diacetylmorphine to oral methadone prior to the completion of a randomized controlled trial against those who were involuntarily transitioned at the end of the 12-month trial, and found that the mean prior 30 days of illicit heroin use was higher in the involuntary group than the voluntary group at 24 months (adjusted mean difference: -5. Opioids are often taken in larger amounts or over a longer period than was intended
The presence of at least 2 of these symptoms indicates an OUD
The severity of the OUD is defined as:
# MILD:
The presence of 2 to 3 symptoms
# MODERATE:
The presence of 4 to 5 symptoms
# SEVERE:
The presence of 6 or more symptoms 2 There is a persistent desire or unsuccessful efforts to cut down or control opioid use The pre-and post-injection assessments y are completed by a qualified health professional or other trained staff if supervised by a health professional to ensure the safety of patients. The pre-injection assessment ensures that the patient is not intoxicated, including by centrally-acting sedatives or stimulants, or in any other acute condition that would increase the risk of an adverse event with the use of injectable hydromorphone or diacetylmorphine. The post-injection assessment is performed to inform dosing (e.g., lowering dose if sedation occurs) and ensure safety (e.g., respond to respiratory depression). Patients may leave the premises when they are deemed fit to do so after the minimum 15-minute observation period post dose.
y The pre-and post-intake assessment protocol has been adapted from the protocol used at Providence Health Care's Crosstown Clinic in Vancouver, BC.
# Pre-Injection Assessment
A qualified health professional or other appropriately trained staff, including peer staff, if supervised by a qualified health professional will complete the following, in order to assess the safety of providing each patient's dose:
Assess for signs of intoxication, including severe agitation, dyskinesia, sedation, slurred speech, or smelling of alcohol.
A sample pre-injection assessment form appears in Table 3 below. If initial assessment results in suspicion of recent use of psychoactive substances, the staff member should discuss with the patient whether they have consumed illicit drugs (including any nonprescribed pharmaceutical drug) or alcohol. Where observation warrants further assessment (e.g., slurred speech, unsteady gait, smells of alcohol), a health professional or other staff if supervised by a health professional (physician, nurse practitioner, Registered Nurse, Registered or Licensed Practical Nurse, Registered Psychiatric Nurse, or pharmacist) trained to administer breathalyzer testing should check that the patient's blood alcohol level does not exceed 0.05%.
If the patient is judged to be intoxicated (whether through observation or results of pre-injection assessment, including breathalyzer results if applicable), the dose should be postponed or withheld.
If the patient is judged safe to receive their dose, their patient chart and medication administration record should be checked to ensure that intoxication did not occur at the last dose, and that no prolonged absence (greater than 3 days or 9 appointments) has occurred.
If sedation did occur at the last dose and this is thought to be due to the prescribed iOAT medication, the prescriber should be consulted before further doses are administered. The prescriber should reduce the dose, typically starting with the last dose that did not cause sedation. The post-dose evaluation duration may need to be extended. If this lowered dose is tolerated, further up-titration may then be pursued (if needed), typically in smaller increments. If sedation was the result of one-time illicit substance use and the patient presents for their next dose alert and the pre-dose assessment does not indicate sedation, there may not need to be a dose adjustment. If the patient continues to experience sedation, their dose may need adjustment and their ongoing substance use should be managed. See Ongoing Substance Use.
If a prolonged absence has occurred (more than five days), the patient should be re-titrated following the process outlined in Appendix 7.
If intoxication did not occur at the last dose and no prolonged absence has occurred, the dose should be given as prescribed.
# Post-Injection Assessment
Patients should be asked to stay in the clinic for a minimum of 15 minutes after they inject their medication. Qualified health professionals or other trained staff if supervised by a health professional (physician, nurse practitioner, Registered Nurse, Registered or Licensed Practical Nurse, Registered Psychiatric Nurse, or pharmacist) can use this period to observe and engage with patients.
After 15 minutes has elapsed, a qualified health professional or other trained staff if supervised by a health professional (physician, nurse practitioner, Registered Nurse, Registered or Licensed Practical Nurse, Registered Psychiatric Nurse, or pharmacist) will conduct the post-injection assessment, observing any signs of intoxication including dyskinesia, sedation, slurred speech, agitation, or decreased respiration rate.
A sample post-injection assessment form appears in Table 4 below.
# Table 4: Post-Injection Assessment
After a minimum of 15 minutes, once a patient is deemed fit to leave the clinic (i.e., is showing no signs of intoxication), they may do so.
If a patient seems to be intoxicated, a pulse oximeter should be used and/or a vital sign assessment should be completed and documented in the patient's chart.
If a patient must be kept for more than the initial 15-minute period post-injection, this should be documented in their patient chart and medication administration record. In this case, the postinjection assessment should be administered at 15-minute intervals until the patient meets all criteria or other medical intervention is required. The patient's prescriber should be advised and a reduction in subsequent dose should be considered.
# Pasero Opioid-induced Sedation Scale (POSS)
The Pasero Opioid-induced Sedation Scale (POSS) is used to assess level of sedation in patients receiving opioids. Because sedation level predicts opioid-induced respiratory depression and precedes other clinically significant events, 155 using the POSS scale provides a consistent way to measure sedation and provide follow-up when needed. At any time during the titration period, a physician, nurse practitioner, nurse or (where applicable) pharmacist (in collaboration with the prescribing physician or nurse practitioner) may order a lower dose or a more gradual titration based on patient response and safety concerns. In order to allow flexibility, the patient can also request a lower dose or a more gradual titration process, such as only increasing the dose by 5mg or not taking a second dose. The most predictable, though rare, side effect during titration is oversedation, which is manageable with dose reductions and a modified (slower) titration schedule.
For iOAT programs that do not have capacity for titrations 7 days a week, it is recommended that the titration process be started between Monday and Wednesday to avoid the need for dose increases on the weekend.
The prescriber may adjust the dosage once per day, or as needed, until the patient feels comfortable (i.e., reduced cravings and withdrawal symptoms) and does not show any excessive intoxication or respiratory depression or until the maximum dose is reached (200mg/dose and/or 500mg/ day for hydromorphone; 400mg/dose and/or 1000mg/day for diacetylmorphine). Dose increases are discouraged on weekends and holidays if the prescriber is not available.
It should be noted that some patients may miss titration sessions due to unstable housing and other issues, and thus the initiation may require a modified protocol over multiple days. Three doses per day is better studied; however, clinical practice in British Columbia has shown that many individuals do well on two doses per day.
Note: For the supervised pharmacy-based model, where titration occurs at the prescriber's office or clinic, it is recommended that initiation of treatment be scheduled such that the first pharmacywitnessed dose does not fall on a weekend or other day in which the prescriber is unavailable.
Table 6 below summarizes the dosages used during the induction process for quick reference.
# Consider co-prescription of oral OAT (see below).
As each patient goes through the titration process, they should stop at the dose where they are comfortable and have alleviated withdrawal and cravings. This will be their ongoing dose. If the patient is oversedated post-injection, the prescriber should be consulted to determine if the next dose should be lowered and to assess any changes in the patient's health status prior to their next dose. The prescriber may order a lower dose at the next injection, with the option to continue to titrate up depending on how the new dose is tolerated.
Table 7 below summarizes the dosages used during the induction process for quick reference.
# Alternate Titration Protocols
Clinical experience from British Columbia, where fentanyl has infiltrated the illicit opioid supply, has shown that the above recommended titration protocols may be insufficient in ameliorating withdrawal symptoms and cravings in some individuals who have developed a very high opioid tolerance due to fentanyl. For this reason, titration protocols have been adapted by some iOAT programs.
Two alternate titration protocols are offered below (a three doses per day and a two doses per day protocol), which were developed according to clinical expertise by iOAT providers in Vancouver, BC. Although these alternate protocols have been used in clinical practice, it should be understood that they have not been rigorously evaluated for safety or their impact on retention. comfortable and have alleviated withdrawal and cravings. This will be their ongoing dose. If the patient is oversedated post-injection, the prescriber should be consulted to determine if the next dose should be lowered and to assess any changes in the patient's health status prior to their next dose. The prescriber may order a lower dose at the next injection, with the option to continue to titrate up depending on how the new dose is tolerated.
# Alternate Titration Protocols
Due to the higher risk of adverse events and sedation with diacetylmorphine compared to hydromorphone, 13 accelerated titration protocols for diacetylmorphine are not recommended.
# Co-Prescription of Oral OAT
Oral OAT is frequently co-prescribed with iOAT in order to prevent withdrawal and cravings between iOAT doses, particularly overnight during the longest between-dose period, as the injectable medications are relatively short-acting. In the randomized controlled trials studying supervised injection diacetylmorphine, methadone was co-prescribed in two trials, 43,156 and available for various reasons (to prevent withdrawal over-night, for travel, to reduce attendance to one or two times per day) in five trials. 13,14,140,157,158 Where listed, the average methadone dose ranged from 8mg to 60mg per day. 13,43,140,156 A dose of oral OAT (i.e., SROM or methadone) may be taken daily under supervision to bridge between doses, with the longest gap between doses occurring overnight. Caution and safety should guide co-prescription, while working to ensure patient comfort. Nurses and/or pharmacists should assess the patient each day during the titration period to ensure the co-prescribed oral OAT is appropriately dosed. Co-prescribed oral OAT can be given at any time, based on the patient's comfort (for example, with the first injection of the day, with the last injection of the day, or separately in the evening).
There is insufficient data to guide specific target dosing of supplemental oral OAT, however, it should be guided by patient preference and clinical effect. Induction of co-prescribed methadone should follow the process outlined in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. Guidance on induction of SROM can be found in the BCCSU's A Guideline for the Clinical Management of Opioid Use Disorder. Oral OAT may be started in advance if practical matters require waiting to start iOAT, at the same time as iOAT induction, or after a patient has been titrated onto iOAT.
An example titration chart of both hydromorphone and methadone follows in Table 12. z This chart is informed by clinical expertise and represents one possible way of co-prescribing methadone with hydromorphone, in a two-doses per day setting in which the patient is still experiencing discomfort and cravings after the initial three-day titration. De-intensification of treatment may be appropriate and/or required for one of four reasons. The first is when a patient has stabilized on iOAT and decides, with their prescriber, that a lower-intensity iOAT model is appropriate (for example, moving from the Comprehensive and Dedicated Model of Care to the Integrated or Embedded Model, see iOAT Operations Guidance). When switching models of care, the prescriber should ensure that existing psychosocial supports will remain in place, if possible.
The second is patient-initiated transition to oral OAT which is covered in more detail below. The third situation in which de-intensification would occur is when a patient is discontinued from iOAT as a consequence of behaviour such as violence or diversion (attempted or successful). The final reason a patient may require de-intensification of treatment is if they have been convicted of a crime and face a period of incarceration.
This guideline should be understood as a living document, which will be refined as more evidence and clinical experience emerges from expanded iOAT provision. The following sections on de-intensifying treatment to oral OAT are based on the best evidence currently available. Clinical judgment, close monitoring, and, when appropriate, consultation with addiction specialists with experience in iOAT provision should further guide the process of de-intensifying treatment in order to ensure the safety of patients transitioning from iOAT to a less intensive treatment. Strategies for transitioning between hydromorphone and diacetylmorphine (and the reverse) are also provided below.
# Transition from Hydromorphone to Diacetylmorphine
Transition from hydromorphone to diacetylmorphine (using a 1:2 potency ratio with a 25% dose reduction to account for incomplete cross tolerance, see Conversion Table in Appendix 9) will be subject to availability of diacetylmorphine (see iOAT Operations Guidance). Patients and prescribers may collaboratively choose to transition to diacetylmorphine if the patient is not benefitting sufficiently or experiencing unacceptable side effects. It should be noted that diacetylmorphine may pose an increased risk of adverse events (e.g., histamine reactions, seizures, and overdose) compared to injectable hydromorphone. 13 See Appendix 11 for a table of serious side effects for both medications. See Medication Selection and Preparation for considerations on initial selection of iOAT medication.
# Transition from Diacetylmorphine to Hydromorphone
Patients and prescribers may collaboratively choose to transition from diacetylmorphine to hydromorphone (using a 2:1 potency ratio with a 25% dose reduction to account for incomplete cross tolerance, see Conversion Table in Appendix 9) if the patient is not benefitting sufficiently or experiencing unacceptable side effects. It should be noted that diacetylmorphine may pose an increased risk of adverse events (e.g., histamine reactions, seizures, and overdose) compared to injectable hydromorphone. 13 See Appendix 11 for a table of serious side effects for both medications. See Medication Selection and Preparation for considerations on initial selection of iOAT medication.
# Transition from Hydromorphone or Diacetylmorphine to Methadone
Transition from injectable hydromorphone to oral methadone (see Conversion Table in Appendix 9) may be patient-initiated due to a desire to de-intensify treatment, in which case gradual transition is appropriate. The pace of transition and approach used should follow the same approach used for transitioning patients from any high-dose short-acting opioid onto methadone while gradually lowering the dose of hydromorphone. Province-specific guidelines for methadone induction should be followed and can be found in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. Due to inter-individual differences, which can vary widely among patients, clinical judgement should be used in the transition process.
# Transition from Hydromorphone or Diacetylmorphine to Slow-Release Oral Morphine
Due to the preliminary nature of research on using SROM to de-intensify iOAT, there is no existing clinical protocol to follow. It is recommended that clinical judgment be used in gradually decreasing the hydromorphone or diacetylmorphine dose while simultaneously up-titrating the SROM dose.
One titration approach would start with a 10% hydromorphone/diacetylmorphine dose decrease per week, with concurrent increase in SROM. The speed of transition should be guided by the patient's goals and subjective experiences (e.g., cravings, withdrawal symptoms, sleep). General induction and dosing recommendations for SROM can be found in the BC Centre on Substance Use's A Guideline for the Clinical Management of Opioid Use Disorder. Patients should be under closer clinical review during this transition time and expert physicians should be consulted.
Although the evidence base for SROM is less robust than for other oral OAT medications (methadone and buprenorphine/naloxone), research has demonstrated that it is a safe and effective alternative to first-line treatment options, particularly in patients who have not benefited from first-line treatment options in the past. 159,160 Slow-release oral morphine may also confer specific advantages for patients engaged in iOAT who wish to transition to lower-intensity treatment, as the majority of these patients have not previously demonstrated benefit from oral methadone or buprenorphine/naloxone prior to iOAT initiation, and may wish to try an alternative treatment. Further, there is some evidence that supplemental SROM may help to reduce iOAT dose and frequency of daily injections among those individuals interested in doing so. A brief overview of the literature regarding use of SROM in the treatment of OUD, including as a supplement to ongoing iOAT, is provided below.
A 2014 two-phase study investigating the safety and efficacy of SROM compared to methadone in adults with moderate to severe OUD who had been in methadone maintenance programs for at least 26 weeks found those on SROM reported fewer cravings, higher levels of treatment satisfaction, and lower levels of stress. In the first phase, patients were randomly assigned to receive either methadone or SROM for 11 weeks. In the second phase, the medications were switched, so each patient received both methadone and SROM for 11 weeks each. After the second 11-week phase, patients from both groups were offered a 25-week extension of SROM. Those individuals who switched from methadone to SROM during the study's extension period reported zero loss of efficacy or tolerance to medication. 161 Slowrelease oral morphine's non-inferiority 161 and favourable side effect profile compared to methadone for the treatment of OUD 44 (specifically its lack of association with a prolonged QTc and subsequent risk for arrhythmia and fewer drug-drug interactions) make it a suitable alternative to methadone.
For patients receiving iOAT and supplementary oral OAT, there is some research evidence that switching from supplementary methadone to supplementary SROM may offer advantages for patients wishing to de-intensify treatment (reduction in iOAT dose or frequency of daily injections). In a small observational study (n=12), former participants in the Randomized Injectable Opiate Treatment Trial (RIOTT) maintained on injectable diacetylmorphine supplemented with oral methadone underwent a planned transition from supplemental methadone to SROM with no planned decrease in their iOAT dose. 162 Patients were started on a 1:6 (methadone:SROM) dose ratio with a 25-30% reduction in initial SROM dose to maintain stable peak concentrations. The transition was performed over five days, with half of the original methadone dose prescribed on day 1, 30% of the original methadone dose on day 2, 20% on day 3, and no methadone prescribed thereafter. 162 Prior to the transition, all 12 patients had identified reduction of their injectable medication dose as a treatment goal. Study results indicate that, 10 weeks after the transition from supplemental methadone to SROM, patients were able to reduce the daily dose of diacetylmorphine from an average of 382mg to 315mg. 162 Patients also reported fewer cravings and improved sleep and quality of life after switching from supplementary methadone to SROM. Although more research is needed, this preliminary study suggests that supplementary SROM may be a viable alternative to methadone, and may have advantages in patients wishing to reduce their daily iOAT dose and/or those considering transition to oral OAT. It should be highlighted that this is a small observational study and additional research is needed in order to optimize transitions from iOAT to SROM.
# Transition from Hydromorphone or Diacetylmorphine to Buprenorphine/Naloxone
There is currently very limited literature on transitioning from iOAT to buprenorphine/naloxone. 163 Several patients have been successfully transitioned using the Bernese method (i.e., starting with a very low dose of buprenorphine/naloxone overlapping with iOAT, with small daily dose increases until iOAT is stopped abruptly once a sufficient dose of buprenorphine/naloxone has been reached) in Switzerland. 163 Additionally, a small number of patients have been successfully transitioned in Vancouver, both in in-patient withdrawal management facilities, following the BC-specific induction guidelines which can be found in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder, and using the Bernese method in an outpatient setting. Transition to buprenorphine/ naloxone should follow the same approach used for transitioning patients from any high-dose shortacting opioids onto buprenorphine/naloxone. Province-specific guidance can be found in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. It is recommended that patients transitioning from iOAT to buprenorphine/naloxone be seen frequently after their induction to maintain continuity of care, given the intensity of the injectable treatment they are transitioning out of.
# Provider-Initiated De-Intensification of Treatment
Although this document emphasizes that patients should never be cut off from treatment, there are circumstances in which provider-initiated de-intensification of treatment from iOAT to oral OAT is indicated. These circumstances include situations where patient behaviour represents a threat to safety, including violence against staff or other patients, or attempted or successful diversion. Decisions to initiate de-intensification of treatment should be made with the recognition that this de-intensification of treatment, if initiated by the health care provider rather than patient, may be accompanied by deterioration of the patient's physical and mental health.
Provider-initiated de-intensification of treatment is not recommended for a first attempt at diversion. Reasons for attempted or successful diversion should be explored with the patient. The treatment team should then meet to discuss strategies to prevent and manage further diversion attempts. Clinical judgment should be used to determine if a short-term conversion to oral OAT is necessary while determining the treatment team's response to diversion.
For provider-initiated conversion to oral OAT due to behaviour such as violence or diversion, it may be done more rapidly using the conversion table in Appendix 9, with a 25-30% reduction in oral OAT dose to account for incomplete cross-tolerance. In this case, prescribers must work closely with patients to create a treatment plan with additional supports to mitigate potential risk of involuntary de-intensification of treatment.
# De-Intensification of Treatment Due to Incarceration
Patients who have been convicted of a crime and face a period of incarceration must be transitioned to a suitable oral OAT option prior to, or as quickly as possible following, their entry into the correctional system. The medication-specific transition recommendations above should be followed. If transition to oral OAT is not possible prior to incarceration, the community prescriber should contact the most responsible physician (MRP) in the correctional facility to inform them that the patient is on iOAT and will thus have a high opioid tolerance and make recommendations for the management of OUD and transition to oral OAT while the patient is subject to a custodial environment.
# Management
Immediately begin management if assessment indicates a dose intolerance. Naloxone should be used alongside the principles of basic life support along with cardiopulmonary resuscitation for trained individuals (CPR; compressions plus ventilation).
The goal of naloxone administration is to:
- Achieve adequate spontaneous ventilation (RR>10/min) Opioids should not be given for acute treatment of opioid withdrawal following treatment for a dose intolerance.
# Two-Spirit:
A term used by some North American Indigenous societies to describe people with diverse gender identities, gender expressions, gender roles, and sexual orientations. Dual-gendered, or 'two-spirited' people have been and are viewed differently in different Indigenous communities. ee
Lesbian: A woman whose enduring physical, romantic, and/or emotional attraction is to other women. Some lesbians may prefer to identify as gay (adj.) or as gay women. ff
# Gay:
The adjective used to describe people whose enduring physical, romantic, and/or emotional attractions are to people of the same gender. ff
Bisexual: A person who has the capacity to form enduring physical, romantic, and/or emotional attractions to those of the same gender and those of another gender. People may experience this attraction in differing ways and degrees over their lifetime. ff
Trans: Trans is an umbrella term that describes a wide range of people whose gender and/or gender expression differ from their assigned sex and/or the societal and cultural expectations of their assigned sex. ff
Queer: An adjective used by some people, particularly younger people, whose sexuality is not heterosexual. Once considered a pejorative term, queer has been reclaimed by some 2SLGBTQ+ people to describe themselves; however, it is not a universally accepted term even within the 2SLGBTQ+ community. ff Medical management: Medical management for opioid use disorder is medically focused, unstructured, informal counselling provided by the treating clinician in conjunction with pharmacological treatment. Medical management includes but is not limited to, performing health and wellness checks, providing support and advice, assessing motivation and identifying barriers to change, creating a treatment plan, fostering medication adherence, optimizing dosing, supporting treatment adherence and relapse prevention, and providing referrals to appropriate health and social services.
Mutual-support/peer-support programs: Support that is provided through a network of peers through meetings, open discussions of personal experiences and barriers to asking for help, sponsorship, 12-step programs, and other tools of recovery. Examples include Alcoholics Anonymous, Narcotics Anonymous, SMART Recovery, and LifeRing Secular Recovery.
ee Definition borrowed and lightly adapted from Qmunity's "Queer Terminology from A to Q" ff Definitions borrowed and lightly adapted from GLAAD Media Reference Guide Diacetylmorphine: A short-acting, semi-synthetic opioid, diacetylmorphine has a rapid onset of action and a short half-life. Injected diacetylmorphine avoids first-pass metabolism and crosses rapidly into the brain where it is deacetylated into an inactive 3-monoacetylmorphine and an active 6-monoacetylmorphine which is then deacetylated into morphine, which acts as a full mu (μ) opioid receptor agonist. Injectable diacetylmorphine is used as a treatment for severe opioid use disorder in Canada and several European jurisdictions.
Hydromorphone: A short-acting, semi-synthetic mu (μ) opioid receptor agonist. Due to regulatory barriers limiting access to diacetylmorphine, hydromorphone was studied as an alternative to diacetylmorphine for the treatment of severe opioid use disorder and found to be non-inferior.
Methadone: A long-acting synthetic opioid that acts as a full mu (μ) opioid receptor agonist.
It has a half-life of approximately 24 to 36 hours and is well absorbed. In Canada, it is most frequently administered as an oral solution, generally given as a single daily dose. Methadone tablets are also available in a limited context (e.g., for travel) in some jurisdictions.
# Slow-release oral morphine:
A 24-hour slow-release formulation of morphine, a full agonist at the mu (μ) opioid receptor, that is taken orally once per day. In Canada, slow-release oral morphine is available as a capsule containing polymer-coated pellets (to slow absorption and release) of morphine sulfate. Its elimination half-life is approximately 11 to 13 hours. It is currently approved for pain management in Canada, and its use for treatment of opioid use disorder would be considered off-label.
Opioid antagonist: Medication that works by blocking opioid receptors, preventing the body from responding to opioids. Opioid antagonist medications may be used to rapidly displace opioid agonist molecules from receptors in an overdose situation (e.g., naloxone), or to facilitate continued abstinence from using opioid drugs (e.g., naltrexone). In Canada, naloxone is available in an intramuscular injection or intranasal spray (depending on availability), while naltrexone is available as an oral tablet taken once per day.
# Opioid use disorder (OUD):
A problematic pattern of opioid use leading to clinically significant impairment or distress that meets the DSM-5 Diagnostic Criteria for Opioid Use Disorder (see Appendix 4). Opioid use disorder includes the use of synthetic and/or naturally derived opioids, whether prescribed or illegally obtained. The DSM-5 terminology represents a deliberate shift away from DSM-IV terminology of "opioid abuse" or "opioid dependence", which may be considered pejorative and/or stigmatizing, to describe this condition.
Psychosocial supports: Non-therapeutic social support services that aim to improve overall individual and/or family stability and quality of life, which may include community services, social and family services, temporary and supported housing, income-assistance programs, vocational training, lifeskills education, and legal services.
Trauma-informed practice: Health care and other services grounded in an understanding of trauma that integrate the following principles: trauma awareness; safety and trustworthiness; choice, collaboration, and connection; strengths-based approaches, and skill-building. Trauma-informed services prioritize safety and empowerment and avoid approaches that are confrontational.
Treatment refractory: Refers to opioid use disorder which has been treated with standard first-line pharmacological treatments, with the individual experiencing insufficient benefit and/or continuing to use illicit opioids and experiencing poor physical and mental health as well as poor social integration. It should be noted that there has been an intentional shift away from the use of "treatment refractory," as it may inadvertently perpetuate stigma against individuals with opioid use disorder. This document uses this term, when necessary, to reflect its use in the scientific literature. However, substance use disorders are known to be chronic, relapsing conditions which may require multiple treatment approaches across the lifespan, thus rendering such a term and concept otherwise moot.
# APPENDIX 6: HEALTH CARE PROVIDER ADMINISTRATION OF INJECTABLE MEDICATION
While the ability to self-administer medication is one of the considerations for eligibility, it is recognized that there may be time-limited, discrete events such as injury that require assistance from health care providers to ensure continuity of care. In some circumstances, there may be other clinical or psychosocial indications for health care provider administration of injectable medication, in order to enable a client with specific needs to access iOAT. In these cases, and depending on the model of care and jurisdiction, health care providers may provide subcutaneous or intramuscular (IM) injections in the deltoid, ventrogluteal, or dorsogluteal muscles. Standard protocols for IM injection including rotating sites and matching site to volume of medication should be followed. Nurses may be able to provide intravenous (IV) injection when requested by the patient and determined appropriate. Regional differences may exist in terms of what medications can be administered by IV injection by various nursing professionals. Where possible, institutional policies should be developed to outline appropriate orders required, standard protocols for IV injection, and necessary staff education.
Indications that iOAT may be appropriate despite inability to inject on an ongoing basis may include lacking the skills (e.g., a patient whose partner administered street drugs intravenously for them) or the ability to self-inject (e.g., disability or mobility issues). It is recommended that clinical judgment be used in these situations to determine if iOAT with health care provider administration is the most appropriate treatment.
# APPENDIX 7: TITRATION PROCESS
The following outlines the recommended titration process for iOAT.
As with the general process for iOAT, doses are self-administered intravenously, intra-muscularly, or subcutaneously under supervision, with physicians, nurse practitioners, Registered Nurses, Registered Psychiatric Nurses, Licensed Practical Nurses, and, in some jurisdictions, pharmacists able to administer injectable medications when clinically indicated (see Appendix 6).
# Hydromorphone Titration Protocol 1-Three Doses Per Day
# Day 1 (Total Dose Range=60-90mg)
# Consider co-prescription of oral OAT (see below).
# Hydromorphone Titration Protocol 2-Two Doses Per Day
For patients who will be receiving two doses of hydromorphone per day, at the discretion of their prescriber, patients may be titrated onto a two-dose schedule. A suggested titration schedule follows. Those needing additional guidance should consult an experienced iOAT provider.
# Day 1 (Total Dose Range=60-120mg)
# Day 3 (Maximum Day 3 Total Dose=540mg)
Administer the maximum tolerated amount at Dose 3, Day 2 for each of the 3 doses on Day 3. After consulting with the prescriber, adjust the dosage once a week until the patient feels comfortable (i.e., reduced cravings and withdrawal symptoms) and does not show any excessive intoxication or respiratory depression or until the maximum dose is reached (400mg/dose and/or 1000mg/day). Dose increases are discouraged on weekends and holidays, if prescribers are not available. Maximum individual dose=180mg.
# Diacetylmorphine Titration Protocol 2-Two Doses Per Day
For patients who will be receiving two doses of diacetylmorphine per day, at the discretion of their prescriber, patients may be titrated onto a two-dose schedule. A suggested titration schedule follows. Those needing additional guidance should consult an experienced iOAT provider.
# Day 1 (Total Dose Range=120-240mg)
# Consider co-prescription of oral OAT (see below).
# Day 2 (Total Dose Range=260-360mg)
# Consider co-prescription of oral OAT (see below).
# Day 3 (Total Dose Range=400mg)
Doses 1 and 2 on Day 3 will often be the ongoing final dose for the patient. If all previous doses were well tolerated, doses on Day 3 should be 200mg
As each patient goes through the titration process, they should stop at the dose where they are
# APPENDIX 8: EXAMPLE DOSE REDUCTION PROTOCOL
For individuals who have stabilized on a maintenance dose who miss 6 consecutive doses or 2 days (whichever is first) but fewer than 9 doses or 3 days (whichever is first), their dose should be reduced by 1/3 (one-third). Each subsequent dose can be increased by 25mg until they are back at their regular dose. aa aa Adapted from PHS Community Services Society in Vancouver, BC.
# APPENDIX 9: CONVERSION TABLE
The following conversion table can be used to determine an equivalent dosage for the purpose of travel (for example, converting to witnessed ingestion of SROM for travel to a funeral) or longer term (for example, if someone is entering the corrections system or hospitalized in a facility where iOAT is not feasible or is clinically contraindicated). Ideally, travel is planned in advance, allowing for a slow titration from iOAT to oral OAT following province-specific guidelines, which can be found in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. It is recognized, however, that emergency travel (e.g., a funeral or family emergency) is at times required. In these cases, the below table can be used along with patient education to minimize safety risks. Although there is more evidence supporting the use of methadone for travel, the authors of this document favour the use of SROM, with daily witnessed ingestion, for its improved safety profile, including significantly less variability in required dosage.
# IMPORTANT SAFETY NOTE:
The conversion table below is approximate and clinical judgment should guide conversions, including reducing the target dose by 25% from the figure given in the table due to incomplete cross-tolerance. Patient safety must be prioritized in converting from iOAT to oral OAT and should follow standard principles for safe conversions between injectable and oral opioid medication routes of administration, as this table outlines approximate equianalgesic doses only for IV conversions between HM and DAM.
When possible, the converted travel dose should be trialled for a few days prior to travel to prevent destabilization.
Patients should be provided with take-home naloxone kits and training on how to administer naloxone. It is ideal to have family or friends who can observe them for sedation or respiratory depression.
Dose conversion should be calculated cautiously and multiple-day prescriptions of oral OAT should be prescribed with recognition of the cumulative effects of dosing.
Most patients do well on doses of methadone between 60-120mg per day. 33 To ensure patient safety, it is recommended that this target dose range not be exceeded and that a maximum dose of 1200mg SROM not be exceeded.
# APPENDIX 11: COMMON AND SERIOUS SIDE EFFECTS
Hydromorphone and diacetylmorphine can cause the same side effects as other opioids, including sedation, nausea and vomiting, constipation, miosis, flushing, and pruritus. 164 The 3-glucoronide metabolite of hydromorphone has been implicated in neuroexcitation symptoms (e.g., tremor, myoclonus, cognitive dysfunction). 165 In addition, long-term opioid use, including iOAT, may lead to abnormalities in the endocrine system, mainly affecting the gonadal axis and leading to hypogonadism. 22,23 In line with this, low testosterone levels and erectile dysfunction have been associated with long-term opioid use (including oral OAT) in males, 24 and menstrual disturbances in females. 22 Osteoporosis and reduced bone mineral density can also result from hypogonadism. Specific serious side effects noted in clinical trials are provided in the table below.
Diacetylmorphine may pose an increased risk of other adverse events (e.g., histamine reactions, seizures, and overdose) compared to injectable hydromorphone 13 and oral methadone. 11,12 Studies in Europe and Canada have reported instances of significant respiratory depression events in people receiving injectable opioids, at an overall rate of about 1 in every 6000 injections, which is significantly lower than the risk present when injecting street heroin. 12 In the 12-month NAOMI trial, two SAEs involving sepsis or other infections were reported, while three SAEs involving abscesses or cellulitis were reported, across a total of 89,924 injections. 14 In the SALOME trial, over the 180-day treatment period, 18 adverse events involving infectious complications were reported (14 cellulitis, 4 subcutaneous abscesses) over a total of 85,451 injections, which translates to 3.4% and 4.8% of all adverse events deemed related to injectable hydromorphone and diacetylmorphine treatment, respectively. 38 Urine drug testing (UDT) can be used to help guide patient care, to ensure patients are aware of which substances they are ingesting if using illicit substances, and to start a conversation on harm reduction and safety. Unlike with oral OAT, where regular and random UDT are considered standard of care, regular and mandatory call-back UDT are not considered standard care for iOAT, due to both the low risk of diversion and the high frequency of contact with care providers.
Other than the initial UDTs performed to confirm illicit opioid use, there is no required number of UDTs for iOAT programs. Point-of-care UDT may be useful for providing immediate feedback to patients and for making prompt treatment decisions, when potentially harmful substances are detected, as well as monitoring trends. Typically, point-of-care UDT can be used to detect amphetamines, benzodiazepines, cocaine, opioids (morphine, codeine, heroin metabolite, opium, and sometimes hydromorphone), oxycodone, buprenorphine, and methadone. Specific substances tested for will vary by product and manufacturer. Given the public health emergency in parts of Canada, point-of-care tests should include fentanyl.
Given the risk of fentanyl contamination in illicit substances, including stimulants and other nonopioids, it is recommended that prescribers discuss drug checking with patients and the option for urine or take-home fentanyl testing.
It is emphasized that UDT should not be used punitively and should not lead to discharge for ongoing stimulant or opioid use. Patients who are showing signs of instability or disclose ongoing illicit substance use may benefit from using UDT to guide more intensive follow-up and reassessment. Following discussion with the patient about any underlying issues contributing to treatment instability, prescribers can consider adjusting iOAT dose, prescribing a supplemental daily dose of oral methadone or SROM, or adjusting supplemental oral OAT dose if current dose is inadequate; increasing the frequency of clinical appointments in order to provide more intensive support, monitoring and assessment; and/or providing referrals to adjunct psychosocial and community-based supports, as appropriate. If treatment intensification does not adequately address clinical or social instability, and/or if patient safety is a serious concern, prescribers and patients may need to consider alternative treatment options or care settings, such as the comprehensive and dedicated supervised iOAT model of care (see iOAT Operations Guidance).
# APPENDIX 13: RESPONDING TO DOSE INTOLERANCES
Each iOAT program should have its own protocols in place for responding to dose intolerances and other adverse events, including required documentation. The following provides general guidance on how to respond to dose intolerances, adapted from the BC Centre for Disease Control's Administration of Naloxone Decision Support Tool. This guidance can be adapted to local practice setting and should be tailored to each specific site.
# Clinical Features of Dose Intolerance:
Signs and symptoms of opioid intoxication (dose intolerance) include:
- Decreased respiratory rate or absence of respirations. A respiratory rate of fewer than 10-12/ min is the best clinical predictor of opioid intoxication
- Oxygen saturation of <90% on room air
- Gurgling or snoring-type sounds
- Slow, erratic, or absent heart rate - Vomiting
- Altered mental status (minimally responsive to unresponsive)
- Constricted (pinpoint) pupils (however, the presence of pinpoint pupils alone is not sufficient to diagnose opioid intoxication)
- Cold and clammy skin (may appear cyanotic , especially around the lips or nailbeds, in individuals with lighter skin; may appear grayish or ashen in individuals with darker skin)
# Assessment
Assessment should be rapidly performed to determine if dose intolerance is suspected and whether naloxone administration is indicated. The assessment should also look for factors that might complicate the management of dose intolerance and necessitate rapid referral to a hospital setting. The predose assessment may identify complicating factors. Special considerations: An initial dose of 0.2mg IM/SC may be administered in advanced practice settings where extra supports (e.g., supplemental oxygen, pulse oximetry) are available and capacity exists for continued resuscitation and monitoring.
# Information on Naloxone HCL
In these advanced practice settings, 911 may not necessarily be required, if adequate staffing and training support the capacity to continually monitor individuals and resuscitate and provide care as needed.
Naloxone's duration of action (20-90 minutes) is shorter than that of all opioids. Thus, individuals should be observed until the opioid effect has worn off.
# Follow-Up Care
The effects of naloxone wear off after 20-90 minutes, while the effects of opioids last much longer. Individuals should be monitored for a minimum of 2-3 hours following the last dose of naloxone. If necessary, provide additional doses of naloxone. Advise clients to not use more opioids for a minimum of 2-3 hours following the last dose of naloxone. While I am receiving hydromorphone/diacetylmorphine treatment, I will not obtain opioid prescriptions or other psychoactive medications (e.g., sleeping pills or pain medication) from other doctors, nurse practitioners, clinics, or elsewhere. If I need opioids for the treatment of acute pain, I will inform the prescriber that I am on iOAT and will agree to communication between this prescriber and my iOAT prescriber to help coordinate safety. For my safety, I give consent to my hydromorphone/diacetylmorphine prescriber to communicate with my pharmacist and any other physicians or nurse practitioners currently or previously involved in my care, and to check my province's prescription monitoring program. I will work with my treatment team to develop a treatment plan and set goals. We will review them regularly and change as needed. In addition to hydromorphone/diacetylmorphine, I can participate in counseling or peer-support groups and other programs as part of my treatment plan. My treatment team will give me information about the options and programs available in my community. My treating team may include some or all of the following: prescriber, nurses, social worker, pharmacist, and others.
My treating team will work collaboratively and respectfully with me in planning treatment and providing care. I can expect confidentiality about my treatment from my treatment team and other health care providers. My personal information will not be shared except with other health care providers as I agreed to above. I understand that confidentiality will need to be breached if I am a danger to myself or others or if a child is at risk. I can decide if I want to continue, stop, or change my treatment plan at any time. I agree to make this decision with my prescriber.
Hydromorphone/diacetylmorphine treatment will require multiple daily trips to the facility where I receive my medication, which may impact my work, school, or other responsibilities. If I do not attend the facility where I receive my medication for 3 consecutive doses or 1 day (number of missed doses may change once I am clinically stable), my prescriber and I will discuss the reasons for missed doses. I understand that missing more than 6 to 9 doses (3 days) may cause a loss of tolerance and may require that, for my safety, I take a lower dose until I stabilize. If I am assessed to be intoxicated during the pre-injection assessment, my dose will be postponed or withheld for my safety.
I have discussed potential side effects and adverse events (seizure, overdose, constipation, pruritus , hypogonadism , and sleep apnea) associated with iOAT with my health care provider and we have agreed on plans to mitigate risk. I will not be cut off from treatment. If hydromorphone/diacetylmorphine is not providing the results expected, my prescriber will work with me to adjust my dosage, increase psychosocial supports, and/or explore other treatment options.
If my prescriber can no longer provide care for me, they will refer me to another prescriber who can.
# Injectable Opioid Agonist Treatment Agreement and Consent
# I understand that I am expected to:
Provide urine for drug testing when asked.
Provide urine samples at the clinic and that these samples are not to be altered. Urine samples that are cold or appear to have been altered will be treated as a serious issue and may affect my treatment plan. Avoid using alcohol or other drugs, such as prescription or over the counter opioid medications, sleeping pills, or tranquilizers. I understand that combining these medications with hydromorphone/diacetylmorphine can lead to overdose and other serious harms and may affect my treatment plan. Notify any health care provider that I receive care from that I am taking hydromorphone/diacetylmorphine for treatment of opioid use disorder. Notify my primary care provider if I become pregnant (if applicable).
I understand that I must inform my prescriber if I am pregnant, suspect I may be pregnant, or if I am planning a pregnancy. Treat staff and other patients with respect.
# I confirm that:
This form has been reviewed in detail with the patient and they understand its content fully. This should be reviewed again when the patient is not in withdrawal. The patient was given time to ask questions and seek clarification before signing this document.
The evidence for other treatment options was reviewed, and the patient agrees to hydromorphone/diacetylmorphine. Information and resources to support psychosocial treatment interventions and supports will be provided to the patient.
The provincial prescription drug monitoring program was reviewed (where applicable) to identify other prescribed medications, and will be checked at each subsequent appointment. A treatment plan with clear goals was developed with the patient, and will be reviewed and documented regularly during treatment. The Provincial Opioid Addiction Treatment Support Program, which provides training for nurse practitioners and physicians to diagnose and treat opioid use disorder using evidence-based treatments along a continuum of care, including iOAT.
The Addiction Care and Treatment Online Course, which provides addiction medicine training for family physicians, specialists, nurses, nurse practitioners, pharmacists, and other healthcare practitioners involved in addiction care and treatment.
# Glossary
Addiction treatment: In this document, addiction treatment refers to ongoing or continued care for substance use disorder(s) delivered by a trained care provider. For opioid use disorder, this could include evidence-based pharmacological treatment (opioid agonist or antagonist treatment), evidence-based psychosocial treatments, residential treatment, or combinations of these treatment options. Addiction treatment may be provided in outpatient or inpatient settings. In isolation, withdrawal management, harm-reduction services, low-barrier housing, and unstructured peer-based support would not be considered "addiction treatment".
Cultural safety and humility: Cultural safety can be understood as an outcome in which people feel safe when receiving care in an environment free from racism and discrimination. It results from respectful engagement that seeks to address power imbalances that are inherent in the healthcare system. Cultural humility is a process undertaken to understand, through self-reflection, personal and systemic biases and to develop and maintain respectful processes and relationships based on mutual trust; it requires humbly acknowledging oneself as a learner when attempting to understand another person's experience. dd Diversion: Any non-intended or non-medical use of a prescribed opioid (including prescribed opioid agonist medication), or use by any individual other than the individual for whom it was prescribed.
# Harm reduction:
Policies and programs that aim to minimize immediate health, social, and economic harms (e.g., transmission of infectious disease, overdose mortality, criminal activity) associated with the use of psychoactive substances, without necessarily requiring a decrease in substance use or a goal of abstinence. Examples include needle and syringe exchange programs, take-home naloxone programs, supervised injection or consumption services, and outreach and education programs for high-risk populations.
Health care provider: A trained and qualified health care provider empowered to provide care related to iOAT, including supervision of medication administration and, in some jurisdictions and models of care, health care provider administered intramuscular or subcutaneous injection. May refer to doctors, nurse practitioners, Registered Nurses, Registered Psychiatric Nurses, Licensed Practical Nurses, and pharmacists.
2SLGBTQ+: Two-Spirit, lesbian, gay, bisexual, trans, queer, and other gender and sexually diverse individuals.
dd Definitions borrowed and lightly adapted from the First Nation's Health Authority.
Opioid agonist: Any substance that binds to and activates mu (μ) opioid receptors, providing relief from withdrawal symptoms and cravings in people with opioid use disorder, and pain relief if used for chronic pain management. Oral opioid agonists used for treating opioid use disorder include methadone, buprenorphine, and slow-release oral morphine. Injectable opioid agonists used for treating opioid use disorder include diacetylmorphine and hydromorphone.
Opioid agonist treatment (OAT): Opioid agonist medications prescribed for the treatment of opioid use disorder. Opioid agonist treatment is typically provided in conjunction with provider-led counselling; long-term substance-use monitoring (e.g., regular assessment, follow-up, and urine drug tests); comprehensive preventive and primary care; and referrals to psychosocial treatment interventions, psychosocial supports, and specialist care as required. In this document, OAT refers to long-term (>6 months) treatment with an opioid agonist medication that has an evidence base for use in the treatment of opioid use disorder. "Opioid agonist treatment (OAT)" is the preferred terminology, representing an intentional shift from the use of "opioid substitution treatment (OST)", "opioid maintenance treatment (OMT)", and "opioid replacement therapy (ORT)".
Buprenorphine: A long-acting synthetic opioid that acts as a partial mu (μ) opioid receptor agonist with a half-life of approximately 24 to 42 hours. Buprenorphine has a high affinity for the opioid receptor, but as a partial agonist has a lower intrinsic activity or effect at the opioid receptor compared to full agonist opioids. These pharmacological properties create a "ceiling" on opioidergic effects-including respiratory depression-at higher doses. Buprenorphine's high affinity for the opioid receptor also confers an antagonistic effect on other opioids; it preferentially binds to the receptor and displaces other opioids if they are present, which can cause precipitated withdrawal (see below). In Canada, buprenorphine is available in a combined formulation with naloxone (see below). Buprenorphine implant and depot injections were recently approved by Health Canada, but have not yet been added to provincial formularies.
Buprenorphine/naloxone: A 4:1 combined formulation of buprenorphine and naloxone, available as a sublingual tablet in Canada. Naloxone is an opioid antagonist with poor oral bioavailability when swallowed or administered sublingually, and is included to deter non-medical injection and insufflation. When buprenorphine/naloxone is taken as directed sublingually, the naloxone component has negligible effects and the therapeutic effect of buprenorphine predominates. However, if diverted for use via insufflation, subcutaneous, intramuscular, or intravenous routes, sufficient naloxone is absorbed to induce some withdrawal symptoms in physically dependent active opioid users. Buprenorphine/naloxone is generally taken once daily, but due to its favourable safety profile and pharmacological properties, it can also be prescribed at higher doses on alternate-day schedules.
# Psychosocial treatment interventions:
Structured and/or manualized treatments delivered by a trained care provider that incorporate principles of cognitive behavioural therapy, interpersonal therapy, motivational interviewing, dialectical behaviour therapy, contingency management, structured relapse prevention, biofeedback, family and/or group counselling. Psychosocial interventions may include culturally specific approaches such as traditional healers, elder involvement, and Indigenous healing ceremonies.
Recovery: A process of change through which individuals improve their health and wellness, live a self-directed life, and strive to reach their full potential. gg
Relapse: May be defined differently by each person, however, a general definition would include a re-emergence of or increase in severity of opioid use disorder symptoms and/or harms related to opioid use following a period of stability.
Stabilization: Stabilization will be patient-specific, depending on each patient's circumstances and needs and how they change over time. Patients' DSM-5 diagnoses, physical and mental health comorbidities, and social determinants of health (e.g., poverty, homelessness) should be identified at baseline and tracked over time. Stabilization includes clinical stabilization (e.g., lack of cravings, improved sleep quality and duration, and overall wellbeing) as well as psychosocial stabilization (e.g., integrating new activities, re-connecting with family, and attaining safe housing).
Trauma: Trauma can be understood as an experience that overwhelms an individual's capacity to cope. Trauma can result from a series of events or one significant event. Trauma may occur in early life (e.g., child abuse, disrupted attachment, witnessing others experience violence, or neglect) or later in life (e.g., accidents, war, unexpected loss, violence, or other life events out of one's control). Trauma can be devastating and can interfere with a person's sense of safety, sense of self, and sense of selfefficacy. Trauma can also impact a person's ability to regulate emotions and navigate relationships. People who have experienced trauma may use substances or other behaviours to cope with feelings of shame, terror, and powerlessness.
# Intergenerational trauma:
The transmission of historical oppression and unresolved trauma from caregivers to children. The concept of intergenerational or historical trauma was developed by Indigenous peoples in Canada in the 1980s to explain the cycle of trauma they were seeing in their communities due to the residential school system, loss of culture, and colonization more broadly. May also be used to describe the emotional effects, adaptations, and coping patterns developed when living with a trauma survivor.
gg Borrowed from the Substance Abuse and Mental Health Administration's "SAMHSA's Working Definition of Recovery: 10 Guiding Principles of Recovery" | # Legal Disclaimer
While the individuals and groups involved in the production of this document have made every effort to ensure the accuracy of the information contained in this treatment guideline, please note that the information is provided "as is" and that CIHR and CRISM make no representation or warranty of any kind, either expressed or implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest extent possible under applicable law, CIHR and CRISM disclaim and will not be bound by any express, implied, or statutory representation or warranty (including, without limitation, representations or warranties of title or non-infringement).
This guideline is intended to give an understanding of a clinical problem and outline one or more preferred approaches to the management of the problem. This guideline is not intended as a substitute for the advice or professional judgment of a health care professional, nor is it intended to be the only approach to the management of a clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medication conditions. If you need medical advice, please contact a local health care professional. 1.0 INTRODUCTION ............................................................................................................................................
# TABLE OF CONTENTS
EXECUTIVE
# Executive Summary
Opioid use disorder (OUD) is one of the most challenging forms of substance use disorder facing the health care system in Canada and a major driver of the recent increase in overdose deaths across the country. In 2018, at least 4,460 Canadians died from an opioid overdose, with 94% determined to be unintentional (accidental) overdoses. This represents a 48% increase in overdose deaths from 2016 and a 9% increase from 2017. The recent emergence of street fentanyl, carfentanil, and other highly potent synthetic opioids increasingly cut into heroin and other street drugs is a pressing public health concern that has contributed significantly to the overdose emergency. Fentanyl and other synthetic analogues were implicated in 73% of opioid-related deaths in Canada in 2018, compared to 67% in 2017 and 50% in 2016. Although pan-Canadian opioid-related deaths were not tracked prior to 2016, it is known that there were at least 655 deaths in which fentanyl was determined to be a cause or contributing cause between 2009 and 2014, compared to an estimated 3,256 deaths involving fentanyl or fentanyl analogues in 2018 alone. This unprecedented public health emergency underscores the importance of developing comprehensive, collaborative, compassionate, and evidence-based health services to address the harms related to untreated OUD. Injectable opioid agonist treatment (iOAT) is an evidence-based, high intensity, costeffective treatment option for OUD for those patients who have not benefitted from other treatments and those whose individual situations and needs indicate they may benefit from injectable opioid agonist treatment.
When OUD is treated effectively, the benefits are not only to the individual (e.g., reduction in morbidity and mortality) but also to the community (e.g., reduced activity in the criminal justice system). Along these lines, the primary aim of iOAT is to improve the health of the individual, by reducing overdose risk and other imminent health and social harms associated with ongoing injection drug use. The second aim of iOAT is to engage individuals in addiction treatment who have not benefited from less-intensive treatments or who have been otherwise unable to access other forms of treatment. Patients may not benefit from oral medications such as buprenorphine/naloxone, methadone, and slow-release oral morphine (SROM) for a variety of reasons, including side effects, cravings persisting despite optimal oral opioid agonist treatment (OAT) dosing or being unable to reach a therapeutic dose. Repeated oral treatment attempts without significant benefit for these patients may result in increased risk of poor health and social outcomes, including fatal and non-fatal overdose(s).
This guideline recommends that iOAT should be considered for individuals with severe, treatment refractory opioid use disorder and ongoing illicit injection opioid use; that both diacetylmorphine and hydromorphone may be appropriate treatment options; and that iOAT should be provided as an open-ended treatment, with decisions to transition to oral OAT made in collaboration with the patient.
The Canadian Research Initiative in Substance Misuse (CRISM), a Canadian Institutes of Health Research (CIHR)-funded research network, assembled an expert interdisciplinary committee composed of 30 individuals, including representation from physicians, nurses, pharmacists, people with lived experience, researchers, and front-line staff. This clinical guideline was developed to provide three key clinical recommendations as well as clinical guidance on the provision of iOAT. Recommendations and clinical guidance are based on a structured literature review and clinical expertise. Its partner document, National Injectable Opioid Agonist Treatment for Opioid Use Disorder Operational Guidance, provides guidance on the implementation, operation, and evaluation of iOAT programs.
# Introduction
This document provides a brief overview of the rationale for and evidence supporting the use of injectable opioid agonist treatment (iOAT) for the management of opioid use disorder (OUD) followed by in-depth clinical guidance for the provision of iOAT. Considerations from the literature and clinical experience in Canada and other jurisdictions are provided, offering a framework for how to build a clinical practice of iOAT. However, the unique nature of each person's situation requires clinical judgement in order to determine the best course of treatment.
National Injectable Opioid Agonist Treatment for Opioid Use Disorder Operational Guidance (iOAT Operational Guidance), a partner guideline to this clinically-focused document, provides guidance on implementing an iOAT program and operational considerations.
# BRIEF OVERVIEW OF iOAT RATIONALE AND EVIDENCE
In 2018, at least 4,034 Canadians died from an opioid overdose, with 94% determined to be unintentional (accidental) overdoses. a This represents a 48% increase in overdose deaths from 2016 and a 9% increase from 2017. 1 The recent emergence of street fentanyl, carfentanil, and other highly potent synthetic opioids increasingly cut into heroin and other street drugs, including cocaine and methamphetamine, is a pressing public health concern that has contributed significantly to the overdose emergency. Contamination of street drugs is ongoing and progressive, with new agents such as benzodiazepine analogues being found in substances sold as opioids. Fentanyl and other synthetic analogues were implicated in 73% of opioid-related deaths in Canada in 2018, compared to 67% in 2017 and 50% in 2016. 1 Although pan-Canadian opioid-related deaths were not tracked prior to 2016, it is known that there were at least 655 deaths in which fentanyl was determined to be a cause or contributing cause between 2009 and 2014, 2 compared to an estimated 3,256 deaths involving fentanyl or fentanyl analogues in 2018 alone. 1 a Epidemiological data and research literature often use the term "overdose" or "accidental overdose" to refer to fatal and non-fatal dose intolerances to both prescription and illicit opioids. In the context of the drug supply being contaminated with fentanyl and other highly potent synthetic opioids, fatal and non-fatal overdoses may be reasonably considered "poisonings", as the adulteration of the drug supply makes it difficult if not impossible to determine a safe dose without knowing the composition and strength of illicit opioids and other substances which may also contain highly potent synthetic opioids.
This unprecedented public health emergency underscores the importance of developing comprehensive, collaborative, compassionate, and evidence-based health services to address the harms related to untreated OUD. Opioid agonist treatment (OAT) has proven to be the most effective approach to reducing all-cause mortality in individuals with opioid use disorder 3 and harms associated with illicit opioid use, including morbidity and mortality. [4][5][6][7][8] Individuals with severe opioid use disorder who inject opioids may not adequately benefit from oral OAT medications for a variety of reasons, including cravings persisting despite optimal OAT dosing, patients being unable to reach a therapeutic dose, insufficient improvements in health, social function, or quality of life, or opting not to initiate oral OAT (e.g., previous experience with oral OAT including intolerable reactions to specific medication b or insufficient reduction in craving and illegal drug use). Individuals who inadequately benefit from first-line medications, or whose circumstances and risks otherwise indicate that they may benefit from iOAT, like other individuals using illicit opioids, face significant risks, including premature death, non-fatal overdose, blood-borne infectious diseases (e.g., HIV and hepatitis C), violence, and arrest. 9,10 Meta-analyses have shown that, among individuals who are treatment refractory c to methadone, prescription injectable diacetylmorphine-administered under the supervision of trained health professionals in a clinic setting-is beneficial in terms of reducing illicit opioid use, premature treatment discontinuation (or "treatment drop-out"), criminal activity, incarceration, and mortality as well as improving overall health and social functioning. [11][12][13][14] In response to regulatory barriers limiting the provision of diacetylmorphine for the treatment of OUD in Canada, the SALOME (Study to Assess Longer-term Opioid Medication Effectiveness) trial compared injectable hydromorphone to injectable diacetylmorphine and found both medications, delivered in identical conditions, showed positive outcomes such as high retention rates (over 77% intention to treat [ITT]; over 92% per protocol [PP] analysis), reduction of street opioid use (from daily to a few days per month), and reduction in illegal activities. 13 A more in-depth review of evidence supporting iOAT for the treatment of OUD is available in Appendix 1.
In jurisdictions where diacetylmorphine is currently not available, or in patients where it is contraindicated or unsuccessful, hydromorphone provides an effective, licensed alternative. 13 b Although side effects for opioids are a class effect, individuals may have different experiences on different opioid medications.
c It should be noted that there has been an intentional shift away from the use of "treatment refractory," as it may inadvertently perpetuate stigma against individuals with opioid use disorder. This document uses this term, when necessary, to reflect its use in the scientific literature. However, substance use disorders are known to be chronic, relapsing conditions which may require multiple treatment approaches across the lifespan, thus rendering such a term and concept otherwise moot.
# DEVELOPMENT PROCESS
See Appendix 2 for details of the development process and review process.
# 1.2.i Intended Audience
The target audience of this document is iOAT prescribers, pharmacists, and nurses, however, there is clinical utility for other members of iOAT care teams, including psychologists, social workers, peer workers, addiction counsellors, case managers, team leaders, program managers, other health care providers, and organizations that provide substance use disorder and addictions treatment and care. Clinical and operational leads may find this document useful in informing the implementation of iOAT. Although this document is primarily written for clinicians and other health care providers, individuals with lived experience of opioid use disorder may wish to read all or part of the document to inform their understanding of treatment options. Additional materials intended for people who use drugs and materials for the general public are available on the CRISM website.
# PURPOSE AND SCOPE
This guideline was created to provide a framework to assist with the clinical practice of iOAT. This includes recommended eligibility considerations; prescription of iOAT; titration, stabilization, and transitions off iOAT; conversion to alternate OAT; supervision of injection; and referral to ancillary services. This guideline does not include guidance on program implementation and other operational issues. Its partner document, iOAT Operations Guidance, provides an overview of potential models of care for this treatment and guidance on selecting the most appropriate model for each site; recommendations on prescriber and staff competencies; guidance on obtaining and preparing injectable medications; and guidance on implementing evaluation of iOAT programs.
This document should be understood as a living document, which will be updated by the National iOAT Clinical Guideline Committee regularly to reflect changes in evidence, policy, and practice.
As the implementation and expansion of iOAT progresses, regulatory and training frameworks will emerge and be added to this and its partner guideline.
# Clinical Recommendations
This clinical guideline makes three key recommendations regarding the provision of injectable opioid agonist treatment. These recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework, which was developed to provide a transparent and systematic approach for making clinical practice recommendations. 15 These three key recommendations are based on the existing literature on iOAT, including two systematic reviews and meta-analyses. The rest of the guidance in this guideline can be understood as clinical guidance informed by the existing literature and reached by consensus of the experts on the National Injectable Opioid Agonist Treatment for Opioid Use Disorder Clinical Guideline Subcommittee.
The GRADE approach rates evidence quality as high, moderate, low, or very low. Evidence quality can also be understood as certainty of evidence or confidence in the estimated effect size.
Recommendations can be rated as either strong or conditional. More information on the GRADE system can be found in Appendix 2; the full recommendations and accompanying evidence summaries can be found in Appendix 3.
# Recommendation
# Quality of Evidence
# Strength of Recommendation
# Clinical Practice Guidance
# Summary of Clinical Practice Guidance
# General considerations
Individuals with severe opioid use disorder who inject opioids and have continued to experience significant health/and or social consequences who have not benefitted from previous attempts at oral opioid agonist treatment, or other circumstances and risks that indicate they may benefit from iOAT.
# p. 21
# Eligibility
Recommended considerations for eligibility in concert with clinical judgment and precautions p. 21
# Medication selection
Both hydromorphone and diacetylmorphine are reasonable choices, based on availability, patient choice, and prescriber judgment p. 30
# Titration process
The titration protocol should be followed.
# Administration of injectable medications
Generally, up to 3 visits per day are recommended.
Individuals should self-administer under supervision of a qualified health professional.
Patients may inject intravenously, intramuscularly, or subcutaneously.
Intravenous injection is recommended in upper extremities only. Lower extremity injection should be discussed and risks identified for those who cannot find an appropriate site in their upper extremities or who otherwise prefer intravenous injection in their legs or feet.
Intramuscular sites should be identified by a qualified health professional and rotated according to established practice standards.
# p. 32
# Post-intake assessment
Performed by a qualified health professional or other trained staff member supervised by a health professional to ensure safety and attend to dose intolerance or other adverse event.
p. 31, Appendix (p. 73)
# Co-prescription of oral OAT
Consider co-prescription of slow release oral morphine or methadone to prevent withdrawal and cravings between iOAT doses, particularly overnight.
# p. 34
# Missed doses
The short-acting nature of iOAT medications requires adequate supervision for missed doses. Refer to missed doses protocol.
# p. 36
# Ongoing substance use
Ongoing substance use while on iOAT may be an indication to intensify treatment, which may include dose increases, transferring to a more intensive model of care, and/or increasing psychosocial and other supports. See Ongoing Substance Use for substance-specific guidance.
p. 42
# GENERAL CONSIDERATIONS
Injectable opioid agonist treatment is generally considered for individuals d with severe OUD who inject opioids and have continued to experience significant health and/or social consequences related to their OUD despite past experience or attempts with appropriately dosed oral OAT e (per CRISM's National Guideline for the Clinical Management of Opioid Use Disorder), previous attempts at oral OAT without being able to achieve a therapeutic dose, or other circumstances and risks that indicate the patient may benefit from iOAT. It is important that all health care providers maintain thorough documentation of treatment offers, treatment attempts, overdoses, and patient outcomes in order to ensure that individuals are appropriately transitioned through the continuum of treatment and care, and to document the need for iOAT, when appropriate. Rather than specific doses and dates, the context of the person's life should guide clinician judgment and patients should be adequately counselled on treatment options across the spectrum of care.
The following eligibility considerations are based on published primary literature and experience from existing clinical programs. However, these clinical programs were developed prior to the illicit drug supply in many parts of Canada being contaminated with highly potent synthetic opioids such as fentanyl and carfentanil. Given the high risk of fatal and non-fatal overdose for individuals using illicit opioids in markets where the drug supply has been contaminated, eligibility considerations should address the clinical context. The following eligibility considerations were compiled with the clinical determination, based on decades of clinical and research experience with OAT and iOAT, that pharmaceutical grade opioids prescribed under supervision with sterile injection supplies are safer than illicit opioids.
# PATIENT POPULATION AND ELIGIBILITY
# 3.2.i Eligibility Considerations
As individual situations vary, considerations for eligibility are presented below, with the recognition that individual patients may not meet all of the listed criteria, while other criteria not listed could make a compelling case for program admission. Prescribers f are advised to use these considerd In line with other clinical guidelines, this document primarily refers to recipients of iOAT as patients, however, where appropriate, other terms such as "individuals", "clients", and "service users" are used to reflect the collaborative and non-hierarchical relationship providers and service users should develop. When working with individuals, their preferred terminology should be sought and mirrored.
e For the sake of simplicity, both oral (methadone and slow-release oral morphine) and sublingual (buprenorphine/naloxone, trade name Suboxone) opioid agonist treatments are referred to as oral OAT in this document.
f This term denotes physicians and nurse practitioners authorized to prescribe iOAT.
ations to guide clinical judgment and collaborative decision-making in determining, with the individual, which treatments have the highest likelihood of ensuring the goals of care, which should include survival, reduction in the harms related to drug use, increased quality of life, and any other patient-defined goals based on their context and needs. It should be noted that these eligibility considerations were informed by inclusion and exclusion criteria in randomized trials and modified according to expert consensus.
# Minimum Required Criteria
The assessment and confirmation of these minimum criteria for iOAT are required:
• Confirmed and documented history of injection drug use with opioids and severe opioid use disorder (see DSM-5 criteria in Appendix 4); and
• Current opioid injection drug use confirmed by patient report, signs of injection drug use (e.g., fresh puncture wounds or "track" marks), and documented opioid-positive urine drug tests; and
• Capacity to consent to the treatment (see Capacity to Consent in this document for those under 18), including the ability to understand:
-Level of intensity of treatment -Alternate treatment options -Potential risks and side effects of iOAT -Requirements of inclusion in the program.
Additional eligibility considerations for injectable opioid agonist treatment for those who meet the minimum required criteria include:
• Ability to attend clinic or pharmacy or (where offered) receive home nurse visits up to three times daily; g g Some programs may provide more than three doses per day, such as in jurisdictions where high potency (≥50mg/mL) hydromorphone is not covered, to ensure that patients can receive their needed dose, whereas others may only provide twice-daily doses. Clinical experience in British Columbia has shown that many individuals do well on two doses per day.
• Able to self-administer (i.e., inject via intravenous, intramuscular, or subcutaneous route) medication under supervision or willing to learn, or depending on jurisdiction, model of care, and staffing model, willing to receive health care provider or peer injection (see Appendix 6 in this document for more information on health care provider administration of injectable medications);
• Previous experience with therapeutic dose of oral OAT (per CRISM's National Guideline for the Clinical Management of Opioid Use Disorder) while continuing to experience significant health and social consequences related to their OUD and continued regular injection opioid use, previous attempts at oral OAT without being able to achieve a therapeutic dose, or other circumstances and risks that indicate the individual may benefit from iOAT; and
• Significant risk of medical consequences of injection opioid use that would likely benefit from increased health system involvement and engagement in care, or existing significant medical and/ or psychiatric comorbidities (e.g., HIV-positive and antiretroviral non-adherence, acute hepatitis, cardiopulmonary disease, severe mental health disorders, history of multiple overdoses).
In addition to the above considerations, the iOAT prescriber, with their patient's consent, should consult members of that person's extended care network (e.g., addiction counsellor, outreach worker, supervised consumption site staff, mental health worker) in order to gain a robust understanding of each patient's individual circumstances. For example, an outreach worker may have important information about the health needs of an individual, such as the circumstances of a recent overdose event.
Those same health and service providers should, in partnership with the patient, formulate biopsychosocial treatment goals in the same manner as for oral OAT. Prior to admission, individuals identified as likely to benefit from iOAT should go through an admission process that involves full informed consent and a recommended peer orientation to ensure program regulations, time commitments, and other requirements are fully understood.
The appropriateness of iOAT should be determined by the patient in concert with their primary care provider and the iOAT prescriber (if different from their primary care provider). As such, the decision of starting treatment with iOAT relies not simply on a list of criteria, but on the prescriber-patient relationship, patient experience, input from the patient's network of care providers (who may have relevant information, for example, knowledge of overdoses), and clinical judgement. Clinical judgment and patient preference should balance the benefits and risks of iOAT (which include risk of overdose, seizure, and soft tissue infection) as well as the potential patient burden of up to three visits per day. If the patient is currently receiving oral OAT, the iOAT prescriber should consult with the oral OAT prescriber as part of the assessment process. Additionally, a two-prescriber review for iOAT eligibility may be considered where feasible, and is especially recommended in situations where an individual has not previously been trialed at least once on appropriately dosed oral OAT. While the above criteria are not exhaustive, they reflect current best practices in multiple jurisdictions for determining iOAT eligibility.
# 3.2.ii Precautions and Cautions
# Eligibility Precautions
Caution should be exercised when prescribing iOAT in:
• Youth (under 25 years; see Youth in this document) and older adults, h in whom oral OAT or other forms of treatment may be more appropriate.
• Pregnant people or people who become pregnant while receiving iOAT (see Pregnancy in this document).
• Individuals with active moderate or severe alcohol use disorder, due to increased overdose risk.
Patients should be treated concurrently for both OUD and alcohol use disorder.
• Individuals with active moderate or severe benzodiazepine use disorder and those prescribed benzodiazepines or z-drugs (e.g., zopiclone, zolpidem). While not necessarily an absolute contraindication, given that concurrent use of benzodiazepines and opioids increases the risk of respiratory depression, overdose, and death, [17][18][19] caution is warranted. Completing a benzodiazepine taper prior to initiation of iOAT is recommended as the preferred approach. i
• Individuals with chronic medical conditions such as respiratory, hepatic or renal disease, acute conditions, or a history of recent head injury.
• Individuals with renal failure. There is evidence indicating that the hydromorphone-3-glucoronide metabolite accumulates in renal failure. 21 Hydromorphone should be used carefully in this setting, although hydromorphone has been used in renal failure patients with no adverse effects. Nephrology consultation is recommended in patients with:
-GFR < 45 -Urine ACR > 30mg/mmol -Acute kidney injury in absence of readily reversible cause.
h Rather than a specific age range for older adults, determinations should be made based on function, frailty, and specific needs (e.g., living independently, needing extra support, or residing in long-term care facilities). Frailty can be assessed using the Clinical Frailty Scale. 16 In addition, forthcoming guidelines on treating opioid use disorder in seniors should be consulted when appropriate.
i In line with a recent report from the FDA in the US encouraging prescribers to provide OAT for people with OUD even in the context of active benzodiazepine use due to the high risk of overdose from untreated or undertreated opioid use disorder, 20 and in the absence of data regarding risks associated with iOAT and benzodiazepine use, concurrent benzodiazepine use disorder is considered a strong precaution but one that may be handled in more intensive models of care and according to clinical judgment. In those cases, a concurrent benzodiazepine taper should be initiated with iOAT treatment.
• The risk of opioid toxicity inherent in using short-acting medication as is prescribed in iOAT should be individually considered in each case.
# General Cautions for Treatment
• Long-term opioid use, including both illicit opioid use and opioid agonist treatment, may lead to abnormalities in the endocrine system, mainly affecting the gonadal axis and leading to hypogonadism. 22,23 In line with this, low testosterone levels and erectile dysfunction have been associated with long-term opioid use (including oral OAT) in males 24 and menstrual disturbances in females. 22 Osteoporosis and reduced bone mineral density can also result from hypogonadism. Clinicians should discuss the potential hormonal changes from chronic opioid use before initiating iOAT and should monitor for its impacts as part of routine care.
• Prescribers should carefully consult the pharmacist associated with their iOAT program regarding drug-drug interactions, j including psychotropic medications with sedative effects (e.g., gabapentinoids, 25,26 antipsychotics).
• Individuals with coagulation disorders should be preferentially prescribed oral OAT, due to potential increased risk of bleeding or venous clotting following injection.
# 3.2.iii Hospitalization
Individuals on iOAT may have comorbidities which put them at increased risk for hospitalization, whether for acute or chronic health conditions. Hospitalization, whether for an acute event or longerterm, should not be understood as an absolute contraindication for iOAT eligibility. Injectable opioid agonist treatment inductions (see Medication Induction) can be performed in a hospital setting with adequate hospital policies and procedures in place. When hospital inductions are performed, the patient should be clinically stable and a physician with expertise in iOAT should assess the patient in hospital. Individuals with existing injection-related infection should be considered medically stable prior to iOAT initiation (e.g., not admitted to ICU, already on appropriate antibiotic therapy, stable vital signs, afebrile) and should receive closer supervision and education around sterile injection techniques. In addition, hospital-based inductions must be done in coordination with an outpatient prescriber and/or program who agrees to receive the patient into care following discharge. See Hospitalization and Acute Pain Events in this document for more information on treating patients on iOAT in hospital.
j Prescribers may also consult the Canadian Pharmacists Association's RxTx tool, available as a subscription both online and in a mobile app, or other subscription-based drug interaction tools.
# 3.2.iv Youth
The research to date on iOAT has not included participants younger than 18 years old (19 in British Columbia). Thus, the research evidence presented here has been extrapolated from studies conducted in adult populations, with the recognition that prescribers may encounter adolescent (aged 12-17 years) and young adult (aged 18-25 years) populations with severe OUD who do meet some or all of the considerations for eligibility for iOAT in their practice. While it is outside the scope of this guideline to make specific recommendations for the treatment of adolescents and young adults, physicians and nurse practitioners should use all available information and their best judgment when considering treatment options for any individual who is at high risk of overdose death, including use of available and evidence-based pharmacotherapy where indicated and appropriate and with the support of appropriate agencies such as local health authorities, youth-oriented programs, and the ministry charged with the protection of children in each province. Treatment decisions for youth (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) should be made by or with consultation from health care professionals with experience in treatment of adolescents and young adults with substance use disorders. If administration of pharmacotherapy to this population is beyond scope of practice, expertise, or experience, care providers should refer such patients to a health care professional with experience in treatment of adolescents and young adults with substance use disorders. For additional guidance in treating youth with opioid use disorder, see the BC Centre on Substance Use's Treatment of Opioid Use Disorder for Youth-Guideline Supplement.
# Capacity to Consent
As with any treatment, youth under the legal age of majority in Canada do not necessarily need parental consent in order to receive treatment. Capacity to consent for these youth is determined based on the capacity to fully understand the treatment and possible consequences of treatment, except in Quebec, where the age of consent is 14 years and older, 27 and New Brunswick, where the age of consent is 16 unless two medical practitioners are in agreement that the individual is capable of consenting and that the medical procedure in question is in the patient's best interest. 28 A patient under the legal age of majority seeking treatment who is determined able to understand the treatment and give consent should not require parental permission or notification. Informed consent and discussion of rationale for treatment should be documented, and the limits of confidentiality should be discussed (for example, duty to report). For more information on determining capacity to provide consent in those under the age of majority, refer to guidance from the Canadian Medical Protective Association 27 and Royal College of Physicians and Surgeons of Canada. 28
# Youth-Centered Environment and Approach
Several studies have found that youth (adolescents and young adults) experience the adult-oriented environment of most treatment services as a barrier to accessing and continuing treatment. [29][30][31] It should be noted, however, that the evidence base is for substance use disorder treatment more generally, and oral OAT where specified, rather than iOAT. Injectable opioid agonist treatment programs serving youth should ensure that they are relevant, engaging, and accessible in order to engage patients in care. 31 While, generally, the elements that improve retention in adults also apply to youth (e.g., staff who are well-trained, clear policies, and low staff turnover), 32 several youth-specific factors have been identified. These include confidentiality of services, 33 inclusion of family members, the opportunity to develop close relationships with staff, use of pharmacological treatments when appropriate, a combination of pharmacological treatments and psychosocial treatment interventions and supports, and ensuring treatment is provided without a pre-determined end date. 29 Youth receiving opioid agonist treatment in the United States identified several factors that impact youth engagement in treatment, including a reluctance to access treatment in locations populated by older patients who appeared to have more experience with substance use, as well as the relatability of language and environment. 29 Inclusion of peer navigators and peer support may also support a youth-centered approach, for example, by helping youth who may be ambivalent about receiving care from adult professionals who have not experienced OUD feel more comfortable accessing treatment. Peer support staff, with their own lived experience of OUD, can offer hope, model problem-solving skills, and offer an example of the benefits of participating in OUD treatment. 34 Where feasible, OAT programs for youth may include iOAT provision. Where youth-specific programs are not feasible, considering the age range of clients and staff when referring youth may prove beneficial for patient retention and the success of the treatment. This consideration should be extended to pharmacy services for youth receiving OAT.
# 3.2.v Pregnancy and People of Child-Bearing Capacity
To date, published evidence on the feasibility and safety of iOAT during pregnancy is limited to two European case reports, both of which attribute positive pregnancy outcomes to the continuation of treatment with diacetylmorphine in the case of women with severe opioid use disorder and multiple comorbidities. 35,36 In view of the paucity of evidence supporting the safety of iOAT for this population, oral treatment options should always be offered before contemplating the initiation or continuation of iOAT. For transition from iOAT to oral OAT, methadone or slow-release oral morphine may be preferable to buprenorphine/naloxone as it does not require a period of opioid abstinence prior to induction.
However, the potential harms of initiating iOAT should be weighed against the considerable risk of morbidity and mortality associated with untreated opioid use disorder in the case of individuals with severe opioid use disorder who have been unable to stabilize with other options. Similarly, for individuals who are stable on iOAT prior to pregnancy, the likelihood of relapse to non-medical opioid use and associated harms should be carefully assessed when considering treatment de-intensification. In addition to the published case reports, there have been a small number of cases of successful iOAT continuation through pregnancy provided by services across Europe (M. Vogel, MD, Written communication, November 22, 2017). Decisions concerning the initiation and continuation of iOAT should be made with caution and in consultation with an addiction specialist. The patient's informed consent should be obtained and documented prior to initiating this treatment.
All patients of childbearing capacity starting iOAT should be offered screening for pregnancy at intake, with contraceptive counselling and prescriptions offered as appropriate, and ongoing sexual health and pregnancy planning provided (as is standard in primary care). This is in consideration of the fact that the majority of pregnancies among individuals with substance use disorders are unplanned. 37 In addition, pregnant individuals with substance use disorders may present for prenatal care relatively late in their term due to various social and personal barriers such as fear of losing custody of their children. Family planning services and treatment should also be offered to patients who are currently pregnant in order to reduce the likelihood of a subsequent unplanned pregnancy as short intervals between pregnancies may disrupt ongoing treatment and amplify potential risks to recovery and long-term health. 37
# PRESCRIBING INJECTABLE MEDICATIONS
# 3.3.i Initial Considerations
This document is intended to provide guidance on the clinical practice of iOAT provision. Detailed guidance regarding iOAT practice implementation is outside the scope of this document (see iOAT Operations Guidance); however, there are certain minimum requirements which must be considered and addressed at the outset. These include:
• Determining who may prescribe iOAT in each jurisdiction-this may include both physicians and nurse practitioners and will be determined by the appropriate authorities and regulatory bodies in each jurisdiction. See iOAT Operations Guidance.
• Appropriate prescriber training:
-Each jurisdiction will have its own expectations for training, as determined by ministries of health, regional health authorities, and/or regulatory colleges.
-At minimum, previous training and experience with both methadone-and buprenorphine/ naloxone-based oral OAT prescribing, completion of iOAT-specific training, and a preceptorship (which could be completed remotely through telehealth) are recommended.
-The BC Centre on Substance Use provides online training on iOAT prescribing through the Provincial Opioid Addiction Treatment Support Program.
• Clinical supervision with a consultant or team leader • Support of a local pharmacy for medication procurement
• Capacity to provide methadone and/or SROM along with iOAT
• Colocation of psychosocial services, primary care, other medical care (e.g., hepatitis C treatment, wound care, HIV/AIDS treatment), psychiatric care, or well-developed referral pathways
• Consultation on local regulatory framework for provision of hydromorphone and diacetylmorphine (see iOAT Operations Guidance)
• Patient orientation-goals of iOAT, policies and procedures, as well as patient rights and responsibilities should be included in patient orientation. This may include a checklist discussed between staff and patient, peer orientation, and/or other approaches.
k Toward the Heart has multiple resources on reducing stigma, including training modules and guidance on respectful language.
# 3.3.ii Medication Selection and Preparation
Both hydromorphone and diacetylmorphine can be considered a reasonable choice, however, selection of medication will be subject to availability of diacetylmorphine (see iOAT Operations Guidance for more information).
The SALOME trial, a non-inferiority trial, found that hydromorphone is non-inferior to diacetylmorphine. 13 However, while diacetylmorphine has significantly more evidence supporting its efficacy in treating OUD, it may pose an increased risk of adverse events (e.g., seizures, oversedation) compared to injectable hydromorphone. 13,38 See Appendix 11 for a table of serious side effects for both medications. For these reasons, either medication is a reasonable choice, based on availability, patient choice, and prescriber judgement. If the individual is not benefitting sufficiently or is experiencing unacceptable side effects, they should be given the option to transition to the other medication. See iOAT Operations Guidance for information on availability of diacetylmorphine.
# Preparing and Dispensing Hydromorphone
Hydromorphone may be prepared at point of care for immediate use or in advance if appropriate infrastructure and procedures are in place. Beyond use dating is dependent upon several factors, including equipment and infrastructure. Injectable opioid agonist treatment programs should refer to the National Association of Pharmacy Regulatory Authorities (NAPRA) sterile compounding standards 39 and bylaws of each province's regulatory body for pharmacies. Please see the relevant regulatory body's website for more information on bylaws. Health authorities should be involved in providing the service or contracting for pharmacy services within their area. The decision of which format is to be utilized will vary based on the number of individuals for whom the medication is needed in a particular setting as well as available infrastructure and resources. Advanced compounding is recommended, when possible, to prevent drug wastage and potential for diversion; however, the lack of an embedded pharmacy to provide this service should not preclude consideration of offering this treatment to patients who would benefit.
# Dispensing and Preparing Diacetylmorphine
Currently, diacetylmorphine is available in 100mL (100mg/mL) vials. In the future, as access to diacetylmorphine expands, and if a Canadian supplier is secured, diacetylmorphine may be prepared at point of care for immediate use or in advance if appropriate infrastructure and procedures are in place. Beyond use dating is dependent upon several factors, including equipment and infrastructure.
Injectable opioid agonist treatment programs should refer to the National Association of Pharmacy Regulatory Authorities (NAPRA) sterile compounding standards 39 and bylaws of each province's regulatory body for pharmacies. Please see the relevant regulatory body's website for more information on bylaws. Health authorities should be involved in providing this medication or contracting for pharmacy services within their area. It is important to note that the procurement mechanisms for access to diacetylmorphine are evolving rapidly, and while this document will be updated regularly, the CRISM website will provide the most up-to-date information.
# 3.3.iii Medication Provision
# Supervision of Injections
Service users self-administer under supervision of a qualified staff member. Any appropriately trained unregulated health care worker may supervise injection as long as a regulated health professional is also in the room and can attend to any issues that may arise. Training for staff members involves orientation to an existing supervised injection program, along with training on conducting pre-and post-injection assessments, responding to dose intolerances, and aftercare.
Supervision of self-administered injection involves completing a pre-injection assessment, direct observation of the injection and disposal of equipment, and a post-injection assessment (see following section for more information on pre-and post-injection assessments). Each visit, including pre-injection assessment, administration of medication, and post-injection assessment, takes between 30 and 45 minutes.
# Pre-and Post-Injection Assessment
The purpose of the pre-injection assessment, completed by a qualified health professional or other trained staff if supervised by a health professional (physician, nurse practitioner, nurse or pharmacist), is to ensure that the patient is not intoxicated, including by centrally-acting sedatives and/or stimulants, or in any other acute clinical condition that would increase the risk of an adverse event with the use of iOAT. Cautions could include intoxication due to the use of stimulants resulting in the participant being actively psychotic or agitated in a way that would pose an immediate safety risk to themselves, staff, or other service users. Appropriate actions in response to these cautions may include holding the dose, reducing the dose, and/or delaying the dose. Prior to iOAT initiation, preand post-dose injection assessment procedures should be discussed with the service user and agreed upon as a requirement of the program.
In line with appropriate local regulatory body and nursing standards, any qualified health professional or other trained staff supervised by a health professional can conduct the post-injection assessments; however, any doubts or uncertainties must be reported to a regulated health professional (e.g., physician, nurse practitioner, nurse, or pharmacist) who will complete the post-injection assessment.
Patients can leave the premises when they are deemed fit to do so after the minimum 15-minute observation period post-dose. l The post-injection assessment time period should be extended if any of the following are present and are not part of the patient's usual disposition: drowsiness, slow response, or slurring. The post-injection observation period may be an ideal time to engage service users in psychosocial services and other medical care, although some individuals may not wish to engage after receiving their dose.
Clinical experience shows that some individuals experience a histaminergic reaction (e.g. swelling, itching) after injecting hydromorphone or diacetylmorphine; this can be managed through dose adjustments and/or provision of oral diphenhydramine or other antihistamines.
The pre-and post-injection assessment protocols can be found in Appendix 5.
# Administration of Injectable Medications
It is recommended that patients have access to the iOAT program up to three times per day, however, some programs may provide additional doses per day when feasible and required. m Patients selfadminister their prepared dose under the supervision of a qualified health professional. Patients may inject intravenously, intramuscularly, or subcutaneously. For safety reasons and to promote sustainable injection processes, it is recommended that intravenous injection be encouraged only in the upper extremities (hands or arms, no jugular or femoral vein use permitted), while intramuscular injections can be allowed in deltoid, ventrogluteal, or dorsogluteal muscles. However, for individuals who cannot find appropriate sites in their upper extremities or who otherwise prefer intravenous injection in their legs, the risks of intravenous injection should be discussed and an informed decision may be made to inject in legs or feet. Subcutaneous injection or short-term transition to oral OAT is also an option for those patients who need to give their veins a rest to heal venous damage.
More guidance on operational considerations is covered in iOAT Operations Guidance, however, each program must ensure the necessary supplies for safe injection are available, including tourniquets, Steri-Wipes, and needles of various gauges. Patients should also receive education on safer injection practices. Vancouver Coastal Health, CATIE, and Here to Help all have useful patient-facing materials on safer injection.
Injection sites should be identified in consultation with a physician, nurse practitioner, Registered Nurse, Registered Psychiatric Nurse, Registered Practical Nurse, or pharmacist (in jurisdictions where pharmacists are permitted to administer medications intramuscularly) and rotated, with the total volume of medication for injection taken into consideration for the most appropriate site, according to l Each program should create a policy on post-dose observation periods, depending on the context and patient population, which prioritizes patient safety.
m See footnote g, p. 22.
established practice standards (i.e., a large volume should be injected into a large muscle). When clinically indicated and feasible given the particular model of care and jurisdiction (see iOAT Operations Guidance), a physician, nurse practitioner, Registered Nurse, Registered Psychiatric Nurse, Licensed or Registered Practical Nurse, or pharmacist (hereafter referred to as health care provider) can administer the medication intramuscularly or subcutaneously. Nurses with phlebotomy or IV insertion certification may be able to provide IV injection when requested by the patient and determined appropriate. See Appendix 6 for more information on health care provider administration of injectable medication.
It should be noted that route of administration may impact tolerance, and patients should be observed more closely when they switch route of administration (e.g., switching from IM to IV). Some clients may choose to inject some of their dose intravenously and then inject the rest intramuscularly. In these cases, the needle tip should be changed to accommodate each route of administration.
# 3.3.iv Medication Induction
# Selection of Dose
Due to high inter-individual variability, each individual's dose must be carefully determined. There are no fixed doses for optimal stable dosing of hydromorphone or diacetylmorphine for individuals with an opioid use disorder. The upward titration at the start of therapy should begin with a safe dose and follow the protocol outlined in Appendix 7.
Dose increases need to be tolerated in order to continue at that dose. Doses that are not tolerated, as per assessment during the pre-or post-injection assessment periods, should be reduced. Doses should be titrated to clinical effect (i.e., reduction or cessation of illicit opioid use and opioid cravings) and avoidance of side effects (e.g., sedation, narcotic bowel, opioid-induced hyperalgesia).
# Hydromorphone
Maximum hydromorphone dosages are based on a 2:1 potency ratio of hydromorphone to diacetylmorphine, which was observed in the SALOME study and is supported by clinical experience at Providence Health Care's Crosstown Clinic. 40 Maximum recommended daily doses of hydromorphone can be found in Table 1 below, however, clinical experience in British Columbia shows that there may be clinical exceptions for those who continue to experience cravings and/or withdrawal symptoms. These exceptions should be made according to clinical judgment, with the reason for the exception documented.
# Diacetylmorphine
Maximum diacetylmorphine dosages are based on the Swiss clinical studies and were adopted by all of the other settings. 40 Maximum recommended daily doses of diacetylmorphine can be found in Table 1 above, however, clinical experience in British Columbia shows that there may be clinical exceptions for those who continue to experience cravings and/or withdrawal symptoms. These exceptions should be made according to clinical judgment, with the reason for the exception documented.
# Titration Process
The initial adjustment of the medication dose should be done over a two-to five-day titration period.
A three-day titration period has been shown to be safe, 41 however, clinical practice may vary due to specific patient needs and operational considerations. At any time during the titration period, prescribers can lower a patient's dose or suggest a more gradual titration based on the patient's response and safety concerns. Doses must be titrated specifically for each individual in order to achieve a safe and effective dose for each person. A lower starting dose or a slower titration process can be followed, per the patient's medical history or clinical experience, under the direction of the prescribing physician or nurse practitioner. Patients, in consultation with and under the guidance of their prescriber, can adjust the dose and frequency of daily injection sessions (up to three). Such adjustments can be considered after a visit between the prescriber and the patient, review of the dose received history and, if appropriate, consulting with at least one nurse (or other health care provider) who has been directly involved in pre-and post-assessment and supervision of current dosing schedule for that patient. A recommended titration process can be found in Appendix 7.
# Co-Prescribed Oral Opioid Agonist Treatments
Oral OAT is frequently co-prescribed with iOAT in order to prevent withdrawal and cravings between iOAT doses, particularly overnight during the longest between-dose period, as the injectable medications are relatively short-acting. In this way, co-prescription of oral OAT helps provide greater clinical n See footnote g, p. 22.
stability. Another potential benefit of co-prescription of oral OAT may be the facilitation of transitions to oral OAT alone. Clinical trials have included co-prescribed methadone, however, SROM may also be considered. o Buprenorphine/naloxone is not an appropriate co-prescription; due to its high affinity for the opioid receptor, it preferentially binds to the receptor and displaces other opioids if they are present, which can cause precipitated withdrawal.
# Dosing Recommendations
Induction of co-prescribed methadone should follow the process outlined in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. Guidance on induction of SROM can be found in the BCCSU's A Guideline for the Clinical Management of Opioid Use Disorder. Oral OAT may be started in advance if practical matters require waiting to start iOAT, at the same time as iOAT induction, or after a patient has been titrated onto iOAT.
Co-prescribed oral OAT doses can be given at any time of day. However, it is recommended that SROM be given at a similar time each day to avoid withdrawal, as the preparation is slow-release over 24 hours only, so the effect will not extend beyond 24 hours. Generally, supplemental oral OAT doses should be witnessed, however, prescribers may follow CRISM's National Guideline for the Clinical Management of Opioid Use Disorder's guidance on take-home dosing or provincial standards, when appropriate.
Because of prior experiences receiving only oral OAT with insufficient reduction of cravings and withdrawal symptoms, some individuals may prefer to try iOAT with no co-prescribed oral OAT, on the assumption that oral OAT does not benefit them. Some patients will find a sufficient reduction in cravings and withdrawal symptoms from iOAT alone. For those who are continuing to experience cravings, withdrawal symptoms, or other negative symptoms like disrupted sleep, consider recommending co-prescription of oral OAT to aid their sleep and help provide a baseline level of physical comfort and well-being.
# Stable Range of Co-Prescribed Oral Opioid Agonist Treatments
Similar to iOAT doses, co-prescribed oral OAT doses must be determined individually for each patient and will depend, in part, on the patient's goals and circumstances. Doses should be titrated to a dose where there are no withdrawal symptoms between iOAT doses, but may be titrated further in accordance with CRISM's National Guideline for the Clinical Management of Opioid Use Disorder or provincial standards.
o See Appendix 10 for more information on SROM and iOAT including co-prescription and transition from iOAT to SROM. See CRISM's National Guideline for the Clinical Management of Opioid Use Disorder for a review of evidence supporting the use of slow-release oral morphine more broadly for opioid use disorder.
# MEDICATION STABILIZATION
# 3.4.i Stable Dose Ranges
Stable doses must be determined individually for each patient and will depend, in part, on the patient's goals and circumstances. A therapeutic dose range has not been established with iOAT, and it is not possible to predict the dose an individual will need based on their history of illicit drug use or previous OAT dosing. Doses should be titrated to a dose where there are no withdrawal symptoms between iOAT doses. While stable doses must be individually determined, mean daily doses from randomized controlled trials on iOAT may be instructive (diacetylmorphine: 443mg; 11 hydromorphone: 244mg 11,13 ).
Some patients may wish to further adjust their dose as they achieve psychosocial stabilization and integrate new activities into their lives, for example, once they start working or re-connect with family.
In addition to overall wellbeing and a lack of cravings, sleep quality and duration may also indicate when the right dose for a patient has been reached.
For patients wishing to increase their dose, it is recommended that each dose be increased by 10mg (to a maximum of 30mg per day) for hydromorphone and 20mg (to a maximum of 60mg per day) for diacetylmorphine, as long as each dose increase is well tolerated, until their symptoms resolve and they are comfortable, or they reach the recommended dose maximums (200mg/dose and 500mg/ day for hydromorphone; 400mg/dose and 1000mg/day for diacetylmorphine).
# 3.4.ii Missed Doses
All iOAT programs should have a missed dose protocol in place which lowers the dose immediately and requires re-titration. When considering the most appropriate missed dose schedule, clinicians should consider opioid tolerance and prioritize safety, with more conservative re-titration approaches used when doses have been missed and tolerance is expected to have been lowered (for example, a patient who has been in a custodial setting without continued illicit opioid use or access to oral OAT).
The following missed dose protocol is based on expert consensus and may be modified based on clinical judgment and considerations about safety and tolerance.
• If a new, not-yet stabilized patient misses 3 consecutive doses or 1 day (whichever is first), they should restart the titration process following the titration protocol in Appendix 7.
• If a stabilized patient misses 6 consecutive doses or 2 days (whichever is first), their reason for missing doses should be discussed, their best estimate of the amount and frequency of illicit opioid use should be recorded and, according to clinical judgment, they may receive their usual or a reduced dose provided they meet the pre-dose assessment requirements. See Appendix 8 for an example dose reduction protocol.
• If a stabilized patient misses 9 consecutive doses or 3 days (whichever is first), their reason for missed doses should be discussed, and they should be re-titrated entirely following the titration protocol in Appendix 7.
Unlike the long-acting oral OAT formulations, iOAT medications are short-acting. As such, toxicity effects are more likely to emerge shortly after dose administration, allowing them to be quickly identified within the post-dose observation period in a clinical setting. This may allow for necessary dose adjustments to be made prior to each subsequent dose during the re-titration period to ensure tolerability.
If a client misses a dose or a day, a staff member should follow up with them to ensure their safety and support them in continuing treatment and address any barriers that are interfering with their adherence to treatment. If the client chooses to reduce the frequency with which they receive doses, it should be documented in their chart. In the event that a dose is held due to intoxication found in the pre-dose assessment, it should be considered a missed dose.
The missed dose protocol should be discussed with the patient prior to initiation and agreed to as a requirement of the program.
# CONTINUING CARE
As with any chronic condition, individuals on iOAT should receive comprehensive and continuing care. This should include ongoing review and assessment of adequacy of dosage, side effects, drugdrug interactions, patient goals, physical and mental health, and psychosocial domains including housing, relationships, and finances. Both daily program visits and prescriber appointments can be used for building therapeutic relationships, providing education about harm reduction and safe injection practices, offering supports and referrals to appropriate services, and promoting health and healthy behaviours.
Urine drug testing (UDT) can be used to help guide patient care, to ensure patients are aware of which substances they are ingesting if using illicit substances, and to start a conversation on harm reduction and safety. Unlike with oral OAT, where regular and random UDT are considered standard of care, regular and mandatory call-back UDT are not considered standard care for iOAT, due to both the low risk of diversion and the high frequency of contact with care providers. See Appendix 12 for more information on UDT.
# TREATMENT TRANSITIONS
This document recommends that iOAT should be provided as an open-ended treatment, given two post-randomized controlled trial observational studies that have found a loss of treatment benefit when prescription diacetylmorphine treatment was discontinued at a predetermined end date (see Appendix 3). 42,43 This document also recommends the use of a stepped and integrated continuum of care model for treatment of OUD, where treatment intensity is continually adjusted to match individual patient needs and circumstances over time and recognizes that many individuals may benefit from the ability to move between treatments. This includes intensification (e.g., initiating iOAT when oral OAT approaches have not been met with success) as well as routine strategies to de-intensify treatment (e.g., transitioning from iOAT to oral OAT) when patients achieve successful outcomes and wish to transition to lower intensity treatments. It is further recommended that iOAT prescribers support appropriate movement along the continuum of care for patients by being comfortable with prescribing both iOAT and all forms of OAT and routinely discussing treatment goals with patients (and families, when appropriate), including plans for medically supported transition to oral OAT. Discussion of de-intensification of treatment should not involve pressuring patients into moving to other treatment options, but rather outline treatment options and their potential risks and benefits.
As individuals stabilize, they may be ready to move to lower intensity treatments (including oral OAT) or move from an acute care setting to a community-or pharmacy-based iOAT program (see Models of Care in iOAT Operations Guidance). Any decisions to de-intensify care from iOAT to oral OAT should be made between patient (and their family, if included in their care), iOAT prescriber, and any other relevant health care providers. This decision should be made with the understanding that treatment modalities across the continuum of care for OUD that were previously insufficient may be appropriate and effective at different times in a person's life, depending upon health and general life circumstances.
Patients should not have their treatment discontinued without consent. If, for example, a patient's prescriber retires or moves, the patient should have the choice to be transferred to another iOAT prescriber, be slowly titrated off of iOAT, or transitioned to oral OAT.
As with intensification of treatment, de-intensification of treatment should not be understood as necessarily a permanent change. If a patient is not benefitting sufficiently from oral OAT, they should be offered the opportunity to immediately reinitiate iOAT. Patients should have the opportunity to trial transitioning to oral OAT and to transition from iOAT to oral OAT and back as many times as necessary in order to maintain their safety and meet their needs and goals.
More information on strategies for de-intensifying treatment can be found in Appendix 10.
# 3.6.i Dosage Equivalence with Oral Methadone and Slow-Release Oral Morphine
In order to maintain an average degree of saturation of the opiate receptors by opioids to prevent withdrawal symptoms and avoid over-dosage, for those receiving a daily supplemental dose of oral methadone or SROM, it is critical to establish a conversion factor for switching between methadone or SROM and hydromorphone or diacetylmorphine.
The opioid bioavailability of the individual pharmaceutical agents must be considered when converting dosages. A 100% bioavailability of injectable medication is assumed, irrespective of whether it is administered intravenously, subcutaneously, or intramuscularly. The calculation is always based on the intended effective opioid dose.
The conversion should be based on doses received, not prescribed. See the conversion table in Appendix 9.
# 3.6.ii Hospitalization and Acute Pain Events
Individuals on iOAT may have comorbidities which put them at increased risk for hospitalization, whether for acute or chronic physical or mental health conditions. For example, in the North American Opiate Medication Initiative (NAOMI) trial, 53.4% of participants had a chronic medical problem, 62.9% were hepatitis C positive, and 9.6% were HIV positive. 14 For this reason, planning for management of hospitalization and/or acute pain events must be included when initiating community-based treatment.
The following components are recommended in order to support continuity of care:
• Protocol in place for acute care prescribers and addiction medicine consult services to contact the community prescriber;
• Protocol in place for the community prescriber to contact the in-hospital most responsible provider (MRP) to inform them that the patient is on iOAT and, thus, will have a high opioid tolerance; p p Provincial electronic medical records or prescription monitoring programs are ideal, however, in jurisdictions lacking these systems, programs should provide patients with documents (for example, a wallet card) that can be given to acute care providers.
• Protocol in place for community prescriber to contact addiction medicine consult team (AMCT) in hospitals where these services exist. In the absence of these services, the community provider should be consulted to support in-patient care.
• Protocol in place for the hospital team providing care to access date and size of last dose received by patient (for example, uploaded to provincial electronic health record or prescription monitoring program, where possible); and
• Contact information for all iOAT programs, including ability to contact program outside of program hours. Program contact information, including on-call phone number should be included in provincial electronic health record or prescription monitoring program, where possible.
Patients experiencing acute pain events will likely require non-opioid analgesics as well as additional opioids to manage acute pain. Like with oral OAT, the baseline opioid dose will not address acute pain; patients will require higher and more frequent opioid dosing if they have an acute pain event.
In addition, when continued in hospital, the iOAT dose may need to be adjusted due to the medications being prescribed for management of acute pain.
In hospital settings where appropriate protocols and procedures are in place, iOAT may be continued (with self-administration or nurse-provided IM or subcutaneous doses). Expert consultation is important for these patients, as doses may need to increase (e.g. acute pain) or decrease (e.g., acute illness leading to an inability to tolerate regular outpatient dose). In hospital settings where iOAT is not feasible or available, alternative oral opioids (for example, oral hydromorphone or SROM) should be provided, with expert consultation to ensure adequate dose and tolerability is instituted.
# 3.6.iii Considerations for Transitioning Off of iOAT
Once they have reached stability, some individuals may request to transition to an alternative treatment.
In other situations, the care team may identify one or more of the following signs that transitioning to oral OAT may be appropriate or necessary and should be discussed with the patient:
• Patient request to transition to less intensive treatment;
• Patient not attending for all doses (Note: this may indicate a need for adjustment of the treatment schedule or dose);
• After an adequate trial of iOAT, patients not deriving benefit from treatment (e.g., escalating substance use-including non-opioid substances, repeated episodes of toxicity despite dose adjustments, no reduction in illicit opioid use or related harms);
• Any situation that jeopardizes staff or other patient safety or security and cannot be resolved through other means;
• Cognitive and/or physical health decline resulting in inability to consent to treatment or selfadminister medication; or
• New or evolving physical health conditions that exclude use of high-dose opioid treatment or could be worsened by high-dose opioid treatment (e.g., severe respiratory disease requiring long-term oxygen, renal failure, hepatic failure).
Whenever possible, the decision to transition off of iOAT should be made collaboratively with the patient, with an understanding that the benefits of iOAT may vary between patients and should be based, in part, on patient goals. Examples of benefits include reduced illicit substance use, increased stability, fewer overdoses, less money spent on drugs, and less criminal involvement. If a patient has been stable and meeting their goals on iOAT, they should be offered the opportunity to transition to oral OAT in a non-coercive manner that respects the long-term goals of the patient, which, for some individuals, may include an opioid-free life. Treatment decisions should be made collaboratively and be guided by patient goals, needs, and safety.
# 3.6.iv Short-term Transition to Oral Treatment for Travel
If individuals receiving iOAT need to travel, they may receive prescriptions for methadone or SROM. Generally, for a single-day trip, patients would be provided with a prescription for witnessed ingestion of SROM, due to its superior safety profile compared to methadone. 44 For longer absences, daily witnessed ingestion of SROM at a community pharmacy is recommended. Conversely, a slow transition (over 7 to 14 days) to methadone is possible. If the pharmacy is located outside of the patient's province of residence, the prescriber should call the pharmacy to ensure daily witnessed ingestion of SROM or methadone is possible. Note: Prescriptions filled outside of the province of residence may not be reimbursed by the patient's provincial drug plan.
For conversions to oral OAT for travel, because of the potential variability in bioequivalency when switching opioids, standard opioid conversions should be used in concert with clinical judgment. All SROM doses should be witnessed ingestion at the dispensing pharmacy. Any missed doses should be reported to the prescriber. See Appendix 9 for more details on conversion.
# 3.6.v Transition to Oral Treatment Due to Incarceration
Incarceration should not result in inadequate treatment for OUD, and best efforts should be made to provide the best standard of care for OUD regardless of setting. However, at this point in time, iOAT is not provided to individuals in correctional facilities in Canada. It should be noted, however, that there are two prison-based iOAT programs currently in operation in Switzerland. 45 In addition, a 2018 case study reported on the successful integration of iOAT into a drug court treatment program in Vancouver, BC, with positive health and social outcomes reported for the individual. 46 Patients who have been convicted of a crime and face a period of incarceration must be transitioned to a suitable oral OAT option prior to, or as quickly as possible following, their entry into the correctional system. Detailed recommendations for managing this transition can be found in Appendix 10 of this document.
When an individual receiving iOAT enters a correctional facility, the treatment plan should include the following components:
• Protocol in place for MRP in correctional facility to contact the community prescriber;
• Protocol in place for community prescriber to contact MRP in correctional facility to inform them that patient is on iOAT and, thus, will have a high opioid tolerance; q
• Protocol in place for community prescriber to communicate and make recommendations for management should a patient be subjected to a custodial environment while on iOAT;
• Protocol in place for the care team in the correctional setting providing care to access date and size of last dose received by patient (for example, uploaded to provincial electronic health record or prescription monitoring program, where possible); and
• Contact information for all iOAT programs, including ability to contact program outside of program hours. Program contact information, including on-call phone number should be included in provincial electronic health record or prescription monitoring program, where possible.
# 3.6.vi Continuity of Care
Regardless of which decisions are made regarding transition from iOAT to oral OAT, individuals should have continued access to the ancillary services offered as part of the iOAT program (for example, social workers, housing workers, psychosocial supports) to ensure that continuity is maintained and patients continue to receive a high quality of care.
# ONGOING SUBSTANCE USE
Ongoing substance use while on iOAT may be an indication to intensify treatment, which may include dose increases, transferring to a more intensive model of care, or increasing psychosocial and other q Provincial electronic medical records or prescription monitoring programs are ideal, however, in jurisdictions lacking these systems, programs should provide patients with documents (for example, a wallet card) that can be given to corrections staff.
supports. If a patient is found to be intoxicated during the pre-assessment, their dose should be postponed or withheld to ensure safety (see Appendix 5). Repeated findings of intoxication in the pre-assessment should be discussed with the patient and should be addressed in a substance-specific manner as outlined below. As described in Harm Reduction-Oriented Care, patients should be advised of the risk of overdose due to contamination of the illicit drug supply with fentanyl and other highly potent synthetic opioids (including non-opioid substances such as benzodiazepines and stimulants), receive education and, where possible, access to a variety of harm reduction strategies, including takehome naloxone, drug-checking facilities, and fentanyl test strips. It should be noted, however, that drug-checking and fentanyl test strips are not well validated and are not available in all jurisdictions.
# 3.7.i Non-prescribed Opioids
Continued use of illicit (non-prescribed) opioids, ascertained by self-report or urine drug test (see Urine Drug Testing in this document), while on iOAT should be considered an indication to discuss intensification of treatment. Ongoing use at the same intensity as pre-iOAT should be understood as an indication to intensify treatment, however, illicit opioid use in and of itself should not be considered an absolute indication. Some individuals' goals may not include absolute cessation of illicit opioid use.
In those cases, harm reduction and overdose prevention should be discussed and reinforced. In situations where intensification of treatment is indicated, clinical judgment should be used in determining what intensification is appropriate. Intensification of treatment may include adding a daily dose of oral OAT (i.e., SROM or methadone), increasing an existing evening dose of oral OAT, increasing the iOAT dose, transferring to a more intensive model of care (for example, moving from a community health clinic to a comprehensive and dedicated iOAT model), or increasing evidence-based psychosocial treatment interventions and supports. If a patient is continuing to use illicit opioids at the same intensity despite intensification of treatment, clinical judgment should be used to determine appropriate follow up. Reduction from daily illicit injection opioid use may be considered a significant treatment benefit in many cases, however, if the patient is continuing to use illicit opioids or continuing to inject other substances and receiving no benefits from iOAT after intensification and optimization of treatment, treatment cessation may be considered. When considering transition to another treatment approach such as oral OAT, continuity of ancillary services (e.g., mental health care, trauma therapy, primary care) should be ensured. Treatment decisions should be made with the recognition that connection to health care and community are important outcomes of treatment engagement and access to services, and that patients may experience significant benefits from engagement in care, including maintaining housing, connection with family and friends, and decreased crime.
# 3.7.ii Stimulants
If patients are using stimulants (e.g., cocaine or methamphetamine) while receiving iOAT, the risks and benefits of iOAT should be evaluated to ensure that the person is benefiting from the treatment. Injectable opioid agonist treatment is not a treatment for stimulant use disorder and withholding of doses should be based on patient safety, not used to penalize stimulant use. Clinical judgment should be used in determining if intensification of treatment is appropriate. Intensification of treatment may include increasing psychosocial and other supports, such as implementing contingency management. 47 Preliminary evidence from a single-centre RCT in a European HAT program suggests sustained-release dexamphetamine may be effective for concurrent treatment-refractory cocaine use in iOAT patients, however, more research is needed. 48
# 3.7.iii Sedatives (Alcohol and Benzodiazepines)
Ongoing sedative use may indicate a need to intensify treatment. However, due to the additive effect on respiratory depression of both benzodiazepines and alcohol, patients using alcohol and/ or benzodiazepines may require a more intensive model of care to ensure adequate management of the co-occurring substance use and patient safety (see iOAT Operations Guidance). Clinical judgment should be used to determine which interventions are appropriate for each patient.
# Alcohol
Individuals who present for their iOAT dose intoxicated on alcohol should have their dose withheld due to the increased risk for respiratory depression and overdose. These individuals should be screened for alcohol use disorder and brief intervention should be performed. Clinician-delivered brief intervention, including motivational interviewing, has been shown to reduce alcohol consumption in individuals receiving OAT to treat OUD who had problematic alcohol use but did not meet diagnostic criteria for concurrent alcohol use disorder, however, this was specifically in individuals receiving methadone-based OAT. [49][50][51] Due to the high risk of respiratory depression, patients who continue to present for their iOAT dose intoxicated on alcohol should be started on a medication for relapse prevention and agree to ongoing breathalyzer testing before each dose, with doses postponed or withheld if the patient's blood alcohol level exceeds 0.05%. Acamprosate has an established evidence base for safety and efficacy for the treatment of alcohol use disorder. [52][53][54][55][56] For individuals receiving iOAT, acamprosate should be considered along with evidence-based psychosocial treatment interventions and supports for treating concurrent alcohol use disorder, 52,53 and may be dispensed on site. In jurisdictions where acamprosate is not covered by provincial drug plans, an addiction medicine expert should be consulted to discuss other medication options (e.g., topiramate, gabapentin, disulfiram). Due to its effects on opioid receptors, oral naltrexone cannot be used to treat alcohol use disorder in patients who are on opioid agonist treatment.
Although gabapentin has a growing evidence base supporting its use for withdrawal management [57][58][59][60] and preliminary evidence supporting its use in relapse prevention for alcohol use disorder, [61][62][63] there are specific concerns for individuals with opioid use disorder. This includes the possibility of high doses of gabapentin being combined with opioids to potentiate euphoric effects and the additive effects on respiratory suppression, which can increase risk of overdose. 25 A 2017 Canadian study found that concomitant use of opioid medications and gabapentin increased the risk of fatal overdose by 49%, with moderate and high daily doses increasing fatal opioid overdose risk by 60% compared to those with no concomitant gabapentin use. 26
# Benzodiazepines
Given the known severe risks associated with concomitant use of opioids and benzodiazepines, [17][18][19] patients with OUD who were using benzodiazepines and illicit (non-medical and/or illegal) opioids concurrently should, ideally, have completed a benzodiazepine taper prior to iOAT initiation. Management of concurrent benzodiazepine use will depend on clinical judgment and model of care, with patient safety prioritized. Prescribers are encouraged to engage a second opinion as needed.
Patients who begin using benzodiazepines while receiving iOAT should have the risks of concurrent use discussed with them and initiate a benzodiazepine taper. An increase in treatment intensity, including a more intensive model of care, or increasing evidence-based psychosocial treatment interventions and supports may be required.
# 3.7.iv Tobacco
Mortality in smokers is almost three times higher than in non-smokers, 64 and is causally linked to significant morbidity including pulmonary disease, coronary heart disease, chronic obstructive pulmonary disease, diabetes mellitus, and multiple cancers including lung, esophageal, and stomach. 65 A 2018 population-based study found that 39% of deaths in individuals with opioid use disorder were due to smoking-related conditions. 66 Disproportionately high rates of tobacco use have been found in individuals receiving treatment for opioid use disorder compared to general population prevalence rates. [67][68][69][70] Looking specifically at individuals receiving iOAT, 94% of participants in the SALOME trial reported tobacco smoking at baseline, with a similar percentage reporting smoking at 6 months. 71 Although tobacco use disorder is commonly undertreated in addictions treatment, 72 a 2016 Cochrane systematic review found a consistent association between tobacco cessation interventions-both pharmacotherapy and counselling combined with pharmacotherapy-and tobacco abstinence in individuals in treatment and recovery for substance use disorders, with no evidence showing an effect on abstinence from alcohol and other drugs. 73 Despite common assumptions to the contrary, 44-80% of individuals receiving substance use disorder treatment are interested in tobacco cessation. 74 Evidence-based treatments for tobacco use disorder, including nicotine replacement therapy, varenicline, and bupropion, should be integrated into iOAT care and delivered onsite when possible.
# 3.7.v Cannabis
Ongoing cannabis use is not an indication to discontinue iOAT. Patients who are using cannabis recreationally may benefit from a discussion of the recommendations made in the Lower-Risk Cannabis Use Guidelines. 75 Patients who are using medical cannabis should be monitored by their iOAT prescriber to ensure the benefits they receive outweigh the potential harms.
# FAMILY AND SOCIAL CIRCLE INVOLVEMENT IN CARE
This document emphasizes the important role of families-as defined by patients, which may include romantic partners, close friends, and other people of significance who may or may not be legally recognized as family-as partners in patient care when appropriate, and recommends the inclusion of family members in decision-making processes and care at all levels when deemed appropriate by the adult patient and their care team. Patients should not be pressured to include family members and should be given full discretion on the decision to include family, if at all. Family members wanting support should be referred to external services and supports, to avoid overlap of service providers, which may impact client trust and create concerns about confidentiality or perceived conflicts of interest.
In the case of youth, parental participation in the treatment of youth should be actively encouraged, if appropriate, and family members should be supported with sufficient information and training.
Offering or referring out to group or individual sessions for parents and/or caregivers (e.g., parent guidance sessions) is recommended. In addition to providing emotional support, family members can also function as caregivers and may help ensure that patients regularly attend for their doses and keep appointments. 76 A family history should be taken, when possible, to identify and treat any mental health or substance use issues requiring treatment in the youth's family. It should also be noted that not all youth have healthy or positive relationships with their family members and decisions to include family members in care should be guided by an understanding of the family dynamic and the patient's wishes.
If the patient determines family involvement would be a positive element in their treatment plan, care providers are encouraged to educate family members about available options and resources and provide as much patient-specific information as possible within the boundaries set by each province's privacy legislations. The care team must have current and complete knowledge of consent protocols for releasing information. In the context of this document, the term 'family' encompasses all relations that are important to the patient, including significant others who are not legally recognized as family.
# PATIENT-CENTRED CARE
Research suggests that incorporating patient-centred approaches into the clinical management of substance use disorders can improve retention in care, treatment satisfaction, and health outcomes. [77][78][79] In addition to recognizing the unique needs, values, and preferences of each patient, patient-centred care aims to engage and empower patients as experts in their own care, including acting as the primary agent for reducing harms related to substance use, setting individualized treatment goals that are realistic and meaningful, and selecting treatment options or interventions that will best support achieving their individual goals. 80 From this foundation of inclusion and encouraging personal agency, providers can build on the therapeutic relationship, while keeping patients safe from the harms associated with street opioid use and reducing the risks associated with iOAT.
As is the standard of care for management of any complex or chronic medical condition, all iOAT prescribers should provide patient-centred medical management including general support and unstructured counselling to patients receiving iOAT, regardless of the model of iOAT care employed. In this context, medical management is defined as medically-focused, informal counselling that includes, but is not limited to, performing health and mental wellness checks, offering non-judgmental support and advice, assessing motivation and exploring barriers to change, developing a holistic treatment plan, promoting alternative strategies for managing stress, and providing referrals to health and social services when requested or appropriate. Establishing a trusting, respectful, and collaborative therapeutic relationship with patients remains a cornerstone of treating substance use disorders in clinical practice.
# 3.9.i Motivational Approach
Motivational interviewing (MI) is a counselling approach that empowers the patient to develop motivation to change, and creates a therapeutic alliance that is predominantly a partnership, rather than an expert/patient dynamic. 81 Motivational interviewing techniques have been adapted for use in primary care settings to support behavioural change and improve self-management for a range of health conditions including HIV/AIDS, diabetes, cardiovascular disease, and substance use disorders. [82][83][84] Motivational interviewing-based counselling does not require professional specialization and can be delivered by primary care physicians, nurse practitioners, nurses, pharmacists, and other health professionals who have completed education and training in its delivery. 85 In practice, clinicians engage patients in guided discussion about health behaviours while adhering to the general principles of MI, which are to: 1) express empathy, 2) support self-efficacy, 3) avoid arguing or power struggles, 4) roll with resistance, and 5) develop understanding of discrepancy. 86 The intended outcome is to bring awareness to any discrepancies between current behaviours and future goals.
A 2011 systematic review of MI for treatment of substance use disorders (59 RCTs, n=13,342) found that MI significantly reduced substance use in comparison to no treatment. 85 Further, review results indicated that MI was as effective as other active psychosocial modalities (e.g., cognitive behavioural therapy) as well as assessment and feedback in reducing substance use, although overall the effects were modest in scale. 85 The strongest treatment effects were observed immediately post-intervention, with progressively weaker effects observed at each consecutive follow-up, such that no significant effects were observed more than 12 months post intervention. 85 Additional systematic reviews have reported that MI appears to be most effective when delivered in an individual format rather than group settings, and in combination with assessment and feedback. 82 It should be noted that there is limited evidence supporting MI for OUD specifically 87,88 and a lack of evidence examining MI in the provision of iOAT, however, motivational interviewing is a common general approach to addiction care across substances.
# 3.9.ii Trauma-informed Care
Due to the higher prevalence of histories of trauma and comorbid post-traumatic stress disorder among individuals with substance use disorders compared to the general population, 89 prescribers should be familiar with the principles of trauma-informed practice (e.g., trauma awareness; safety and trustworthiness; choice, collaboration, and connection; strengths-based approaches and skill building). There are several useful resources for learning about and integrating trauma-informed practice. These include the
# 3.9.iii Providing Care to Groups at Risk of Marginalizing Experiences
The social determinants of health can be understood as "the social and economic factors that influence people's health." 90 They include income, housing, social exclusion, gender, aboriginal status, race, and disability status, among others, 90 which impact health along a social gradient, with those at the lowest socioeconomic levels experiencing the worst health outcomes. 91 Clinicians providing care to groups at risk of marginalizing experiences in addition to being an injection drug user (includingbut not limited to-Indigenous peoples, racialized people, gender and sexual minorities, women, and people living in poverty) should be sensitive to the ways that these social locations are subject to unequal distribution of power, economic opportunity, and resources, 91 and aware of the fact that a person's multiple social locations (e.g., gender, race, and sexuality) interact with and impact each other, 92 and should endeavour to remove barriers to accessing care patients may experience.
Health care providers should be sensitive to the power differentials inherent in the provider-patient relationship and the ways that the social locations of each (including, but not limited to, race, gender, and class) can further those differentials, as well as the likelihood of previous, concurrent, and future negative experiences in the health care system due to discrimination. EQUIP Health Care provides several resources as well as a Health Equity Toolkit to support health care providers to implement equity-oriented care into primary health care practice.
Each patient will have their own needs, which must be addressed, depending on the social location(s) they inhabit. Examples may include a translator for individuals with limited English or French (depending on provider), connection to immigrant and/or refugee services, and/or referral to gender affirming care for transgender individuals. Safety should be prioritized for all patients, including emotional and cultural safety. Patients belonging to groups at risk of marginalizing experiences may also benefit from patient advocacy, for example, to secure housing, apply for disability assistance, or access psychosocial services, and all patients will benefit from health care providers working to prevent and mitigate stigma by avoiding and rejecting stigmatizing language, labels, and behaviour.
# Cultural Safety and Humility When Working with Indigenous Peoples
Health care providers hold social and institutional power, which is amplified when non-Indigenous health care providers treat Indigenous patients. Internalized negative attitudes about Indigenous peoples inform patient-provider relationships and can thus impact the quality of care provided and the client health care experience. 93 The provider-patient relationship is also impacted by health care providers' knowledge of Indigenous cultures, health care providers' understandings of Indigenous health disparities without historical and social context, and the history of colonization in Canada. 93 Structural violence, which can be understood as systemic exclusion, disadvantage, and discrimination, shapes the health of Indigenous peoples in Canada and globally. 94 It is well documented that Indigenous peoples in Canada are at increased risk of premature morbidity and mortality compared to non-Indigenous populations, 95 and multiple factors are believed to shape these social and health inequalities. Factors that impact health inequalities in all populations, such as environment, access to preventive and primary healthcare, and social determinants of health are believed to have a role, as do factors that are unique to the experiences of Indigenous peoples in Canada, including the impacts of colonization, intergenerational trauma, cultural deprivation, forced assimilation, and systemic racism and discrimination. 96,97 Research that shows that Indigenous peoples are at increased risk of substance-related harms 95,98 should be interpreted within this context. More specifically, it should be understood that Indigenous peoples are not, by definition, "high-risk" populations; rather, factors such as trauma, discrimination, and systemic racism faced by Indigenous peoples have likely created conditions and experiences of marginalization that, in turn, have led to increased use of opioids and other substances in some individuals as a means of coping with historical and cultural trauma exacerbated by stresses such as racism, violence, poverty, and systemic discrimination in their daily lives. 99,100 Specific approaches and understandings have been identified as necessary to provide culturally competent care to Indigenous peoples, 101 these include:
• Understanding the importance of local history and the lasting and multigenerational impacts of colonization and the residential school system;
• Examining, understanding, and acknowledging how health care providers' own values impact the healthcare environment and healthcare encounters;
• Understanding health as encompassing physical, intellectual, emotional, and spiritual wellbeing;
• Understanding the impacts of disparities in the social determinants of health;
• Respecting local traditions, traditional beliefs, and healing practices;
• Recognizing and respecting differences in communication styles, which may be influenced by power imbalances as well as cultural behaviours; r
• Understanding that whole communities may be impacted by what happens to one community member, that the family unit may be a large, extended family, and that hostile healthcare experiences can influence entire communities healthcare seeking attitudes;
• Understanding that cultural healing practices may require that families be involved in the care of clients;
• Approaching patient relationships with respectful curiosity;
• Challenging personal assumptions, being flexible, and being open to changing how things are commonly done; and r For example, less eye contact, long silences, and not answering direct questions or replying with a story or longer narrative response may be the norm for some Indigenous peoples compared to non-Indigenous populations.
• Recognizing and accommodating the need for a translator for those whose primary language is not English or French.
For an understanding of how the dominant healthcare system is frequently hostile and culturally unsafe for Indigenous peoples, and how health care providers may lack insight into how their approaches, behaviours, and programs create barriers to Indigenous community members, this document strongly recommends that non-Indigenous prescribers and staff undertake cultural safety and humility training to improve their ability to establish positive partnerships with Indigenous clients seeking care for substance use and related harms. Cultural safety can be understood as an outcome in which people feel safe when receiving care in an environment free from racism and discrimination, which results from respectful engagement that seeks to address power imbalances inherent in the healthcare system. Cultural humility is a process undertaken to understand, through self-reflection, personal and systemic biases, and to develop and maintain respectful processes and relationships based on mutual trust; it requires humbly acknowledging oneself as a learner when attempting to understand another person's experience. s
# 2SLGBTQ+ Populations
Two-Spirit, lesbian, gay, bisexual, trans, queer, and other gender and sexually diverse individuals (2SLGBTQ+) face unique challenges that should be addressed when providing care to 2SLGBTQ+ patients with substance use disorders. 2SLGBTQ+ individuals report disproportionate rates of substance use, [102][103][104] and enter treatment with greater severity of substance use problems. 105 Suggested explanations for these disproportionate rates include the stress of being in a minority group, dealing with social prejudice and discrimination, internalized stigma, and lack of cultural competence in the health care system. 105,106 Data on OUD specifically in 2SLGBTQ+ individuals is lacking, however, given the high s Definitions borrowed and lightly adapted from the First Nation's Health Authority.
rates of substance use in 2SLGBTQ+ individuals, OUD treatment should be culturally sensitive and include an awareness of the issues that 2SLGBTQ+ individuals are likely to face.
Strategies for working with 2SLGBTQ+ individuals include actively communicating that services are available for 2SLGBTQ+ patients, building relationships with organizations serving diverse marginalized communities, and using inclusive language in forms and clinical materials and during appointments. 105 Although substance use disorder treatment for 2SLGBTQ+ individuals is similar to that for other populations, additional factors must be considered, including acknowledging and affirming the patient's feelings about their sexual and gender identities and the impacts of stigma and discrimination in their lives. 107 Other strategies include respecting that identities are fluid and tailoring care accordingly; mirroring the language that your patients use (e.g., to refer to themselves, their relationships, and their bodies); not assuming sexual activity levels or motives for substance use; and being affirmative-recognizing the ways that individuals successfully practice harm reduction in their lives. 2SLGBTQ+ individuals may also have experienced discrimination in the health care system and thus require extra sensitivity from health care providers in order to build trust. 107 Prescribers should make themselves aware of local support groups and resources for 2SLGBTQ+ individuals. Additional information and guidance can be found in the Substance Abuse and Mental Health Services Administration's publication, A Provider's Introduction to Substance Abuse Treatment for Lesbian, Gay, Bisexual, and Transgender Individuals.
A non-judgmental attitude, active demonstration of awareness of and sensitivity toward trans issues, and a reinforcement of confidentiality can help trans people feel safe approaching care providers. 108 Other ways to demonstrate transgender awareness and sensitivity include placing trans inclusive brochures and posters in waiting rooms, asking about gender identity on intake forms (and avoiding conflating gender and sex t ), 108 and using open-ended questions about sexuality and gender. 107 Additional strategies include being reflexive and acknowledging personal biases; recognizing an individual's intersecting identities (e.g., race, disability, gender, sexuality) and how they may compound and impact patients' experiences of health care; making gender neutral bathrooms available; and respecting that identities and pronouns are fluid and can change. More information on working with trans, Two-Spirit, and gender diverse patients can be found in Trans Care BC's Gender-affirming Care for Trans, Two-Spirit, and Gender Diverse Patients in BC: A Primary Care Toolkit. Additional resources include the Trans Care Program in British Columbia, Rainbow Health Ontario, "Je m'engage"-a guide for Quebec health and social service providers, and the Canadian Professional Association for Transgender Health.
t Sex generally refers to the classification of a person as male, female, or intersex at birth, usually based on the appearance of their external anatomy, whereas gender refers to one's internal, deeply held sense of their gender, which may or may not align with the sex they were assigned at birth. A person's sex should not be assumed to match their gender; for example, that a person will have specific genitalia or reproductive anatomy based on their gender identity.
Two-Spirit u is term used by some North American Indigenous societies to describe people with diverse gender identities, gender expressions, gender roles, and sexual orientations. Dual-gendered, or 'Two-Spirited' people have been and are viewed differently in different Indigenous communities. Additional information on Two-Spirit individuals can be found on the Two Spirit Journal website.
# 3.9.iv Wellness and Self-Defined Progress
One of the goals of treatment across the continuum of care for OUD should be wellness, with an understanding that wellness looks different for each person, with many different possible paths. For some individuals, this may include a concept of recovery, which can be understood as "A process of change through which individuals improve their health and wellness, live a self-directed life, and strive to reach their full potential," 109 while others may have other personal definitions of wellness and progress.
Those seeking wellness require understanding, support, and referral to appropriate services to achieve their goals. Injectable opioid agonist treatment care teams are encouraged to incorporate and use language that promotes wellness in their practice. This includes ensuring respect of the patient's autonomy and individuality, emphasizing skills and strengths, and avoiding reinforcement of paternalistic models of care provision. 110 Additionally, and as appropriate, iOAT prescribers and care teams are encouraged to work collaboratively with patients to develop long-term, personalized, strengths-based wellness plans regardless of the severity, complexity, and duration of their substance use. The importance of peer navigators and peer support should also be recognized across the continuum of care for opioid use disorders. For wellness planning, iOAT providers should consider incorporating peer navigators to support long term, patient-centered treatment goals.
# 3.9.v Role of peers
The vital importance of peer navigators and peer support should be recognized across the continuum of care for opioid use disorders, including individual peer/patient navigation and advocacy as well as the work of drug user organizations, including the Canadian Association of People Who Use Drugs (CAPUD) and the Vancouver Area Network of Drug Users (VANDU), in advocating for expansion of iOAT and the need for it to be low-barrier, especially in the current context of criminalization creating a toxic drug supply contaminated with fentanyl and other highly potent synthetic opioids.
"Nothing About Us Without Us": Greater, Meaningful Involvement of People Who Use Drugs: A Public Health, Ethical, and Human Rights Imperative identifies several important benefits to peer involvement especially relevant for the provision of iOAT. These include more patient "buy-in" to the u Term borrowed and lightly adapted from Qmunity's "Queer Terminology from A to Q " program; the ability for patients' needs to be recognized and addressed; service delivery that meets the needs of patients by being realistic, low-barrier, and useful; and providing a sense of ownership for peers. 111 A qualitative study of a peer-run overdose response program in emergency shelters identified several factors that lead to increased feelings of safety from peer workers compared to non-peer paid staff, including social safety due to shared experiences, an absence of uneven power dynamics, and a perception of being cared for that contrasted with their everyday experiences. 112 Peer workers working at VANDU have identified several significant benefits to their work, including decreased risks associated with sex work, drug dealing, or theft as well as increased social contact, social recognition, structure, collective purpose, and an acknowledgment of their work. 113
# Peer Orientation and Education
Prior to admission, individuals identified as likely to benefit from iOAT should go through an admission process that involves full informed consent and a recommended peer orientation, to ensure program regulations, time commitments, and other requirements are fully understood. Some patients starting iOAT have not previously been engaged in care in the health system; these patients may benefit from peer support in navigating the system and advocacy as needed.
Peers should also be included in educational efforts for potential patients and the larger community.
Working with peers to create clear messaging about the expectations, benefits, and requirements of iOAT will help ensure that new patients have realistic expectations for the treatment.
# 3.9.vi Harm Reduction-oriented Care
Broadly defined, harm reduction refers to policies, programs, and practices that aim to reduce the adverse health, social, and economic consequences of licit and illicit substance use. 114 Across Canada, established harm reduction initiatives include needle/syringe distribution programs, overdose prevention with take-home naloxone, and supervised injection or consumption services. Including these harm reduction approaches within the continuum of addiction care provides additional mechanisms for promoting health and safety in diverse patient populations, including individuals who have difficulties achieving abstinence or who relapse to non-medical opioid use. There is substantial evidence that uptake of harm reduction services is associated with significant decreases in substance-related harms, including risky behaviours, HIV and hepatitis C infection, and overdose deaths. [115][116][117][118][119][120][121][122] In addition, research has shown that participation in harm reduction services can promote entry into addiction treatment. [123][124][125][126] For these reasons, if a patient is at risk of opioid-related harms, providing information and referrals to harm reduction services is a reasonable and appropriate clinical decision, particularly in the current environment of heightened overdose risk. Beyond specific harm reduction interventions, programs should take a non-punitive approach to treatment that utilizes a strengthsbased approach and meets patients where they are.
There are a number of actions clinicians can take to increase awareness of harm reduction services among patients. These include patient education about harm reduction and safer injection practices, including drug-checking services (where available) and take-home fentanyl testing, with a discussion of the limitations of these interventions. In order to provide informed referrals, clinicians should also be aware of harm reduction programs available in the local area and services provided. Additional information on harm reduction principles and available harm reduction services across Canada can be found in the iOAT Operations Guidance.
# 3.9.vii Naloxone
Where possible, all iOAT patients should receive overdose prevention education and a take-home naloxone kit at the start of injectable opioid agonist treatment and have ongoing and continuous access to harm reduction services and supplies. Families, colleagues, friends, and other loved ones should also be engaged to receive overdose response and prevention education and naloxone training. See Appendix 13 for guidance on responding to dose intolerances.
# 3.9.viii Mental Health Care
Mental health and substance use disorders frequently co-occur. Twelve-month prevalence rates for adults in the US with a substance use disorder and any concurrent mental health disorder were 43.3% in 2016, 127 while over 50% of individuals with a severe mental illness are estimated to have problematic substance use. 128 Looking specifically at opioid use disorder, an observational study of individuals receiving methadone-based OAT in Ontario found that 78.5% met diagnostic criteria for at least one comorbid psychiatric disorder, with anxiety disorders most common. 129 A 2017 meta-analysis examining the treatment of mood and anxiety disorders in individuals receiving OAT found psychotherapy and tricyclic anti-depressants most effective. Selective serotonin reuptake inhibitors (SSRIs) were not significantly better than placebo. 130 Patients who present with opioid use disorder should be screened for concurrent mental health disorders, and those who screen positive should receive evidence-based treatment for both. Generally, OUD and any comorbid mental health disorders should be treated concurrently, however, with severe OUD, stabilization-including initiation of iOAT-may be prioritized initially, with concurrent treatment once stability has been achieved.
# 3.9.ix Referral Pathways
As part of their practice, iOAT service providers should establish fully functioning referral pathways to addiction, recovery, and substance use treatment programs in their local area, to ensure access to services meant to improve quality of life and address social determinants of health. Some programs may co-locate or partner with community organizations which provide psychosocial services, others may offer some services on-site (e.g., counselling, housing workers) and refer out to other community services, and others will utilize referral pathways to ensure service users can access the psychosocial services they need and will benefit from. These referral pathways may include outpatient, inpatient, and residential treatment programs; recovery-oriented services including peer-support programs; supportive recovery housing; psychosocial treatment interventions and supports; chronic pain management; primary care; addiction medicine specialist consultation; trauma therapy; and specialized services where appropriate, for example, for women, youth, immigrants and refugees, and Indigenous peoples.
# 3.9.x Treatment Plan
Prescribers should work collaboratively with patients and their care teams to create and continuously revisit treatment plans based on each patient's goals, health, and circumstances. Treatment plans should use a comprehensive approach that includes assessment and treatment of any mental health or other comorbidities, psychosocial treatment interventions including cognitive behavioural therapy and motivational enhancement therapy, psychosocial supports (e.g., housing, education, and employment support), recovery services, and, when appropriate, family involvement in care; however, the creation of a comprehensive treatment plan should not be considered a pre-requisite to initiating iOAT and may be expanded as patients stabilize and their needs and goals change. Treatment plans should factor in age, gender, substance use history and trajectory, any experiences of violence, exploitation, trauma, and other factors that may support or negatively impact treatment adherence, including romantic partners, gender identity, sexual orientation, and family history.
Patients and care teams may also benefit from filling out a client safety care plan or behaviour agreement. This may include identifying triggers or irritants, calming strategies, and an agreement for how staff will respond if a patient is upset. In addition to building this plan or agreement together, the conversation that accompanies this agreement can represent an important relationship-building opportunity. A sample client safety care plan is available on the CRISM website.
# 3.9.xi Cost and Coverage
See iOAT Operations Guidance for information on cost and coverage of iOAT.
# Appendices APPENDIX 1: EVIDENCE SUPPORTING INJECTABLE OPIOID AGONIST TREATMENT FOR OPIOID USE DISORDER Injectable Opioid Agonist Treatment in Other Jurisdictions
The United Kingdom has provided unsupervised prescription injectable diacetylmorphine for the treatment of OUD for over a century. 131 Supervised prescription diacetylmorphine treatment has been available in Switzerland starting with a national clinical study in 1994, 132 and as a standard drug treatment since 1999. In 2008, as part of a national referendum, 68% of Swiss voters supported the permanent institution of a legalized prescription diacetylmorphine program funded by national health insurance. 133 More recently, Germany, Denmark, and the Netherlands have also adopted supervised prescription diacetylmorphine treatment for those with severe, treatment-refractory OUD. 134 In these countries, diacetylmorphine is used for <1% to 12% of all patients engaged in treatment for OUD. [134][135][136] The Comprehensive and Dedicated Injectable Opioid Agonist Treatment Program model has been widely applied in European jurisdictions, v wherein patients receive comprehensive addictions care, with the aim of meeting as many of the patients' health and psychosocial needs as possible on-site. There are both stand-alone clinics and clinics co-located with (or very close to) other addictions and psychosocial services. 134
# Evidence Summary
Two meta-analyses of clinical trials involving patients with long-term, refractory heroin addiction have demonstrated the efficacy of diacetylmorphine in comparison to methadone in terms of reducing illicit heroin use, criminal activity, and involvement in sex work, as well as improving overall health and social functioning. 11,12 These meta-analyses include a 2011 Cochrane Review which examined eight randomized controlled trials and found that supervised injection of diacetylmorphine, paired with flexible doses of methadone, was superior to oral methadone alone in retaining treatment refractory patients in treatment while helping reduce the use of illicit drugs. 11 The authors of the Cochrane review concluded that there is value in co-prescribing diacetylmorphine with flexible doses v Switzerland, Germany, Denmark, and the Netherlands use this model. The UK's unsupervised take-home model and Spain's limited weekday clinics are exceptions.
of methadone and that, due to the higher risk of adverse events, treatment with diacetylmorphine should be considered for those who have not benefited from oral opioid agonist treatment. 11 In 2015, the lead investigators of iOAT treatment trials conducted a systematic review and meta-analysis on the efficacy of injectable diacetylmorphine to complement the Cochrane Review. 12 Six randomized controlled trials (in Switzerland, the Netherlands, Spain, Germany, Canada, and England) were identified and included in the analysis, which found greater reductions in illicit heroin use among individuals who received supervised injectable diacetylmorphine compared to those who received oral methadone treatment only. 12 Further supporting the use of iOAT for those who have not benefitted from oral OAT, a 2017 evidence review undertaken and released by Public Health Ontario concluded that the available literature on iOAT demonstrates efficacy for iOAT over methadone in terms of treatment retention, reduction in illicit drug use, and reduction in criminal activities. 137 Although treatment with diacetylmorphine is a standard of care in a number of countries, 134 it is considered an emerging treatment in Canada and, currently, can only be accessed through Health Canada's Special Access Programme or inclusion in Health Canada's List of Drugs for an Urgent Public Health Need. Due to the restrictions on accessing diacetylmorphine, the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME), a phase 3, double-blind randomized controlled trial conducted in Vancouver, BC, compared diacetylmorphine with injectable hydromorphone in a population of individuals with long-term, treatment-refractory OUD. 13 After six months of treatment, researchers found that injectable hydromorphone was not inferior w to injectable diacetylmorphine for long-term injection street opioid users not currently benefitting from available treatments. x Both medications, delivered in identical conditions, have been shown to have positive outcomes such as high retention rates (over 77% ITT; over 92% PP), reduction of street opioid use (from daily to a few days per month) and illegal activities. 13 Thus, in jurisdictions where diacetylmorphine is currently not available, or in patients where it is contraindicated or unsuccessful, hydromorphone provides an effective, licensed alternative. 13
# Treatment Duration
To date, two studies have found a loss of treatment benefit-that is, an increase in street heroin use post-treatment to levels comparable to that of the control group-when prescription diacetylmorphine treatment was discontinued at a predetermined end date (12 months). 42,43 Thus, the authors of the Treatment Assisted by DAM (diacetylmorphine) study in Belgium, in line with World Health Organization recommendations for other opioid agonist treatments, recommend that supervised injection of diacetylmorphine be provided as an open-ended treatment. 42,138 w This study was a non-inferiority trial, which is a study design based on the assumption that a finding of non-inferiority indicates that the trial medication would prove superior to placebo in a placebo-controlled trial.
x Given that the results of the trial showed non-inferiority to diacetylmorphine, the assumption is made that hydromorphone would show the same (that is, non-inferior) effectiveness as diacetylmorphine. 13
# Expanded Eligibility
The majority of clinical trials evaluating iOAT have restricted participation to individuals who have previously undergone oral OAT treatment; thus, the evidence base can be understood as being supportive of iOAT for the treatment of patients who have not benefited from oral OAT. However, one large randomized trial comparing injectable diacetylmorphine with oral methadone included a subset of participants (n=107 of 1,015 total) with severe OUD but no previous experience with oral OAT. 139,140 Study authors found that outcomes of diacetylmorphine treatment were similar whether individuals had prior oral OAT experience or not, and within the subset of participants with no prior OAT experience, diacetylmorphine was superior to methadone in reducing nonmedical heroin use and criminal involvement, and as effective as methadone in improving overall health and retaining individuals in treatment. 139 Clinical practice in British Columbia has also shifted to broader eligibility considerations, which includes past experience with appropriately dosed oral OAT while continuing to experience significant health and social consequences related to their OUD; multiple attempts at oral OAT without being able to achieve a therapeutic dose; or other circumstances and risks that indicate the individual may benefit from iOAT. In addition, some European jurisdictions have expanded their eligibility criteria beyond those who have tried and not benefitted sufficiently from oral OAT.
# Safety
Optimizing patient safety has been an important factor in the designation of iOAT as an alternative intervention when oral OAT has not been successful (in jurisdictions where iOAT is available), and in requiring doses to be administered in structured, supervised clinical settings. Any frequently administered injectable treatment is associated with higher risks of cutaneous and infectious complications compared to its equivalent oral formulation. In the context of iOAT, the more rapid onset of action and shorter duration to reach peak effects (including respiratory depression) achieved with injection rather than oral ingestion of high-dose, full agonist opioid medications must also be considered. For this reason, and as emphasized throughout this document, iOAT should only be administered in designated clinical settings, with sterile supplies, in clean and safe conditions, and under supervision of qualified staff trained to intervene in the event of an adverse event or emergency. Further, while injectable treatment may confer higher risks of adverse effects than oral treatment, it is important to note that risks of injecting street drugs are considered to be significantly higher than injecting prescribed iOAT.
Studies in Europe and Canada have reported instances of significant respiratory depression events in people receiving injectable opioids, at an overall rate of about 1 in every 6000 injections, which is significantly lower than the risk present when injecting street heroin. 12 Each of these incidents was safely managed with appropriate resuscitation measures, which speaks to the necessity of injection being supervised by trained staff. 12 It should be noted that hydromorphone had significantly fewer adverse events and serious adverse events (SAEs) in the SALOME trial, 13 and thus diacetylmorphine may pose an increased risk of other adverse events (e.g., histamine reactions, seizures, and overdose) compared to injectable hydromorphone 13 and oral methadone. 11,12 The majority of SAEs occur within a few minutes of receiving an injection, 140 therefore, the recommended post-injection supervision period of 15 minutes, which would be required regardless of program type or treatment setting, is sufficient to recognize and resolve the majority of SAEs. Additionally, the combination of prescription diacetylmorphine and flexible doses of oral methadone may have a protective effect against overdose from illicit opioid use not in the treatment setting, as demonstrated by a non-statistically significant reduced mortality risk compared to oral methadone alone. 11,12 An additional concern with ongoing injection-based opioid agonist treatment is heightened risk of infectious complications such as sepsis, osteomyelitis, cellulitis, and abscesses. When the skin is punctured (even with a sterile needle in a clinical setting), it provides a potential port of entry for bacteria or other microorganisms, particularly when the injections are being given multiple times per day (as is the case with diacetylmorphine and hydromorphone). With that said, the risk of infection and infectious sequelae in a sterile and supervised setting is only a fraction of the risk for those injecting illicit drugs. For example, in the 12-month NAOMI trial, two SAEs involving sepsis or other infections were reported, while three SAEs involving abscesses or cellulitis were reported, across a total of 89,924 injections. 141 In the SALOME trial, over the 180-day treatment period, 18 adverse events involving infectious complications were reported (14 cellulitis, 4 subcutaneous abscesses) over a total of 85,451 injections, which translates to 3.4% and 4.8% of all adverse events deemed related to injectable hydromorphone and diacetylmorphine treatment, respectively. 38 Although difficult to compare and more data is needed, this is compared to 6-12 month prevalence rates of skin and soft tissue infections in people who inject illicit drugs, which range from 6.9% to 37.3%. 142 Additionally, the risk of contracting a blood-borne illness (e.g., HIV or hepatitis C) is eliminated with the use of sterile equipment in a supervised setting.
In the majority of the studies on prescribed diacetylmorphine, nurses supervised patients' selfadministration of medication and closely monitored patients to ensure their safety both before (e.g., no signs of intoxication) and after (e.g., no signs of oversedation or respiratory depression) treatment was administered. If an overdose occurred after injection of the medication, supervision allowed for immediate onsite treatment, ensuring the safety of the patient; it is for this reason that supervised administration of iOAT is recommended rather than take-home dosing. 11,12,38 Provision of injectable opioids under supervision also ensures the safety of the community by, for example, preventing diversion of a prescribed injectable opioid into the street for illicit use. While concern has been expressed over security, public safety, and potential for diversion from sites offering prescribed injectable opioids, findings thus far suggest no negative effects for public safety. 12
# Cost Effectiveness
Studies in both Europe and Canada have found injectable diacetylmorphine treatment to be more cost-effective than oral methadone treatment, due to significant reductions in criminal activity and the costs associated. [143][144][145] Similarly, hydromorphone has been found to be more effective and less costly than oral methadone treatment, due to significant reductions in criminal activity and hospitalization and the associated costs. 146 It should be noted that these cost savings rely on the effective negotiation of hydromorphone prices. In addition to cost effectiveness, data from British Columbia shows that individuals receiving injectable hydromorphone and diacetylmorphine gain more qualityadjusted life years (QALYs) than individuals receiving methadone (8.4 [95% CI=7.4 to 9.5]) and ( 8
# APPENDIX 2-DEVELOPMENT PROCESS
# Content Development
The medical writer and committee co-chairs, on behalf of CRISM, developed this national guideline using a structured literature review approach. Relevant search terms and structured search strategies were used to search PubMed, the Cochrane Library databases, and reference lists (up to August 1, 2019) using a hierarchical approach, whereby meta-analyses and systematic reviews were given the most weight, followed by individual randomized controlled trials (RCTs), quasi-experimental studies, observational studies, and, lastly, expert opinion. The medical writer manually reviewed titles, abstracts, and full text of identified citations, selected evidence for inclusion, and compiled narrative evidence reviews, including cost effectiveness data, for the guideline co-chairs and the guideline review panel. Grey literature searches were also conducted for any other existing iOAT guidelines and international researchers and other experts in the field were engaged to determine whether iOAT guidelines exist anywhere in the world. While some individual clinics have various protocols and manuals, this process determined that the BC Centre on Substance Use's 2017 provincial Guidance Document for Injectable Opioid Agonist Treatment for Opioid Use Disorder is the only clinical guidance document in existence, to date. Any questions or uncertainties in the literature search, evidence review, and synthesis processes were brought to the chairs for clarity and consensus.
# Review Process
The National iOAT Clinical Guideline was written by the National iOAT Clinical Guideline Review Committee. Once finalized, the clinical guideline was reviewed by the National iOAT Operational Guidance Review Committee, followed by external review by people with lived experience, experts in the subject matter, and a family member impacted by opioid use disorder.
# Composition of Guideline Review Committee
The CRISM National iOAT Steering Committee was assembled to coordinate guideline preparation activities including recruiting the committee, with representation sought from each of the four CRISM nodes (BC, Prairies, Ontario, and Quebec-Atlantic). The Steering Committee included representation from BC, Alberta, Ontario, and Quebec; each member had relevant expertise, including injectable opioid agonist treatment prescribing, research, and service planning. The Steering Committee decided to create two complementary documents: A clinical guideline and an operational guidance document. To that end, the Steering Committee assembled expert committees for each document. Each member of the Steering Committee was invited to nominate relevant experts from their own province and across the country. As committee members accepted the invitation to join, they were encouraged to nominate additional members to ensure a diverse committee representing a range of experience and expertise. Final committee composition was determined by co-chair consensus. The National iOAT Clinical Guideline Review committee was composed of 30 individuals, including the two co-chairs, which included physicians, nurses and nurse practitioners, pharmacists, people with lived experience, researchers, treatment providers, and front-line staff.
# Development of Recommendations
Recommendations were developed and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool [147][148][149][150] through an iterative consensus process. Draft recommendations were developed by the committee co-chairs and medical writer, then revised by the full committee in two consecutive rounds of review, as described below. Following each round of review, the medical writer revised the recommendations, incorporating all feedback received from committee members. Recommendations were agreed upon by committee consensus. External reviewers did not provide input on the three key recommendations. The committee co-chairs then reviewed and approved the final version of recommendations (more detailed explanation of the evidence underlying each recommendation and score is available in Appendix 3).
# GRADE Approach and Interpretation of Grading
The GRADE approach [147][148][149][150] to rating quality of evidence starts with a simplified categorization of study types (meta-analyses and randomized controlled trials (RCT), quasi-experimental studies, observational studies, and expert opinion), accompanied by initial estimated levels of confidence (high, moderate, low, or very low) in the estimate of a treatment effect. The rating scheme allows for factors that would raise or lower a level of confidence. Factors that would lower confidence in evidence include risk of bias, inconsistency across the RCTs, indirectness, and publication bias; factors that would increase confidence include large effect size and an observed dose-response effect. The final quality ratings are reflective of the confidence in the estimated effect in context of bias and limitations that have been identified, as described below:
• High: We are very confident that the true effect lies close to that of the estimate of the effect.
• Moderate: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
• Low: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
• Very low: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
The GRADE approach uses a binary system to classify strength of recommendations as either strong or weak/conditional. For this guideline, "conditional" was used rather than "weak." It is important to note that, although quality of evidence is an important factor when classifying strength of recommendations, "strong" or "conditional" in this case does not refer exclusively to the quality of evidence underlying a given recommendation. Except for cost and resource allocation, the recommended GRADE factors to classify strength of recommendations were considered:
• Balance between desirable and undesirable effects: The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a conditional recommendation is warranted.
• Quality of evidence: The higher the quality of evidence, the higher the likelihood that a strong recommendation is warranted.
• Values and preferences: The more values and preferences vary, or the greater the uncertainty in values and preferences, the higher the likelihood that a conditional recommendation is warranted.
# Interpretation of Strength of Recommendations
Examples of how a strong versus conditional recommendation could be interpreted by selected audience or user groups are listed below.
A strong recommendation indicates the following:
• For patients: Most people in your situation would want the recommended course of action and only a small proportion would not; you should request discussion with your care provider if the intervention is not offered.
• For clinicians: Most patients should receive the recommended course of action. As an example, in this scenario, an algorithm or decision-making tool would not be necessary-the benefits of the recommended course of action would clearly outweigh any advantages of alternative interventions.
• For health care administrators: The recommendation can be adopted as a policy in most situations.
A conditional recommendation indicates the following:
• For patients: Most people in your situation would want the recommended course of action, but many would not.
• For clinicians: You should recognize that different choices will be appropriate for different patients and that you must help each patient to arrive at a management decision consistent with her or his values and preferences. In this scenario, an algorithm or decision-making tool would be advantageous to determine the best course of action.
• For health care administrators: Policy-making will require substantial debate and involvement of many stakeholders.
# Review of Recommendations
The review process consisted of one round of revisions of the draft guideline recommendations and evidence review by the pan-Canadian review committee. The medical writer and committee co-chairs consolidated guideline revisions as needed to address committee feedback. Differences in opinion or interpretation with regard to the guideline recommendations or the evidence review were resolved through facilitated discussions in a committee teleconference or direct communication. A final decision was reached for all cases without the need for arbitration.
# Management of Competing Interests
This guideline was entirely funded through the CIHR-funded CRISM network and without pharmaceutical industry support. Competing interests were assessed using the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts in Guidelines. 151 No current or ongoing direct competing interests were disclosed by the 30 members of the clinical sub-committee on screening for participation in the review committee. No individual reported a history of employment (either self or family member); consulting or advising; honoraria or fees for training, speaking, or panel discussions; investment interests; grants-in-aid for research, non-monetary research or program support (e.g., equipment, travel, staff salary, facilities); or intellectual property holdings with industry or any commercial entity that could potentially benefit from guideline recommendations. In terms of indirect sources of potential interest or bias, overall, 21 individuals disclosed special interests in relation to the guideline content. These pertained to specific expertise and/or clinical experience (e.g., addiction medicine clinician, academic addictions expert), involvement with provincial OAT or iOAT programs and committees, or research interests and publications. No individual reported that his/her clinical revenue would be influenced by the guideline recommendations. Upon review by the committee co-chairs, none of the potential direct or indirect conflicts of interest or bias disclosed by committee members were deemed to be of sufficient relevance or weight to warrant the members' exclusion from the committee.
All 30 committee members participated in multiple rounds of review and revision of the draft and granted final approval of the guideline contents and clinical recommendations.
# External Review Process
This guideline was reviewed by the National Injectable Opioid Agonist Treatment Operational Guidance Review Committee, which was responsible for the development of its partner document. Following this review, it underwent external review by people with lived experience, experts in the subject matter, and a family member impacted by opioid use disorder.
# Update Schedule/Process
In line with AGREE II criteria, 152 every two years a structured literature search from the last date update will be conducted and the National iOAT Clinical Guideline Committee will be reconvened to determine which updates from research evidence and expert consensus should be added.
# APPENDIX 3-RECOMMENDATIONS AND EVIDENCE SUMMARIES
The GRADE approach [147][148][149][150] rates quality of evidence and strength of recommendation. More information on the GRADE approach is available in Appendix 2. A brief overview of the rating system precedes the recommendations and evidence summaries.
# Quality of Evidence
# High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
# Very low
We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
# Strength of Recommendation
# Strong Conditional
# For patients
Most people in your situation would want the recommended course of action and only a small proportion would not; you should request discussion with your care provider if the intervention is not offered.
Most people in your situation would want the recommended course of action, but many would not.
# For clinicians
Most patients should receive the recommended course of action. As an example, in this scenario, an algorithm or decision-making tool would not be necessary-the benefits of the recommended course of action would clearly outweigh any advantages of alternative interventions.
You should recognize that different choices will be appropriate for different patients and that you must help each patient to arrive at a management decision consistent with her or his values and preferences. In this scenario, an algorithm or decision-making tool would be advantageous to determine the best course of action.
# For health care administrators
The recommendation can be adopted as a policy in most situations.
Policy-making will require substantial debate and involvement of many stakeholders.
# Recommendation 1
Injectable opioid agonist treatment should be considered for individuals with severe, treatment-refractory opioid use disorder and ongoing illicit injection opioid use.
# Quality of Evidence: Moderate
Strength of Recommendation: Conditional
# Remarks:
The rapid onset of action and shorter time to reach peak effects (including respiratory depression) that is achieved with injection rather than oral ingestion of high-dose, full agonist opioid medications necessitate that iOAT be administered in clinical settings, with sterile supplies and in clean and safe conditions, and under supervision of qualified staff trained to intervene in the event of an adverse event or emergency.
The majority of clinical trials evaluating iOAT have restricted participation to individuals who have previously undergone, but not benefited from, oral OAT treatment; thus, the evidence base is supportive of iOAT for the treatment of patients who have not benefited from oral OAT. However, one large randomized trial comparing injectable diacetylmorphine with oral methadone included a subset of participants (n=107 of 1,015 total) with severe OUD but no previous experience with oral OAT. 139,140 Study authors found that outcomes of diacetylmorphine treatment were similar whether individuals had prior oral OAT experience or not, and within the subset of participants with no prior OAT experience, diacetylmorphine was superior to methadone in reducing nonmedical heroin use and criminal involvement, and as effective as methadone in improving overall health and retaining individuals in treatment. 139 Clinical practice in British Columbia has also shifted to broader eligibility considerations, which includes past experience with appropriately dosed oral OAT while continuing to experience significant health and social consequences related to their OUD; multiple attempts at oral OAT without being able to achieve a therapeutic dose; or other circumstances and risks that indicate the individual may benefit from iOAT based on clinical judgment.
This treatment should be offered to and discussed with all those patients who may benefit from it.
It was decided that this recommendation should be conditional due to the high intensity of treatment requiring (in most cases) multiple trips to the clinic or pharmacy per day, which may be experienced as overly onerous for some patients; the increased risk of adverse events compared to oral OAT; 11,12 the potential for other treatment approaches being collaboratively decided as the best option by clinician and patient; and the likelihood that policy-making will require substantial debate and involvement of many stakeholders.
To date, there has not been research conducted specifically looking at iOAT provision in youth. Specific considerations for youth (adolescent-aged 12-17 years; and young adult-aged 18-25 years) populations with severe OUD who do meet some or all of the considerations for eligibility for iOAT in their practice are outlined in this clinical guideline.
# Evidence Summary:
Two systematic reviews, which included meta-analyses, of clinical trials involving patients with longterm, refractory heroin addiction have demonstrated the efficacy of diacetylmorphine in comparison to methadone in terms of reducing illicit heroin use, criminal activity, and involvement in sex work, as well as improving overall health and social functioning. 11,12 These meta-analyses include a 2011 Cochrane Review which found that supervised injection of diacetylmorphine, paired with flexible doses of methadone, was superior to oral methadone alone in retaining treatment refractory patients in treatment (4 RCTs; n=1388, Relative Risk (RR) 1.44 [95% confidence interval (95% CI) 1.19 to 1.75]) 11 and a 2015 systematic review and meta-analysis which found supervised injectable heroin treatment to be superior to methadone in treating treatment refractory opioid use disorder (4 RCTs; n=1377, RR 1.37 [95% CI 1.03 to 1.83]). 12 Both systematic reviews also reported greater reductions in illicit drug use (both heroin and other illicit substances), however, due to heterogeneity in reporting, these were reported narratively rather than included in the meta-analyses.
In response to restrictions on accessing diacetylmorphine in Canada, the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) compared diacetylmorphine with injectable hydromorphone in a population of patients (n=202) with long-term, treatment-refractory OUD. 13 Both per protocol (PP) and intention to treat (ITT) analyses found that injectable hydromorphone was not inferior to injectable diacetylmorphine for long-term injection street opioid users not currently benefitting from oral opioid agonist treatment, in terms of retention rates (≥92% PP; ≥ 77% ITT), reduction of any street opioid use (-0. 13 Thus, in jurisdictions where diacetylmorphine is currently not available, or in patients where it is contraindicated or unsuccessful, hydromorphone provides an effective, licensed alternative. 13 Recommendation 2
For patients who are determined to be likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone are acceptable treatment options.
# Quality of Evidence: Low
Strength of Recommendation: Strong
# Remarks:
Both hydromorphone and diacetylmorphine are approved for the treatment of opioid use disorder in Canada. However, diacetylmorphine must be applied for through the Special Access Programme for individual patients or added to the List of Drugs for an Urgent Public Health Need for a given jurisdiction.
Either medication may be considered a reasonable choice, based on availability, patient choice, and prescriber judgement. If the individual is not benefitting sufficiently or is experiencing unacceptable side effects, they should be given the option to transition to the other medication.
The quality of evidence is rated low due to the discrepancy in evidence supporting each medication, with two systematic reviews supporting the use of diacetylmorphine, and only a single study supporting the use of hydromorphone. The recommendation is rated as strong based on expert consensus, significant clinical experience in British Columbia, reduced risk of adverse events for hydromorphone compared to diacetylmorphine, and the lack of regulatory and supply barriers impacting access to hydromorphone.
# Evidence Summary:
As outlined above, two systematic reviews support the recommendation of diacetylmorphine for the treatment of severe opioid use disorder. 11,12 Due to regulatory barriers which limited access to diacetylmorphine in Canada, the SALOME trial compared injectable hydromorphone to injectable diacetylmorphine in a non-inferiority trial and found no evidence indicating that hydromorphone is inferior to diacetylmorphine. 13,28 Both per protocol and intention to treat analysis found that injectable hydromorphone was not inferior to injectable diacetylmorphine for long-term injection street opioid users not currently benefitting from oral opioid agonist treatment, in terms of retention rates (≥ 92% PP; ≥ 77% ITT), reduction of any street opioid use (-0. While diacetylmorphine has significantly more evidence supporting its efficacy in treating OUD, it may pose an increased risk of adverse events (e.g., seizures, and overdose) compared to injectable hydromorphone. Hydromorphone was associated with a significantly lower risk of both adverse events (0.60 [95% CI 0.39 to 0.90]) and serious adverse events (0.21 [95% CI 0.06 to 0.69) compared to diacetylmorphine. 13 For these reasons, either medication can be considered a reasonable choice, based on availability, patient choice, and prescriber judgement.
# Recommendation 3
Injectable opioid agonist treatment should be provided as an open-ended treatment, with decisions to transition to oral OAT made collaboratively with the patient.
# Quality of Evidence: Low
# Strength of Recommendation: Strong
Remarks:
The quality of evidence is rated low due to the low number of studies evaluating the impact of pre-determined treatment end dates. It was decided that this recommendation should be strong despite the low quality of evidence, due to the risk associated with fentanyl-contaminated illicit opioid use and its alignment with a recommendation from the World Health Organization that opioid agonist treatment be provided as an open-ended treatment. 153 Evidence Summary:
A loss of treatment benefit when prescription diacetylmorphine treatment was discontinued at a predetermined end date has been found in two post-randomized controlled trial observational cohorts. 42,43 Both of these studies found an increase in street heroin use post treatment end to levels comparable to that of the control group. One study found a rapid deterioration in 82% (94/115) of responders in the diacetylmorphine group two months after treatment discontinuation, with mean scores on the constituent scales of the multi-domain outcome index returning to pre-treatment levels, 43 while the other showed a significant increase of street heroin use in the diacetylmorphine group three months after treatment discontinuation (p=0.005, mean number of days of heroin use in past month=8 days at 12 months, mean=14 days at 15 months). 42 Another study compared individuals who voluntarily transitioned from injectable diacetylmorphine to oral methadone prior to the completion of a randomized controlled trial against those who were involuntarily transitioned at the end of the 12-month trial, and found that the mean prior 30 days of illicit heroin use was higher in the involuntary group than the voluntary group at 24 months (adjusted mean difference: -5. Opioids are often taken in larger amounts or over a longer period than was intended
The presence of at least 2 of these symptoms indicates an OUD
The severity of the OUD is defined as:
# MILD:
The presence of 2 to 3 symptoms
# MODERATE:
The presence of 4 to 5 symptoms
# SEVERE:
The presence of 6 or more symptoms 2 There is a persistent desire or unsuccessful efforts to cut down or control opioid use The pre-and post-injection assessments y are completed by a qualified health professional or other trained staff if supervised by a health professional to ensure the safety of patients. The pre-injection assessment ensures that the patient is not intoxicated, including by centrally-acting sedatives or stimulants, or in any other acute condition that would increase the risk of an adverse event with the use of injectable hydromorphone or diacetylmorphine. The post-injection assessment is performed to inform dosing (e.g., lowering dose if sedation occurs) and ensure safety (e.g., respond to respiratory depression). Patients may leave the premises when they are deemed fit to do so after the minimum 15-minute observation period post dose.
y The pre-and post-intake assessment protocol has been adapted from the protocol used at Providence Health Care's Crosstown Clinic in Vancouver, BC.
# Pre-Injection Assessment
A qualified health professional or other appropriately trained staff, including peer staff, if supervised by a qualified health professional will complete the following, in order to assess the safety of providing each patient's dose:
Assess for signs of intoxication, including severe agitation, dyskinesia, sedation, slurred speech, or smelling of alcohol.
A sample pre-injection assessment form appears in Table 3 below. If initial assessment results in suspicion of recent use of psychoactive substances, the staff member should discuss with the patient whether they have consumed illicit drugs (including any nonprescribed pharmaceutical drug) or alcohol. Where observation warrants further assessment (e.g., slurred speech, unsteady gait, smells of alcohol), a health professional or other staff if supervised by a health professional (physician, nurse practitioner, Registered Nurse, Registered or Licensed Practical Nurse, Registered Psychiatric Nurse, or pharmacist) trained to administer breathalyzer testing should check that the patient's blood alcohol level does not exceed 0.05%.
If the patient is judged to be intoxicated (whether through observation or results of pre-injection assessment, including breathalyzer results if applicable), the dose should be postponed or withheld.
If the patient is judged safe to receive their dose, their patient chart and medication administration record should be checked to ensure that intoxication did not occur at the last dose, and that no prolonged absence (greater than 3 days or 9 appointments) has occurred.
If sedation did occur at the last dose and this is thought to be due to the prescribed iOAT medication, the prescriber should be consulted before further doses are administered. The prescriber should reduce the dose, typically starting with the last dose that did not cause sedation. The post-dose evaluation duration may need to be extended. If this lowered dose is tolerated, further up-titration may then be pursued (if needed), typically in smaller increments. If sedation was the result of one-time illicit substance use and the patient presents for their next dose alert and the pre-dose assessment does not indicate sedation, there may not need to be a dose adjustment. If the patient continues to experience sedation, their dose may need adjustment and their ongoing substance use should be managed. See Ongoing Substance Use.
If a prolonged absence has occurred (more than five days), the patient should be re-titrated following the process outlined in Appendix 7.
If intoxication did not occur at the last dose and no prolonged absence has occurred, the dose should be given as prescribed.
# Post-Injection Assessment
Patients should be asked to stay in the clinic for a minimum of 15 minutes after they inject their medication. Qualified health professionals or other trained staff if supervised by a health professional (physician, nurse practitioner, Registered Nurse, Registered or Licensed Practical Nurse, Registered Psychiatric Nurse, or pharmacist) can use this period to observe and engage with patients.
After 15 minutes has elapsed, a qualified health professional or other trained staff if supervised by a health professional (physician, nurse practitioner, Registered Nurse, Registered or Licensed Practical Nurse, Registered Psychiatric Nurse, or pharmacist) will conduct the post-injection assessment, observing any signs of intoxication including dyskinesia, sedation, slurred speech, agitation, or decreased respiration rate.
A sample post-injection assessment form appears in Table 4 below.
# Table 4: Post-Injection Assessment
After a minimum of 15 minutes, once a patient is deemed fit to leave the clinic (i.e., is showing no signs of intoxication), they may do so.
If a patient seems to be intoxicated, a pulse oximeter should be used and/or a vital sign assessment should be completed and documented in the patient's chart.
If a patient must be kept for more than the initial 15-minute period post-injection, this should be documented in their patient chart and medication administration record. In this case, the postinjection assessment should be administered at 15-minute intervals until the patient meets all criteria or other medical intervention is required. The patient's prescriber should be advised and a reduction in subsequent dose should be considered.
# Pasero Opioid-induced Sedation Scale (POSS)
The Pasero Opioid-induced Sedation Scale (POSS) is used to assess level of sedation in patients receiving opioids. Because sedation level predicts opioid-induced respiratory depression and precedes other clinically significant events, 155 using the POSS scale provides a consistent way to measure sedation and provide follow-up when needed. At any time during the titration period, a physician, nurse practitioner, nurse or (where applicable) pharmacist (in collaboration with the prescribing physician or nurse practitioner) may order a lower dose or a more gradual titration based on patient response and safety concerns. In order to allow flexibility, the patient can also request a lower dose or a more gradual titration process, such as only increasing the dose by 5mg or not taking a second dose. The most predictable, though rare, side effect during titration is oversedation, which is manageable with dose reductions and a modified (slower) titration schedule.
For iOAT programs that do not have capacity for titrations 7 days a week, it is recommended that the titration process be started between Monday and Wednesday to avoid the need for dose increases on the weekend.
The prescriber may adjust the dosage once per day, or as needed, until the patient feels comfortable (i.e., reduced cravings and withdrawal symptoms) and does not show any excessive intoxication or respiratory depression or until the maximum dose is reached (200mg/dose and/or 500mg/ day for hydromorphone; 400mg/dose and/or 1000mg/day for diacetylmorphine). Dose increases are discouraged on weekends and holidays if the prescriber is not available.
It should be noted that some patients may miss titration sessions due to unstable housing and other issues, and thus the initiation may require a modified protocol over multiple days. Three doses per day is better studied; however, clinical practice in British Columbia has shown that many individuals do well on two doses per day.
Note: For the supervised pharmacy-based model, where titration occurs at the prescriber's office or clinic, it is recommended that initiation of treatment be scheduled such that the first pharmacywitnessed dose does not fall on a weekend or other day in which the prescriber is unavailable.
Table 6 below summarizes the dosages used during the induction process for quick reference.
# Consider co-prescription of oral OAT (see below).
As each patient goes through the titration process, they should stop at the dose where they are comfortable and have alleviated withdrawal and cravings. This will be their ongoing dose. If the patient is oversedated post-injection, the prescriber should be consulted to determine if the next dose should be lowered and to assess any changes in the patient's health status prior to their next dose. The prescriber may order a lower dose at the next injection, with the option to continue to titrate up depending on how the new dose is tolerated.
Table 7 below summarizes the dosages used during the induction process for quick reference.
# Alternate Titration Protocols
Clinical experience from British Columbia, where fentanyl has infiltrated the illicit opioid supply, has shown that the above recommended titration protocols may be insufficient in ameliorating withdrawal symptoms and cravings in some individuals who have developed a very high opioid tolerance due to fentanyl. For this reason, titration protocols have been adapted by some iOAT programs.
Two alternate titration protocols are offered below (a three doses per day and a two doses per day protocol), which were developed according to clinical expertise by iOAT providers in Vancouver, BC. Although these alternate protocols have been used in clinical practice, it should be understood that they have not been rigorously evaluated for safety or their impact on retention. comfortable and have alleviated withdrawal and cravings. This will be their ongoing dose. If the patient is oversedated post-injection, the prescriber should be consulted to determine if the next dose should be lowered and to assess any changes in the patient's health status prior to their next dose. The prescriber may order a lower dose at the next injection, with the option to continue to titrate up depending on how the new dose is tolerated.
# Alternate Titration Protocols
Due to the higher risk of adverse events and sedation with diacetylmorphine compared to hydromorphone, 13 accelerated titration protocols for diacetylmorphine are not recommended.
# Co-Prescription of Oral OAT
Oral OAT is frequently co-prescribed with iOAT in order to prevent withdrawal and cravings between iOAT doses, particularly overnight during the longest between-dose period, as the injectable medications are relatively short-acting. In the randomized controlled trials studying supervised injection diacetylmorphine, methadone was co-prescribed in two trials, 43,156 and available for various reasons (to prevent withdrawal over-night, for travel, to reduce attendance to one or two times per day) in five trials. 13,14,140,157,158 Where listed, the average methadone dose ranged from 8mg to 60mg per day. 13,43,140,156 A dose of oral OAT (i.e., SROM or methadone) may be taken daily under supervision to bridge between doses, with the longest gap between doses occurring overnight. Caution and safety should guide co-prescription, while working to ensure patient comfort. Nurses and/or pharmacists should assess the patient each day during the titration period to ensure the co-prescribed oral OAT is appropriately dosed. Co-prescribed oral OAT can be given at any time, based on the patient's comfort (for example, with the first injection of the day, with the last injection of the day, or separately in the evening).
There is insufficient data to guide specific target dosing of supplemental oral OAT, however, it should be guided by patient preference and clinical effect. Induction of co-prescribed methadone should follow the process outlined in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. Guidance on induction of SROM can be found in the BCCSU's A Guideline for the Clinical Management of Opioid Use Disorder. Oral OAT may be started in advance if practical matters require waiting to start iOAT, at the same time as iOAT induction, or after a patient has been titrated onto iOAT.
An example titration chart of both hydromorphone and methadone follows in Table 12. z This chart is informed by clinical expertise and represents one possible way of co-prescribing methadone with hydromorphone, in a two-doses per day setting in which the patient is still experiencing discomfort and cravings after the initial three-day titration. De-intensification of treatment may be appropriate and/or required for one of four reasons. The first is when a patient has stabilized on iOAT and decides, with their prescriber, that a lower-intensity iOAT model is appropriate (for example, moving from the Comprehensive and Dedicated Model of Care to the Integrated or Embedded Model, see iOAT Operations Guidance). When switching models of care, the prescriber should ensure that existing psychosocial supports will remain in place, if possible.
The second is patient-initiated transition to oral OAT which is covered in more detail below. The third situation in which de-intensification would occur is when a patient is discontinued from iOAT as a consequence of behaviour such as violence or diversion (attempted or successful). The final reason a patient may require de-intensification of treatment is if they have been convicted of a crime and face a period of incarceration.
This guideline should be understood as a living document, which will be refined as more evidence and clinical experience emerges from expanded iOAT provision. The following sections on de-intensifying treatment to oral OAT are based on the best evidence currently available. Clinical judgment, close monitoring, and, when appropriate, consultation with addiction specialists with experience in iOAT provision should further guide the process of de-intensifying treatment in order to ensure the safety of patients transitioning from iOAT to a less intensive treatment. Strategies for transitioning between hydromorphone and diacetylmorphine (and the reverse) are also provided below.
# Transition from Hydromorphone to Diacetylmorphine
Transition from hydromorphone to diacetylmorphine (using a 1:2 [HDM:DAM] potency ratio with a 25% dose reduction to account for incomplete cross tolerance, see Conversion Table in Appendix 9) will be subject to availability of diacetylmorphine (see iOAT Operations Guidance). Patients and prescribers may collaboratively choose to transition to diacetylmorphine if the patient is not benefitting sufficiently or experiencing unacceptable side effects. It should be noted that diacetylmorphine may pose an increased risk of adverse events (e.g., histamine reactions, seizures, and overdose) compared to injectable hydromorphone. 13 See Appendix 11 for a table of serious side effects for both medications. See Medication Selection and Preparation for considerations on initial selection of iOAT medication.
# Transition from Diacetylmorphine to Hydromorphone
Patients and prescribers may collaboratively choose to transition from diacetylmorphine to hydromorphone (using a 2:1 [DAM:HDM] potency ratio with a 25% dose reduction to account for incomplete cross tolerance, see Conversion Table in Appendix 9) if the patient is not benefitting sufficiently or experiencing unacceptable side effects. It should be noted that diacetylmorphine may pose an increased risk of adverse events (e.g., histamine reactions, seizures, and overdose) compared to injectable hydromorphone. 13 See Appendix 11 for a table of serious side effects for both medications. See Medication Selection and Preparation for considerations on initial selection of iOAT medication.
# Transition from Hydromorphone or Diacetylmorphine to Methadone
Transition from injectable hydromorphone to oral methadone (see Conversion Table in Appendix 9) may be patient-initiated due to a desire to de-intensify treatment, in which case gradual transition is appropriate. The pace of transition and approach used should follow the same approach used for transitioning patients from any high-dose short-acting opioid onto methadone while gradually lowering the dose of hydromorphone. Province-specific guidelines for methadone induction should be followed and can be found in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. Due to inter-individual differences, which can vary widely among patients, clinical judgement should be used in the transition process.
# Transition from Hydromorphone or Diacetylmorphine to Slow-Release Oral Morphine
Due to the preliminary nature of research on using SROM to de-intensify iOAT, there is no existing clinical protocol to follow. It is recommended that clinical judgment be used in gradually decreasing the hydromorphone or diacetylmorphine dose while simultaneously up-titrating the SROM dose.
One titration approach would start with a 10% hydromorphone/diacetylmorphine dose decrease per week, with concurrent increase in SROM. The speed of transition should be guided by the patient's goals and subjective experiences (e.g., cravings, withdrawal symptoms, sleep). General induction and dosing recommendations for SROM can be found in the BC Centre on Substance Use's A Guideline for the Clinical Management of Opioid Use Disorder. Patients should be under closer clinical review during this transition time and expert physicians should be consulted.
Although the evidence base for SROM is less robust than for other oral OAT medications (methadone and buprenorphine/naloxone), research has demonstrated that it is a safe and effective alternative to first-line treatment options, particularly in patients who have not benefited from first-line treatment options in the past. 159,160 Slow-release oral morphine may also confer specific advantages for patients engaged in iOAT who wish to transition to lower-intensity treatment, as the majority of these patients have not previously demonstrated benefit from oral methadone or buprenorphine/naloxone prior to iOAT initiation, and may wish to try an alternative treatment. Further, there is some evidence that supplemental SROM may help to reduce iOAT dose and frequency of daily injections among those individuals interested in doing so. A brief overview of the literature regarding use of SROM in the treatment of OUD, including as a supplement to ongoing iOAT, is provided below.
A 2014 two-phase study investigating the safety and efficacy of SROM compared to methadone in adults with moderate to severe OUD who had been in methadone maintenance programs for at least 26 weeks found those on SROM reported fewer cravings, higher levels of treatment satisfaction, and lower levels of stress. In the first phase, patients were randomly assigned to receive either methadone or SROM for 11 weeks. In the second phase, the medications were switched, so each patient received both methadone and SROM for 11 weeks each. After the second 11-week phase, patients from both groups were offered a 25-week extension of SROM. Those individuals who switched from methadone to SROM during the study's extension period reported zero loss of efficacy or tolerance to medication. 161 Slowrelease oral morphine's non-inferiority 161 and favourable side effect profile compared to methadone for the treatment of OUD 44 (specifically its lack of association with a prolonged QTc and subsequent risk for arrhythmia and fewer drug-drug interactions) make it a suitable alternative to methadone.
For patients receiving iOAT and supplementary oral OAT, there is some research evidence that switching from supplementary methadone to supplementary SROM may offer advantages for patients wishing to de-intensify treatment (reduction in iOAT dose or frequency of daily injections). In a small observational study (n=12), former participants in the Randomized Injectable Opiate Treatment Trial (RIOTT) maintained on injectable diacetylmorphine supplemented with oral methadone underwent a planned transition from supplemental methadone to SROM with no planned decrease in their iOAT dose. 162 Patients were started on a 1:6 (methadone:SROM) dose ratio with a 25-30% reduction in initial SROM dose to maintain stable peak concentrations. The transition was performed over five days, with half of the original methadone dose prescribed on day 1, 30% of the original methadone dose on day 2, 20% on day 3, and no methadone prescribed thereafter. 162 Prior to the transition, all 12 patients had identified reduction of their injectable medication dose as a treatment goal. Study results indicate that, 10 weeks after the transition from supplemental methadone to SROM, patients were able to reduce the daily dose of diacetylmorphine from an average of 382mg to 315mg. 162 Patients also reported fewer cravings and improved sleep and quality of life after switching from supplementary methadone to SROM. Although more research is needed, this preliminary study suggests that supplementary SROM may be a viable alternative to methadone, and may have advantages in patients wishing to reduce their daily iOAT dose and/or those considering transition to oral OAT. It should be highlighted that this is a small observational study and additional research is needed in order to optimize transitions from iOAT to SROM.
# Transition from Hydromorphone or Diacetylmorphine to Buprenorphine/Naloxone
There is currently very limited literature on transitioning from iOAT to buprenorphine/naloxone. 163 Several patients have been successfully transitioned using the Bernese method (i.e., starting with a very low dose of buprenorphine/naloxone overlapping with iOAT, with small daily dose increases until iOAT is stopped abruptly once a sufficient dose of buprenorphine/naloxone has been reached) in Switzerland. 163 Additionally, a small number of patients have been successfully transitioned in Vancouver, both in in-patient withdrawal management facilities, following the BC-specific induction guidelines which can be found in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder, and using the Bernese method in an outpatient setting. Transition to buprenorphine/ naloxone should follow the same approach used for transitioning patients from any high-dose shortacting opioids onto buprenorphine/naloxone. Province-specific guidance can be found in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. It is recommended that patients transitioning from iOAT to buprenorphine/naloxone be seen frequently after their induction to maintain continuity of care, given the intensity of the injectable treatment they are transitioning out of.
# Provider-Initiated De-Intensification of Treatment
Although this document emphasizes that patients should never be cut off from treatment, there are circumstances in which provider-initiated de-intensification of treatment from iOAT to oral OAT is indicated. These circumstances include situations where patient behaviour represents a threat to safety, including violence against staff or other patients, or attempted or successful diversion. Decisions to initiate de-intensification of treatment should be made with the recognition that this de-intensification of treatment, if initiated by the health care provider rather than patient, may be accompanied by deterioration of the patient's physical and mental health.
Provider-initiated de-intensification of treatment is not recommended for a first attempt at diversion. Reasons for attempted or successful diversion should be explored with the patient. The treatment team should then meet to discuss strategies to prevent and manage further diversion attempts. Clinical judgment should be used to determine if a short-term conversion to oral OAT is necessary while determining the treatment team's response to diversion.
For provider-initiated conversion to oral OAT due to behaviour such as violence or diversion, it may be done more rapidly using the conversion table in Appendix 9, with a 25-30% reduction in oral OAT dose to account for incomplete cross-tolerance. In this case, prescribers must work closely with patients to create a treatment plan with additional supports to mitigate potential risk of involuntary de-intensification of treatment.
# De-Intensification of Treatment Due to Incarceration
Patients who have been convicted of a crime and face a period of incarceration must be transitioned to a suitable oral OAT option prior to, or as quickly as possible following, their entry into the correctional system. The medication-specific transition recommendations above should be followed. If transition to oral OAT is not possible prior to incarceration, the community prescriber should contact the most responsible physician (MRP) in the correctional facility to inform them that the patient is on iOAT and will thus have a high opioid tolerance and make recommendations for the management of OUD and transition to oral OAT while the patient is subject to a custodial environment.
# Management
Immediately begin management if assessment indicates a dose intolerance. Naloxone should be used alongside the principles of basic life support along with cardiopulmonary resuscitation for trained individuals (CPR; compressions plus ventilation).
The goal of naloxone administration is to:
• Achieve adequate spontaneous ventilation (RR>10/min) Opioids should not be given for acute treatment of opioid withdrawal following treatment for a dose intolerance.
# Two-Spirit:
A term used by some North American Indigenous societies to describe people with diverse gender identities, gender expressions, gender roles, and sexual orientations. Dual-gendered, or 'two-spirited' people have been and are viewed differently in different Indigenous communities. ee
Lesbian: A woman whose enduring physical, romantic, and/or emotional attraction is to other women. Some lesbians may prefer to identify as gay (adj.) or as gay women. ff
# Gay:
The adjective used to describe people whose enduring physical, romantic, and/or emotional attractions are to people of the same gender. ff
Bisexual: A person who has the capacity to form enduring physical, romantic, and/or emotional attractions to those of the same gender and those of another gender. People may experience this attraction in differing ways and degrees over their lifetime. ff
Trans: Trans is an umbrella term that describes a wide range of people whose gender and/or gender expression differ from their assigned sex and/or the societal and cultural expectations of their assigned sex. ff
Queer: An adjective used by some people, particularly younger people, whose sexuality is not heterosexual. Once considered a pejorative term, queer has been reclaimed by some 2SLGBTQ+ people to describe themselves; however, it is not a universally accepted term even within the 2SLGBTQ+ community. ff Medical management: Medical management for opioid use disorder is medically focused, unstructured, informal counselling provided by the treating clinician in conjunction with pharmacological treatment. Medical management includes but is not limited to, performing health and wellness checks, providing support and advice, assessing motivation and identifying barriers to change, creating a treatment plan, fostering medication adherence, optimizing dosing, supporting treatment adherence and relapse prevention, and providing referrals to appropriate health and social services.
Mutual-support/peer-support programs: Support that is provided through a network of peers through meetings, open discussions of personal experiences and barriers to asking for help, sponsorship, 12-step programs, and other tools of recovery. Examples include Alcoholics Anonymous, Narcotics Anonymous, SMART Recovery, and LifeRing Secular Recovery.
ee Definition borrowed and lightly adapted from Qmunity's "Queer Terminology from A to Q" ff Definitions borrowed and lightly adapted from GLAAD Media Reference Guide Diacetylmorphine: A short-acting, semi-synthetic opioid, diacetylmorphine has a rapid onset of action and a short half-life. Injected diacetylmorphine avoids first-pass metabolism and crosses rapidly into the brain where it is deacetylated into an inactive 3-monoacetylmorphine and an active 6-monoacetylmorphine which is then deacetylated into morphine, which acts as a full mu (μ) opioid receptor agonist. Injectable diacetylmorphine is used as a treatment for severe opioid use disorder in Canada and several European jurisdictions.
Hydromorphone: A short-acting, semi-synthetic mu (μ) opioid receptor agonist. Due to regulatory barriers limiting access to diacetylmorphine, hydromorphone was studied as an alternative to diacetylmorphine for the treatment of severe opioid use disorder and found to be non-inferior.
Methadone: A long-acting synthetic opioid that acts as a full mu (μ) opioid receptor agonist.
It has a half-life of approximately 24 to 36 hours and is well absorbed. In Canada, it is most frequently administered as an oral solution, generally given as a single daily dose. Methadone tablets are also available in a limited context (e.g., for travel) in some jurisdictions.
# Slow-release oral morphine:
A 24-hour slow-release formulation of morphine, a full agonist at the mu (μ) opioid receptor, that is taken orally once per day. In Canada, slow-release oral morphine is available as a capsule containing polymer-coated pellets (to slow absorption and release) of morphine sulfate. Its elimination half-life is approximately 11 to 13 hours. It is currently approved for pain management in Canada, and its use for treatment of opioid use disorder would be considered off-label.
Opioid antagonist: Medication that works by blocking opioid receptors, preventing the body from responding to opioids. Opioid antagonist medications may be used to rapidly displace opioid agonist molecules from receptors in an overdose situation (e.g., naloxone), or to facilitate continued abstinence from using opioid drugs (e.g., naltrexone). In Canada, naloxone is available in an intramuscular injection or intranasal spray (depending on availability), while naltrexone is available as an oral tablet taken once per day.
# Opioid use disorder (OUD):
A problematic pattern of opioid use leading to clinically significant impairment or distress that meets the DSM-5 Diagnostic Criteria for Opioid Use Disorder (see Appendix 4). Opioid use disorder includes the use of synthetic and/or naturally derived opioids, whether prescribed or illegally obtained. The DSM-5 terminology represents a deliberate shift away from DSM-IV terminology of "opioid abuse" or "opioid dependence", which may be considered pejorative and/or stigmatizing, to describe this condition.
Psychosocial supports: Non-therapeutic social support services that aim to improve overall individual and/or family stability and quality of life, which may include community services, social and family services, temporary and supported housing, income-assistance programs, vocational training, lifeskills education, and legal services.
Trauma-informed practice: Health care and other services grounded in an understanding of trauma that integrate the following principles: trauma awareness; safety and trustworthiness; choice, collaboration, and connection; strengths-based approaches, and skill-building. Trauma-informed services prioritize safety and empowerment and avoid approaches that are confrontational.
Treatment refractory: Refers to opioid use disorder which has been treated with standard first-line pharmacological treatments, with the individual experiencing insufficient benefit and/or continuing to use illicit opioids and experiencing poor physical and mental health as well as poor social integration. It should be noted that there has been an intentional shift away from the use of "treatment refractory," as it may inadvertently perpetuate stigma against individuals with opioid use disorder. This document uses this term, when necessary, to reflect its use in the scientific literature. However, substance use disorders are known to be chronic, relapsing conditions which may require multiple treatment approaches across the lifespan, thus rendering such a term and concept otherwise moot.
# APPENDIX 6: HEALTH CARE PROVIDER ADMINISTRATION OF INJECTABLE MEDICATION
While the ability to self-administer medication is one of the considerations for eligibility, it is recognized that there may be time-limited, discrete events such as injury that require assistance from health care providers to ensure continuity of care. In some circumstances, there may be other clinical or psychosocial indications for health care provider administration of injectable medication, in order to enable a client with specific needs to access iOAT. In these cases, and depending on the model of care and jurisdiction, health care providers may provide subcutaneous or intramuscular (IM) injections in the deltoid, ventrogluteal, or dorsogluteal muscles. Standard protocols for IM injection including rotating sites and matching site to volume of medication should be followed. Nurses may be able to provide intravenous (IV) injection when requested by the patient and determined appropriate. Regional differences may exist in terms of what medications can be administered by IV injection by various nursing professionals. Where possible, institutional policies should be developed to outline appropriate orders required, standard protocols for IV injection, and necessary staff education.
Indications that iOAT may be appropriate despite inability to inject on an ongoing basis may include lacking the skills (e.g., a patient whose partner administered street drugs intravenously for them) or the ability to self-inject (e.g., disability or mobility issues). It is recommended that clinical judgment be used in these situations to determine if iOAT with health care provider administration is the most appropriate treatment.
# APPENDIX 7: TITRATION PROCESS
The following outlines the recommended titration process for iOAT.
As with the general process for iOAT, doses are self-administered intravenously, intra-muscularly, or subcutaneously under supervision, with physicians, nurse practitioners, Registered Nurses, Registered Psychiatric Nurses, Licensed Practical Nurses, and, in some jurisdictions, pharmacists able to administer injectable medications when clinically indicated (see Appendix 6).
# Hydromorphone Titration Protocol 1-Three Doses Per Day
# Day 1 (Total Dose Range=60-90mg)
# Consider co-prescription of oral OAT (see below).
# Hydromorphone Titration Protocol 2-Two Doses Per Day
For patients who will be receiving two doses of hydromorphone per day, at the discretion of their prescriber, patients may be titrated onto a two-dose schedule. A suggested titration schedule follows. Those needing additional guidance should consult an experienced iOAT provider.
# Day 1 (Total Dose Range=60-120mg)
# Day 3 (Maximum Day 3 Total Dose=540mg)
Administer the maximum tolerated amount at Dose 3, Day 2 for each of the 3 doses on Day 3. After consulting with the prescriber, adjust the dosage once a week until the patient feels comfortable (i.e., reduced cravings and withdrawal symptoms) and does not show any excessive intoxication or respiratory depression or until the maximum dose is reached (400mg/dose and/or 1000mg/day). Dose increases are discouraged on weekends and holidays, if prescribers are not available. Maximum individual dose=180mg.
# Diacetylmorphine Titration Protocol 2-Two Doses Per Day
For patients who will be receiving two doses of diacetylmorphine per day, at the discretion of their prescriber, patients may be titrated onto a two-dose schedule. A suggested titration schedule follows. Those needing additional guidance should consult an experienced iOAT provider.
# Day 1 (Total Dose Range=120-240mg)
# Consider co-prescription of oral OAT (see below).
# Day 2 (Total Dose Range=260-360mg)
# Consider co-prescription of oral OAT (see below).
# Day 3 (Total Dose Range=400mg)
Doses 1 and 2 on Day 3 will often be the ongoing final dose for the patient. If all previous doses were well tolerated, doses on Day 3 should be 200mg
As each patient goes through the titration process, they should stop at the dose where they are
# APPENDIX 8: EXAMPLE DOSE REDUCTION PROTOCOL
For individuals who have stabilized on a maintenance dose who miss 6 consecutive doses or 2 days (whichever is first) but fewer than 9 doses or 3 days (whichever is first), their dose should be reduced by 1/3 (one-third). Each subsequent dose can be increased by 25mg until they are back at their regular dose. aa aa Adapted from PHS Community Services Society in Vancouver, BC.
# APPENDIX 9: CONVERSION TABLE
The following conversion table can be used to determine an equivalent dosage for the purpose of travel (for example, converting to witnessed ingestion of SROM for travel to a funeral) or longer term (for example, if someone is entering the corrections system or hospitalized in a facility where iOAT is not feasible or is clinically contraindicated). Ideally, travel is planned in advance, allowing for a slow titration from iOAT to oral OAT following province-specific guidelines, which can be found in CRISM's National Guideline for the Clinical Management of Opioid Use Disorder. It is recognized, however, that emergency travel (e.g., a funeral or family emergency) is at times required. In these cases, the below table can be used along with patient education to minimize safety risks. Although there is more evidence supporting the use of methadone for travel, the authors of this document favour the use of SROM, with daily witnessed ingestion, for its improved safety profile, including significantly less variability in required dosage.
# IMPORTANT SAFETY NOTE:
The conversion table below is approximate and clinical judgment should guide conversions, including reducing the target dose by 25% from the figure given in the table due to incomplete cross-tolerance. Patient safety must be prioritized in converting from iOAT to oral OAT and should follow standard principles for safe conversions between injectable and oral opioid medication routes of administration, as this table outlines approximate equianalgesic doses only for IV conversions between HM and DAM.
When possible, the converted travel dose should be trialled for a few days prior to travel to prevent destabilization.
Patients should be provided with take-home naloxone kits and training on how to administer naloxone. It is ideal to have family or friends who can observe them for sedation or respiratory depression.
Dose conversion should be calculated cautiously and multiple-day prescriptions of oral OAT should be prescribed with recognition of the cumulative effects of dosing.
Most patients do well on doses of methadone between 60-120mg per day. 33 To ensure patient safety, it is recommended that this target dose range not be exceeded and that a maximum dose of 1200mg SROM not be exceeded.
# APPENDIX 11: COMMON AND SERIOUS SIDE EFFECTS
Hydromorphone and diacetylmorphine can cause the same side effects as other opioids, including sedation, nausea and vomiting, constipation, miosis, flushing, and pruritus. 164 The 3-glucoronide metabolite of hydromorphone has been implicated in neuroexcitation symptoms (e.g., tremor, myoclonus, cognitive dysfunction). 165 In addition, long-term opioid use, including iOAT, may lead to abnormalities in the endocrine system, mainly affecting the gonadal axis and leading to hypogonadism. 22,23 In line with this, low testosterone levels and erectile dysfunction have been associated with long-term opioid use (including oral OAT) in males, 24 and menstrual disturbances in females. 22 Osteoporosis and reduced bone mineral density can also result from hypogonadism. Specific serious side effects noted in clinical trials are provided in the table below.
Diacetylmorphine may pose an increased risk of other adverse events (e.g., histamine reactions, seizures, and overdose) compared to injectable hydromorphone 13 and oral methadone. 11,12 Studies in Europe and Canada have reported instances of significant respiratory depression events in people receiving injectable opioids, at an overall rate of about 1 in every 6000 injections, which is significantly lower than the risk present when injecting street heroin. 12 In the 12-month NAOMI trial, two SAEs involving sepsis or other infections were reported, while three SAEs involving abscesses or cellulitis were reported, across a total of 89,924 injections. 14 In the SALOME trial, over the 180-day treatment period, 18 adverse events involving infectious complications were reported (14 cellulitis, 4 subcutaneous abscesses) over a total of 85,451 injections, which translates to 3.4% and 4.8% of all adverse events deemed related to injectable hydromorphone and diacetylmorphine treatment, respectively. 38 Urine drug testing (UDT) can be used to help guide patient care, to ensure patients are aware of which substances they are ingesting if using illicit substances, and to start a conversation on harm reduction and safety. Unlike with oral OAT, where regular and random UDT are considered standard of care, regular and mandatory call-back UDT are not considered standard care for iOAT, due to both the low risk of diversion and the high frequency of contact with care providers.
Other than the initial UDTs performed to confirm illicit opioid use, there is no required number of UDTs for iOAT programs. Point-of-care UDT may be useful for providing immediate feedback to patients and for making prompt treatment decisions, when potentially harmful substances are detected, as well as monitoring trends. Typically, point-of-care UDT can be used to detect amphetamines, benzodiazepines, cocaine, opioids (morphine, codeine, heroin metabolite, opium, and sometimes hydromorphone), oxycodone, buprenorphine, and methadone. Specific substances tested for will vary by product and manufacturer. Given the public health emergency in parts of Canada, point-of-care tests should include fentanyl.
Given the risk of fentanyl contamination in illicit substances, including stimulants and other nonopioids, it is recommended that prescribers discuss drug checking with patients and the option for urine or take-home fentanyl testing.
It is emphasized that UDT should not be used punitively and should not lead to discharge for ongoing stimulant or opioid use. Patients who are showing signs of instability or disclose ongoing illicit substance use may benefit from using UDT to guide more intensive follow-up and reassessment. Following discussion with the patient about any underlying issues contributing to treatment instability, prescribers can consider adjusting iOAT dose, prescribing a supplemental daily dose of oral methadone or SROM, or adjusting supplemental oral OAT dose if current dose is inadequate; increasing the frequency of clinical appointments in order to provide more intensive support, monitoring and assessment; and/or providing referrals to adjunct psychosocial and community-based supports, as appropriate. If treatment intensification does not adequately address clinical or social instability, and/or if patient safety is a serious concern, prescribers and patients may need to consider alternative treatment options or care settings, such as the comprehensive and dedicated supervised iOAT model of care (see iOAT Operations Guidance).
# APPENDIX 13: RESPONDING TO DOSE INTOLERANCES
Each iOAT program should have its own protocols in place for responding to dose intolerances and other adverse events, including required documentation. The following provides general guidance on how to respond to dose intolerances, adapted from the BC Centre for Disease Control's Administration of Naloxone Decision Support Tool. This guidance can be adapted to local practice setting and should be tailored to each specific site.
# Clinical Features of Dose Intolerance:
Signs and symptoms of opioid intoxication (dose intolerance) include:
• Decreased respiratory rate or absence of respirations. A respiratory rate of fewer than 10-12/ min is the best clinical predictor of opioid intoxication
• Oxygen saturation of <90% on room air
• Gurgling or snoring-type sounds
• Slow, erratic, or absent heart rate • Vomiting
• Altered mental status (minimally responsive to unresponsive)
• Constricted (pinpoint) pupils (however, the presence of pinpoint pupils alone is not sufficient to diagnose opioid intoxication)
• Cold and clammy skin (may appear cyanotic [blueish], especially around the lips or nailbeds, in individuals with lighter skin; may appear grayish or ashen in individuals with darker skin)
# Assessment
Assessment should be rapidly performed to determine if dose intolerance is suspected and whether naloxone administration is indicated. The assessment should also look for factors that might complicate the management of dose intolerance and necessitate rapid referral to a hospital setting. The predose assessment may identify complicating factors. Special considerations: An initial dose of 0.2mg IM/SC may be administered in advanced practice settings where extra supports (e.g., supplemental oxygen, pulse oximetry) are available and capacity exists for continued resuscitation and monitoring.
# Information on Naloxone HCL
In these advanced practice settings, 911 may not necessarily be required, if adequate staffing and training support the capacity to continually monitor individuals and resuscitate and provide care as needed.
Naloxone's duration of action (20-90 minutes) is shorter than that of all opioids. Thus, individuals should be observed until the opioid effect has worn off.
# Follow-Up Care
The effects of naloxone wear off after 20-90 minutes, while the effects of opioids last much longer. Individuals should be monitored for a minimum of 2-3 hours following the last dose of naloxone. If necessary, provide additional doses of naloxone. Advise clients to not use more opioids for a minimum of 2-3 hours following the last dose of naloxone. While I am receiving hydromorphone/diacetylmorphine treatment, I will not obtain opioid prescriptions or other psychoactive medications (e.g., sleeping pills or pain medication) from other doctors, nurse practitioners, clinics, or elsewhere. If I need opioids for the treatment of acute pain, I will inform the prescriber that I am on iOAT and will agree to communication between this prescriber and my iOAT prescriber to help coordinate safety. For my safety, I give consent to my hydromorphone/diacetylmorphine prescriber to communicate with my pharmacist and any other physicians or nurse practitioners currently or previously involved in my care, and to check my province's prescription monitoring program. I will work with my treatment team to develop a treatment plan and set goals. We will review them regularly and change as needed. In addition to hydromorphone/diacetylmorphine, I can participate in counseling or peer-support groups and other programs as part of my treatment plan. My treatment team will give me information about the options and programs available in my community. My treating team may include some or all of the following: prescriber, nurses, social worker, pharmacist, and others.
My treating team will work collaboratively and respectfully with me in planning treatment and providing care. I can expect confidentiality about my treatment from my treatment team and other health care providers. My personal information will not be shared except with other health care providers as I agreed to above. I understand that confidentiality will need to be breached if I am a danger to myself or others or if a child is at risk. I can decide if I want to continue, stop, or change my treatment plan at any time. I agree to make this decision with my prescriber.
Hydromorphone/diacetylmorphine treatment will require multiple daily trips to the facility where I receive my medication, which may impact my work, school, or other responsibilities. If I do not attend the facility where I receive my medication for 3 consecutive doses or 1 day (number of missed doses may change once I am clinically stable), my prescriber and I will discuss the reasons for missed doses. I understand that missing more than 6 to 9 doses (3 days) may cause a loss of tolerance and may require that, for my safety, I take a lower dose until I stabilize. If I am assessed to be intoxicated during the pre-injection assessment, my dose will be postponed or withheld for my safety.
I have discussed potential side effects and adverse events (seizure, overdose, constipation, pruritus [severe skin itching], hypogonadism [hormonal abnormalities that can lead to low testosterone levels, erectile dysfunction, and menstrual disturbances], and sleep apnea) associated with iOAT with my health care provider and we have agreed on plans to mitigate risk. I will not be cut off from treatment. If hydromorphone/diacetylmorphine is not providing the results expected, my prescriber will work with me to adjust my dosage, increase psychosocial supports, and/or explore other treatment options.
If my prescriber can no longer provide care for me, they will refer me to another prescriber who can.
# Injectable Opioid Agonist Treatment Agreement and Consent
# I understand that I am expected to:
Provide urine for drug testing when asked.
Provide urine samples at the clinic and that these samples are not to be altered. Urine samples that are cold or appear to have been altered will be treated as a serious issue and may affect my treatment plan. Avoid using alcohol or other drugs, such as prescription or over the counter opioid medications, sleeping pills, or tranquilizers. I understand that combining these medications with hydromorphone/diacetylmorphine can lead to overdose and other serious harms and may affect my treatment plan. Notify any health care provider that I receive care from that I am taking hydromorphone/diacetylmorphine for treatment of opioid use disorder. Notify my primary care provider if I become pregnant (if applicable).
I understand that I must inform my prescriber if I am pregnant, suspect I may be pregnant, or if I am planning a pregnancy. Treat staff and other patients with respect.
# I confirm that:
This form has been reviewed in detail with the patient and they understand its content fully. This should be reviewed again when the patient is not in withdrawal. The patient was given time to ask questions and seek clarification before signing this document.
The evidence for other treatment options was reviewed, and the patient agrees to hydromorphone/diacetylmorphine. Information and resources to support psychosocial treatment interventions and supports will be provided to the patient.
The provincial prescription drug monitoring program was reviewed (where applicable) to identify other prescribed medications, and will be checked at each subsequent appointment. A treatment plan with clear goals was developed with the patient, and will be reviewed and documented regularly during treatment. The Provincial Opioid Addiction Treatment Support Program, which provides training for nurse practitioners and physicians to diagnose and treat opioid use disorder using evidence-based treatments along a continuum of care, including iOAT.
The Addiction Care and Treatment Online Course, which provides addiction medicine training for family physicians, specialists, nurses, nurse practitioners, pharmacists, and other healthcare practitioners involved in addiction care and treatment.
# Glossary
Addiction treatment: In this document, addiction treatment refers to ongoing or continued care for substance use disorder(s) delivered by a trained care provider. For opioid use disorder, this could include evidence-based pharmacological treatment (opioid agonist or antagonist treatment), evidence-based psychosocial treatments, residential treatment, or combinations of these treatment options. Addiction treatment may be provided in outpatient or inpatient settings. In isolation, withdrawal management, harm-reduction services, low-barrier housing, and unstructured peer-based support would not be considered "addiction treatment".
Cultural safety and humility: Cultural safety can be understood as an outcome in which people feel safe when receiving care in an environment free from racism and discrimination. It results from respectful engagement that seeks to address power imbalances that are inherent in the healthcare system. Cultural humility is a process undertaken to understand, through self-reflection, personal and systemic biases and to develop and maintain respectful processes and relationships based on mutual trust; it requires humbly acknowledging oneself as a learner when attempting to understand another person's experience. dd Diversion: Any non-intended or non-medical use of a prescribed opioid (including prescribed opioid agonist medication), or use by any individual other than the individual for whom it was prescribed.
# Harm reduction:
Policies and programs that aim to minimize immediate health, social, and economic harms (e.g., transmission of infectious disease, overdose mortality, criminal activity) associated with the use of psychoactive substances, without necessarily requiring a decrease in substance use or a goal of abstinence. Examples include needle and syringe exchange programs, take-home naloxone programs, supervised injection or consumption services, and outreach and education programs for high-risk populations.
Health care provider: A trained and qualified health care provider empowered to provide care related to iOAT, including supervision of medication administration and, in some jurisdictions and models of care, health care provider administered intramuscular or subcutaneous injection. May refer to doctors, nurse practitioners, Registered Nurses, Registered Psychiatric Nurses, Licensed Practical Nurses, and pharmacists.
2SLGBTQ+: Two-Spirit, lesbian, gay, bisexual, trans, queer, and other gender and sexually diverse individuals.
dd Definitions borrowed and lightly adapted from the First Nation's Health Authority.
Opioid agonist: Any substance that binds to and activates mu (μ) opioid receptors, providing relief from withdrawal symptoms and cravings in people with opioid use disorder, and pain relief if used for chronic pain management. Oral opioid agonists used for treating opioid use disorder include methadone, buprenorphine, and slow-release oral morphine. Injectable opioid agonists used for treating opioid use disorder include diacetylmorphine and hydromorphone.
Opioid agonist treatment (OAT): Opioid agonist medications prescribed for the treatment of opioid use disorder. Opioid agonist treatment is typically provided in conjunction with provider-led counselling; long-term substance-use monitoring (e.g., regular assessment, follow-up, and urine drug tests); comprehensive preventive and primary care; and referrals to psychosocial treatment interventions, psychosocial supports, and specialist care as required. In this document, OAT refers to long-term (>6 months) treatment with an opioid agonist medication that has an evidence base for use in the treatment of opioid use disorder. "Opioid agonist treatment (OAT)" is the preferred terminology, representing an intentional shift from the use of "opioid substitution treatment (OST)", "opioid maintenance treatment (OMT)", and "opioid replacement therapy (ORT)".
Buprenorphine: A long-acting synthetic opioid that acts as a partial mu (μ) opioid receptor agonist with a half-life of approximately 24 to 42 hours. Buprenorphine has a high affinity for the opioid receptor, but as a partial agonist has a lower intrinsic activity or effect at the opioid receptor compared to full agonist opioids. These pharmacological properties create a "ceiling" on opioidergic effects-including respiratory depression-at higher doses. Buprenorphine's high affinity for the opioid receptor also confers an antagonistic effect on other opioids; it preferentially binds to the receptor and displaces other opioids if they are present, which can cause precipitated withdrawal (see below). In Canada, buprenorphine is available in a combined formulation with naloxone (see below). Buprenorphine implant and depot injections were recently approved by Health Canada, but have not yet been added to provincial formularies.
Buprenorphine/naloxone: A 4:1 combined formulation of buprenorphine and naloxone, available as a sublingual tablet in Canada. Naloxone is an opioid antagonist with poor oral bioavailability when swallowed or administered sublingually, and is included to deter non-medical injection and insufflation. When buprenorphine/naloxone is taken as directed sublingually, the naloxone component has negligible effects and the therapeutic effect of buprenorphine predominates. However, if diverted for use via insufflation, subcutaneous, intramuscular, or intravenous routes, sufficient naloxone is absorbed to induce some withdrawal symptoms in physically dependent active opioid users. Buprenorphine/naloxone is generally taken once daily, but due to its favourable safety profile and pharmacological properties, it can also be prescribed at higher doses on alternate-day schedules.
# Psychosocial treatment interventions:
Structured and/or manualized treatments delivered by a trained care provider that incorporate principles of cognitive behavioural therapy, interpersonal therapy, motivational interviewing, dialectical behaviour therapy, contingency management, structured relapse prevention, biofeedback, family and/or group counselling. Psychosocial interventions may include culturally specific approaches such as traditional healers, elder involvement, and Indigenous healing ceremonies.
Recovery: A process of change through which individuals improve their health and wellness, live a self-directed life, and strive to reach their full potential. gg
Relapse: May be defined differently by each person, however, a general definition would include a re-emergence of or increase in severity of opioid use disorder symptoms and/or harms related to opioid use following a period of stability.
Stabilization: Stabilization will be patient-specific, depending on each patient's circumstances and needs and how they change over time. Patients' DSM-5 diagnoses, physical and mental health comorbidities, and social determinants of health (e.g., poverty, homelessness) should be identified at baseline and tracked over time. Stabilization includes clinical stabilization (e.g., lack of cravings, improved sleep quality and duration, and overall wellbeing) as well as psychosocial stabilization (e.g., integrating new activities, re-connecting with family, and attaining safe housing).
Trauma: Trauma can be understood as an experience that overwhelms an individual's capacity to cope. Trauma can result from a series of events or one significant event. Trauma may occur in early life (e.g., child abuse, disrupted attachment, witnessing others experience violence, or neglect) or later in life (e.g., accidents, war, unexpected loss, violence, or other life events out of one's control). Trauma can be devastating and can interfere with a person's sense of safety, sense of self, and sense of selfefficacy. Trauma can also impact a person's ability to regulate emotions and navigate relationships. People who have experienced trauma may use substances or other behaviours to cope with feelings of shame, terror, and powerlessness.
# Intergenerational trauma:
The transmission of historical oppression and unresolved trauma from caregivers to children. The concept of intergenerational or historical trauma was developed by Indigenous peoples in Canada in the 1980s to explain the cycle of trauma they were seeing in their communities due to the residential school system, loss of culture, and colonization more broadly. May also be used to describe the emotional effects, adaptations, and coping patterns developed when living with a trauma survivor.
gg Borrowed from the Substance Abuse and Mental Health Administration's "SAMHSA's Working Definition of Recovery: 10 Guiding Principles of Recovery" | None | None |
3503fcdce7168ea341b42abbf8f025ac6d8a5063 | cma | None | # PREAMBLE
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflicts of interest.
# I. INTRODUCTION
This document, the "Advisory Committee Statement: Canadian Immunization Guide Chapter on Influenza and National Advisory Committee on Immunization (NACI) Statement on Seasonal Influenza Vaccine for 2020-2021", updates NACI's recommendations regarding the use of seasonal influenza vaccines.
I.1 New or Updated Information for 2020-2021
Updated wording for the recommendation on the vaccination of health care workers and other care providers NACI recently reassessed the wording for the recommendation on the vaccination of health care workers (HCWs) and other care providers as a group for whom influenza vaccination is particularly recommended. The existing evidence on HCW influenza vaccination and the reduction of morbidity associated with influenza in patients being cared for by a HCW in health care settings was considered in the context of ethics and acceptability. NACI continues to recommend that, in the absence of contraindications, HCWs and other care providers in facilities and community settings should be vaccinated annually against influenza, and recommends the inclusion of this group among the particularly recommended recipients of influenza vaccine. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs and other care providers for their own protection and that of their patients. This group should consider annual influenza vaccination as part of their responsibilities to provide the highest standard of care.
# Recommendation on the use of LAIV in HIV-infected individuals
Live attenuated influenza vaccine (LAIV) has been authorized for use in Canada since 2011, and was previously considered contraindicated by NACI in individuals with HIV. Based on a systematic review of the available literature, NACI has concluded that LAIV is immunogenic in children with stable HIV infection on highly active antiretroviral therapy (HAART) and with adequate immune function. NACI also concluded that, while there is insufficient direct evidence to detect uncommon or rare adverse events (AEs) related to the use of LAIV in HIV infected children, LAIV appears to have a similar safety profile to inactivated influenza vaccine (IIV). In addition, some children and their substitute decision makers may prefer that they receive influenza vaccine through an intranasal spray as opposed to an intramuscular (IM) injection, although preferences will vary.
Therefore, NACI recommends that LAIV may be considered as an option for children 2-17 years of age with stable HIV infection on HAART and with adequate immune function (Discretionary NACI Recommendation). LAIV should be considered only in children with HIV who: have been receiving HAART for ≥4 months; have a CD4 count ≥500/µL if 2-5 years of age, or ≥200/µL if 6-17 years of age (measured within 100 days before administration of LAIV); and have HIV plasma ribonucleic acid (RNA) <10,000 copies/mL (measured within 100 days before administration of LAIV).
While IM influenza vaccination still is considered the standard for children living with HIV by NACI and the Canadian Pediatric and Perinatal HIV/AIDS Research Group, LAIV would be reasonable for children meeting the criteria outlined above, if IM vaccination is not accepted by the patient or substitute decision maker. LAIV remains contraindicated in adults with HIV infection due to the lack of evidence for its immunogenicity and safety, and given that LAIV may be less effective than IIV in adults. Refer to the NACI Statement on the Use of LAIV in HIV-Infected Individuals for additional information supporting this recommendation.
# I.2 Abbreviations for Influenza Vaccines
The abbreviations used in this document for the different influenza vaccines authorized in Canada are as follows: Abbreviations: IIV: inactivated influenza vaccine; IIV3: trivalent inactivated influenza vaccine; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standarddose trivalent inactivated influenza vaccine; IIV4: quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV: live attenuated influenza vaccine; LAIV3: trivalent live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine.
a The numeric suffix denotes the number of antigens contained in the vaccine ("3" refers to the trivalent formulation and "4" refers to the quadrivalent formulation). The hyphenated suffix "-SD" is used when referring to IIV products that do not have an adjuvant, contain 15 µg hemagglutinin (HA) per strain and are administered as a 0.5 mL dose by intramuscular injection; "-Adj" refers to an IIV with an adjuvant (e.g., IIV3-Adj for Fluad ® or Fluad Pediatric ® ); and "-HD" refers to an IIV that contains higher antigen content than 15 µg HA per strain (e.g., IIV3-HD for Fluzone ® High-Dose). b 15 µg HA per strain. c 7.5 µg (in 0.25 mL) or 15 µg (in 0.5 mL) HA per strain. d 60 µg HA per strain.
# I.3 Background
The World Health Organization's (WHO) recommendations on the composition of influenza virus vaccines are typically available in February of each year for the upcoming season in the Northern Hemisphere. The WHO recommends that three influenza strains be included in the trivalent seasonal influenza vaccine: one influenza A(H1N1), one influenza A(H3N2), and one influenza B. Quadrivalent seasonal influenza vaccines should contain the three strains recommended for the trivalent vaccine, as well as an influenza B virus from the lineage that is not included in the trivalent vaccine.
Annual recommendations on the use of influenza vaccine in Canada are developed by the NACI Influenza Working Group (IWG) for consideration by NACI. Recommendations are developed based on a review of a variety of issues, which can include: the burden of influenza illness and the target populations for vaccination; efficacy, effectiveness, immunogenicity, and safety of influenza vaccines; vaccine schedules; and other aspects of influenza immunization. In addition, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing their recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels. These programmatic factors include economics, ethics, equity, feasibility, and acceptability. Details regarding NACI's evidence-based process for developing a statement are outlined in Evidence-based Recommendations for Immunization − Methods of the National Advisory Committee on Immunization.
Health care providers in Canada should offer the seasonal influenza vaccine as soon as feasible after it becomes available in the fall, since seasonal influenza activity may start as early as October in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing, and intensity), opportune moments for vaccination, as well as programmatic considerations. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local public health agencies.
Although vaccination before the onset of the influenza season is strongly preferred, influenza vaccine may still be administered up until the end of the season. Delayed administration may result in lost opportunities to prevent infection from exposures that occur prior to vaccination, and patients should be informed that vaccine administered during an outbreak may not provide optimum protection. Vaccine providers should use every opportunity to administer influenza vaccine to individuals at risk who have not already been vaccinated during the current season, even after influenza activity has been documented in the community.
# II. CANADIAN IMMUNIZATION GUIDE CHAPTER ON INFLUENZA: CLINICAL INFORMATION FOR VACCINE PROVIDERS
The Canadian Immunization Guide (CIG) is written primarily for health care providers (frontline clinicians and public health practitioners) but it is also used by policy makers, program planners, and the general public. The CIG has been a trusted, reader-friendly summary of the vaccine statements provided by NACI since 1979.
The information in this section replaces the influenza chapter of the CIG and is adapted for inclusion in the NACI Statement on Seasonal Influenza Vaccine. With a new NACI Statement on Seasonal Influenza Vaccine required each year, readers will have quick access to the information that they require within one document, whether it is the relevant influenza vaccine information written primarily for frontline vaccine providers as is found in this section, or the more detailed technical information that is found in the rest of this statement, commencing in Section III.
# II.1 Key Information
The following highlights key information for vaccine providers. Please refer to the remainder of this statement for additional details.
# What
- Influenza is a respiratory infection caused primarily by influenza A and B viruses. Seasonal influenza epidemics occur annually in Canada, generally in the late fall and winter months. Influenza occurs globally with an annual attack rate estimated at 5-10% in adults and 20-30% in children (1) .
- Symptoms of influenza typically include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week to 10 days, but some people are at greater risk of severe complications, such as pneumonia or death. Influenza infection can also worsen certain chronic conditions, such as heart disease (2) .
- Both inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) are authorized for use in Canada; some protect against 3 strains of influenza (i.e., trivalent formulation, IIV3) and some protect against 4 strains of influenza (i.e., quadrivalent formulation, IIV4 or LAIV4).
- The influenza vaccine is safe and well-tolerated. The influenza vaccine cannot cause influenza illness because inactivated influenza vaccines do not contain live virus and live attenuated influenza vaccines contain weakened viruses.
# Who
NACI makes the following recommendations for individual-level and public health program-level decision making. Individual-level recommendations are intended for people wishing to protect themselves from influenza or for vaccine providers wishing to advise individual patients about preventing influenza. Program-level recommendations are intended for provinces and territories responsible for making decisions on publicly funded immunization programs. Individual-level and program-level recommendations may differ, as the important factors to consider when recommending a vaccine for a population (e.g., population demographics, economic considerations) may be different than for an individual.
# Recommendation for individual-level decision making
- NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see List 1). These groups include:
-people at high risk of influenza-related complications or hospitalization; -people capable of transmitting influenza to those at high risk; -people who provide essential community services; and -people in direct contact with poultry infected with avian influenza during culling operations.
Influenza vaccine is less immunogenic in infants less than 6 months of age than in older children and adults and does not confer sufficient protection to make the vaccine useful before 6 months of age (3) . Currently authorized influenza vaccines are not indicated for use in infants less than 6 months of age. For these reasons, NACI recommends that influenza vaccine should not be offered to infants less than 6 months of age. However, infants less than 6 months of age are at high risk of influenza-related illness; therefore the influenza vaccine should be offered to their household contacts, care providers, and pregnant women (see List 1).
# Recommendation for public health program-level decision-making
The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors.
- NACI recommends that influenza vaccine should be offered as a priority to the groups for whom influenza vaccination is particularly recommended (see List 1 in the section below).
# People for whom influenza vaccination is particularly recommended
# People capable of transmitting influenza to those at high risk
- Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated: -household contacts of individuals at high risk; -household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine; -members of a household expecting a newborn during the influenza season; Those providing regular child care to children 0-59 months of age, whether in or out of the home; and Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a ship).
# Others
- People who provide essential community services; and People who are in direct contact with poultry infected with avian influenza during culling operations.
a Refer to Immunization of Persons with Chronic Diseases and Immunization of Immunocompromised Persons in Part 3 of the CIG for additional information about vaccination of people with chronic diseases.
# How
The benefits and risks of influenza vaccination should be discussed prior to vaccination, including the risks of not being immunized.
# Choice of influenza vaccine
A variety of influenza vaccines are authorized for use in Canada, some of which are authorized for use only in specific age groups. Therefore, the choice of influenza vaccine has become more complex. Refer to Section II.5 for recommendations on the choice of influenza vaccine by age group.
# Dose and route of administration
The dose and route of administration varies by product (see Section II.6 for details).
- Unadjuvanted IIVs are administered as a 0.5 mL intramuscular (IM) injection for everyone 6 months of age and older;
- MF59-adjuvanted trivalent inactivated influenza vaccine (Fluad ® ) is administered as a 0.5 mL IM injection for adults 65 years of age and older. A pediatric formulation is also available (Fluad Pediatric ® ), and is administered as a 0.25 mL IM injection for children 6-23 months of age;
- LAIV (FluMist ® Quadrivalent) is administered as 0.2 mL given intranasally (0.1 mL in each nostril) for individuals 2-59 years of age.
# Schedule
# NACI recommends that:
- Adults and children 9 years of age and older should receive 1 dose of influenza vaccine each year; and Children 6 months to less than 9 years of age who have never received the seasonal influenza vaccine in a previous influenza season should be given 2 doses of influenza vaccine in the current season, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in any previous season should receive 1 dose of influenza vaccine per season thereafter.
# Contraindications
For all influenza vaccines (IIV and LAIV), NACI recommends that influenza vaccination should not be given to:
- People who have had an anaphylactic reaction to a previous dose of influenza vaccine;
- People who have had an anaphylactic reaction to any of the components of that specific influenza vaccine, with the exception of egg (refer to Section II.7 for more information); -If an individual is found to have an anaphylactic reaction to a component in one influenza vaccine, consideration may be given to offering another influenza vaccine that does not contain the implicated component, in consultation with an allergy expert. Individuals who have an allergy to substances that are not components of the influenza vaccine are not at increased risk of allergy to influenza vaccine. -Egg allergy is not a contraindication for influenza vaccination, as there is a low risk of AEs associated with the trace amounts of ovalbumin allowed in influenza vaccines manufactured using eggs. Egg-allergic individuals may be vaccinated against influenza using any age-appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg, and in any setting where vaccines are routinely administered. -As with any vaccine product, vaccine providers should be prepared for and have the necessary equipment to respond to a vaccine emergency at all times.
- People who have developed Guillain-Barré Syndrome (GBS) within 6 weeks of a previous influenza vaccination (refer to Section II.7 for more information).
-The potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
For LAIV, in addition to the above-mentioned contraindications, NACI also recommends that LAIV should not be given to:
- People with immune compromising conditions, with the exception of children with stable HIV infection on HAART and with adequate immune function (see Section IV.2 for more information); -Immune compromising conditions may be due to underlying disease, therapy, or both;
- People with severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing) or medically attended wheezing in the 7 days prior to the proposed date of vaccination, due to increased risk of wheezing following administration of LAIV; -LAIV is not contraindicated for people with a history of stable asthma or recurrent wheeze.
- Children less than 24 months of age, due to increased risk of wheezing following administration of LAIV;
- Children 2-17 years of age currently receiving aspirin or aspirin-containing therapy, because of the association of Reye's syndrome with aspirin and wild-type influenza infection; -In addition, aspirin-containing products in children less than 18 years of age should be delayed for 4 weeks after receipt of LAIV.
- Pregnant women, because it is a live attenuated vaccine and there is a lack of safety data at this time; -LAIV is not contraindicated in breastfeeding mothers.
- Receipt of an anti-influenza antiviral drug in the previous 48 hours.
Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 of the CIG for a list of all vaccines authorized for use in Canada and their contents and to Vaccine Safety in Part 2 of the CIG for information regarding the management of AEs, including anaphylaxis.
# Precautions
# NACI recommends that:
- Influenza vaccination should usually be postponed in people with serious acute illnesses until their symptoms have abated; -Vaccination should not be delayed because of minor or moderate acute illness, with or without fever.
- If significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa, IIV can be administered or LAIV can be deferred until resolution of the congestion;
- LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection; and LAIV should not be administered until 48 hours after antiviral agents active against influenza (e.g., oseltamivir, zanamivir) are stopped, and those antiviral agents, unless medically indicated, should not be administered until 2 weeks after receipt of LAIV so that the antiviral agents do not kill the replicating vaccine virus.
-If antiviral agents are administered within this time frame (i.e., from 48 hours prevaccination with LAIV to 2 weeks post-vaccination), revaccination should take place at least 48 hours after the antivirals are stopped, or IIV could be given at any time.
- LAIV recipients who are less than 18 years of age should avoid the use of aspirincontaining products for at least 4 weeks after receipt of LAIV.
Refer to Section II.7 for additional information on influenza vaccine-related precautions.
# Simultaneous administration with other vaccines
# NACI recommends that:
- All seasonal influenza vaccines, including LAIV, may be considered for administration at the same time as, or at any time before or after, administration of any other live attenuated or inactivated vaccines (see Section II.6 below for details); -It should be noted that no studies have been conducted on the co-administration of recombinant zoster vaccine (RZV) with adjuvanted or high-dose influenza vaccine. No immune response interference or safety concerns have been demonstrated when RZV is administered concomitantly with standard dose, unadjuvanted vaccine (4) .
- Different injection sites and separate needles and syringes should be used for concomitant parenteral injections.
# Why
- Vaccination is the most effective way to prevent influenza and its complications. Vaccinated individuals who are protected from influenza will not pass infection to others. Although most people will recover fully from influenza infection in 7-10 days, influenza can lead to severe complications, including hospitalization and death.
- Annual vaccination is required because the specific strains in the vaccine are reviewed each year by WHO and are often changed to provide a better match against the viruses expected to circulate in that given year, and because the body's immune response to influenza vaccination is transient and may not persist beyond a year.
# II.2 Epidemiology Disease description
Influenza is a respiratory illness caused by the influenza A and B viruses and can cause mild to severe illness, which can result in hospitalization or death. Certain populations, such as young children, older adults, and those with chronic health conditions, may be at higher risk for serious influenza complications such as viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions.
# Infectious agent
There are two main types of influenza virus that cause seasonal epidemics: Over time, antigenic variation (antigenic drift) of strains occurs within an influenza A subtype or a B lineage. The ever-present possibility of antigenic drift, which may occur in one or more influenza virus strains, requires seasonal influenza vaccines to be reformulated annually, with one or more vaccine strains changing in most seasons.
A
# Transmission
Influenza is primarily transmitted by droplets spread through coughing or sneezing and through direct or indirect contact with respiratory secretions. The incubation period of seasonal influenza is usually 2 days but can range from 1-4 days. Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.
# Risk factors
The people at greatest risk of influenza-related complications are adults and children with chronic health conditions (see List 1), residents of nursing homes and other chronic care facilities, adults 65 years of age and older, children 0-59 months of age, pregnant women, and Indigenous peoples.
# Seasonal and temporal patterns
Influenza activity in Canada is usually low in the late spring and summer, begins to increase over the fall, and peaks in the winter months. Depending on the year, the peak may occur as early as fall or as late as spring. Influenza season in Canada can last from a few weeks to many months, and more than one influenza strain typically circulates each season.
# Spectrum of clinical illness
Symptoms typically include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week or 10 days. However, adults and children with chronic health conditions, adults 65 years of age and older, children 0-59 months of age, residents of long-term care facilities, pregnant women, and Indigenous peoples are at greater risk of more severe complications or worsening of their underlying condition.
# Disease incidence
Global Worldwide, annual epidemics result in approximately one billion cases of influenza, three to five million cases of severe illness, and 290,000 to 650,000 deaths. The global annual attack rate is estimated to be 5-10% in adults and 20-30% in children (1) . For current international influenza activity information, refer to WHO's FluNet website.
# National
Together, influenza and pneumonia are ranked among the top 10 leading causes of death in Canada (5) .The FluWatch program is Canada's national surveillance system, which monitors the spread of influenza and influenza-like illnesses (ILI) continually throughout the year. Since the 2010-2011 season, an average of 30,000 laboratory-confirmed cases of influenza have been reported to FluWatch each year. Although the burden of influenza can vary from year to year, it is estimated that there are an average of 12,200 hospitalizations related to influenza and approximately 3,500 deaths attributable to influenza annually (6,7) . Current influenza activity information can be found on the FluWatch website.
It should be noted that the incidence of influenza is often underreported since the illness may be confused with other viral illnesses and many people with ILI do not seek medical care or have viral diagnostic testing done.
# II.3 Vaccine Products Authorized for Use in Canada
This section describes the influenza vaccine products that are authorized for use in Canada for the 2020-2021 season. All influenza vaccines available in Canada have been authorized by Health Canada. However, not all products authorized for use are necessarily available in the marketplace. The vaccine manufacturers determine whether they will make any or all of their products available in a given market. Provincial and territorial health authorities then determine which of the products available for purchase will be used in their respective publicly funded influenza immunization programs and for which population groups.
The antigenic characteristics of circulating influenza virus strains provide the basis for selecting the strains included in each year's vaccine. Vaccine selection by the WHO generally occurs more than 6 months prior to the start of the influenza season to allow time for the vaccine manufacturers to produce the required quantity of vaccine. All manufacturers that distribute influenza vaccine products in Canada confirm to Health Canada that the vaccines to be marketed in Canada for the upcoming influenza season contain the WHO's recommended antigenic strains for the Northern Hemisphere. Vaccine producers may use antigenically equivalent strains because of their growth properties.
There are two categories of influenza vaccine authorized for use in Canada: inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV). Trivalent (3 strain) vaccines contain one A(H1N1) strain, one A(H3N2) strain, and one influenza B strain from one of the two lineages. Quadrivalent (4 strain) vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage. All influenza vaccines currently authorized for use in Canada are made from influenza viruses grown in eggs.
A summary of the characteristics of influenza vaccines available in Canada during the 2020-2021 influenza season can be found in Appendix A. For complete prescribing information, readers should consult the product monographs available through Health Canada's Drug Product Database.
# Standard-dose inactivated influenza vaccine (IIV-SD)
The standard-dose inactivated influenza vaccines (IIV-SDs) currently authorized for use in Canada are a mix of split virus and subunit vaccines. In split virus vaccines, the virus has been disrupted by a detergent. In subunit vaccines, HA and NA have been further purified by removal of other viral components. These vaccines are unadjuvanted, contain 15 µg HA per strain, and are administered as a 0.5 mL dose by IM injection. Refer to Basic Immunology and Vaccinology in Part 1 of the CIG for more information about inactivated vaccines.
Both trivalent (IIV3-SD: Agriflu ® , Fluviral ® , Influvac ® , and Vaxigrip ® ) and quadrivalent (IIV4-SD: Afluria ® Tetra, Flulaval ® Tetra, Fluzone ® Quadrivalent, and Influvac ® Tetra) products are authorized for use in Canada.
# Adjuvanted inactivated influenza vaccine (IIV-Adj)
The adjuvanted inactivated influenza vaccine (IIV-Adj) currently authorized for use in Canada is a trivalent subunit IIV that contains the adjuvant MF59, which is an oil-in-water emulsion composed of squalene as the oil phase that is stabilized with the surfactants polysorbate 80 and sorbitan triolate in citrate buffer. IIV-Adj contains 7.5 µg HA per strain administered as a 0.25 mL dose by IM injection for children 6-23 months of age (Fluad Pediatric ® ) or 15 µg HA per strain administered as a 0.5 mL dose by IM injection for adults 65 years of age and older (Fluad ® ). Other IIVs do not contain an adjuvant.
# High-dose inactivated influenza vaccine (IIV-HD)
The high-dose inactivated influenza vaccine (IIV-HD) currently authorized for use in Canada is a trivalent unadjuvanted, split virus IIV that contains 60 µg HA per strain and is administered as a 0.5 mL dose by IM injection (Fluzone ® High-Dose).
# Live attenuated influenza vaccine (LAIV)
LAIV is given as an intranasal spray. The influenza viruses contained in LAIV are attenuated so that they do not cause influenza and are cold-adapted and temperature sensitive, so that they replicate in the nasal mucosa rather than the lower respiratory tract. LAIV contains standardized quantities of fluorescent focus units (FFU) of live attenuated reassortants and is given as a 0.2 mL dose (0.1 mL in each nostril).
A quadrivalent product (LAIV4; FluMist ® Quadrivalent) is authorized for use in Canada for children 2-17 years of age and adults 18-59 years of age. The trivalent formulation (LAIV3) is no longer available in Canada.
# II.4 Efficacy, Effectiveness, and Immunogenicity
Efficacy and effectiveness
Influenza vaccine has been shown in randomized controlled clinical trials to be efficacious in providing protection against influenza infection and illness. However, the effectiveness of the vaccine-that is, how it performs in settings that are more reflective of usual health care practicecan vary from season to season and by influenza vaccine strain type and subtype. Influenza vaccine effectiveness (VE) depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype, as well as the health and age of the individual receiving the vaccine. Even when there is a less-than-ideal match or lower effectiveness against one strain, the possibility of lower VE should not preclude vaccination, particularly for people at high risk of influenza-related complications and hospitalization, since vaccinated individuals are still more likely to be protected compared to those who are unvaccinated.
# Immunogenicity
Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are generally achieved by 2 weeks after vaccination; however, there may be some protection afforded before that time.
# II.5 Choice of Seasonal Influenza Vaccine
The decision to include specific influenza vaccines as part of publicly funded provincial and territorial programs depends on several factors, such as cost-effectiveness evaluation and other programmatic and operational factors, such as implementation strategies. Not all products will be made available in all jurisdictions and availability of some products may be limited; therefore, officials in individual provinces and territories should be consulted regarding the products available in individual jurisdictions.
With the availability of influenza vaccines that are designed to enhance immunogenicity in specific age groups or given through a different route of administration, the choice of product has become more complex.
# Choice of influenza vaccine by age group
Recommendations for individual-level decision making NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine. Table 2 provides age group-specific recommendations for the age-appropriate influenza vaccine types authorized for use in Canada.
Recommendations for public health program-level decision making NACI recommends that any of the age-appropriate influenza vaccine types available for use may be considered for people without contraindications to the vaccine. Table 2 provides age group-specific recommendations for the age-appropriate influenza vaccine types authorized in Canada.
# II.6 Vaccine Administration
Dose, route of administration, and schedule
With the variety of influenza vaccines available for use in Canada, it is important for vaccine providers to note the specific differences in age indication, route of administration, dosage, and schedule for the products that they will be using (see Table 3). Key relevant details and differences between vaccine products are also highlighted in Appendix A.
For influenza vaccines given by the IM route, the anterolateral thigh muscle is the recommended site in infants 6-12 months of age. The anterolateral thigh or the deltoid muscle can be used for toddlers and older children. The deltoid muscle of the arm is the preferred injection site in adolescents and adults. For more information on vaccine administration, please refer to Vaccine Administration Practices in Part 1 of the CIG. f Evidence suggests moderate improvement in antibody response in infants, without an increase in reactogenicity, with the use of full vaccine doses (0.5 mL) for unadjuvanted inactivated influenza vaccines (8,9) . This moderate improvement in antibody response without an increase in reactogenicity is the basis for the full dose recommendation for unadjuvanted inactivated vaccine for all ages. For more information, refer to Statement on Seasonal Influenza Vaccine for 2011-2012. g Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.
# Booster doses and revaccination
Booster doses are not required within the same influenza season. However, children 6 months to less than 9 years of age who have not previously received the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses (see Table 3). Only one dose of influenza vaccine per season is recommended for everyone else. Two doses of seasonal influenza vaccine in older adults do not appear to improve the immune response to the vaccine compared to one dose (11) .
# Serological testing
Serologic testing is not necessary before or after receiving seasonal influenza vaccine.
# Storage requirements
Influenza vaccine should be stored at +2°C to +8°C and should not be frozen. Refer to the individual product monographs for further details. Refer to Storage and Handling of Immunizing Agents in Part 1 of the CIG for additional information.
# Simultaneous administration with other vaccines
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Studies have been done showing no interference when administering LAIV3 concomitantly with: measles, mumps, rubella (MMR); measles, mumps, rubella, varicella (MMRV); or oral polio live vaccines (10,12,13) . No studies have been done to assess the possibility of interference between LAIV and other live vaccines, or on LAIV given before or after other live vaccines. Additional information regarding simultaneous administration with other vaccines can be found in Section IV.4 of this statement.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of an inactivated influenza vaccine would avoid this theoretical concern. Note that the timing rules related to two parenteral live vaccines (e.g., MMR and varicella vaccines) still apply. For more information regarding vaccination administration timing rules, please refer to Timing of Vaccine Administration in Part 1 of the CIG.
When more than one injection is given at a single clinic visit, it is preferable to administer them in different limbs. If it is not possible to do so, injections given in one limb should be separated by a distance of at least 2.5 cm (1 inch). A separate needle and syringe should be used for each injection.
The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. Vaccine providers should take the opportunity to vaccinate eligible people against pneumococcal disease when influenza vaccine is given.
# Simultaneous administration with recombinant zoster vaccine
RZV is a recombinant adjuvanted subunit herpes zoster vaccine (Shingrix ® , GlaxoSmithKline) that is authorized for use in Canada in adults 50 years of age and older; therefore, the target age group for herpes zoster vaccine and influenza vaccine overlap. RZV has been shown to be safe and effective when given concomitantly with unadjuvanted, standard dose influenza vaccines (4) . However, no studies have been conducted that have assessed the co-administration of RZV with adjuvanted or high dose influenza vaccine (14) . It should be noted that that the RZV and IIV-adj currently authorized for use in Canada contain the adjuvants AS01B and MF59 respectively. How these adjuvants may interact when RZV and IIV-adj are administered concomitantly is not known.
# II.7 Vaccine Safety and Adverse Events
Post-marketing surveillance of influenza vaccines in Canada has shown that seasonal influenza vaccines have a safe and stable profile. In addition to routine surveillance, every year during the seasonal influenza vaccination campaigns, PHAC and the Federal/Provincial/Territorial Vaccine Vigilance Working Group (VVWG) of the Canadian Immunization Committee conduct weekly expedited surveillance of AEFIs for current influenza vaccines in order to identify vaccine safety signals in a timely manner. Refer to the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) web page for more information on post-marketing surveillance and AEFIs in Canada.
All influenza vaccines currently authorized for use in Canada are considered safe for use in people with latex allergies. The multi-dose vial formulations of inactivated influenza vaccine that are authorized for use in Canada contain minute quantities of thimerosal, which is used as a preservative (15,16) to keep the product sterile. Large cohort studies of administrative health databases have found no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders (17) . All single dose formulations of IIV and LAIV are thimerosal-free. Refer to Vaccine Safety in Part 2 of the CIG for additional information.
# Common adverse events
With IM administered influenza vaccines, injection site reactions are common but are generally classified as mild and transient. IIV3-Adj tends to produce more extensive injection site reactions than unadjuvanted IIV3, but these reactions are also generally mild and resolve spontaneously within a few days. IIV3-HD tends to induce higher rates of systemic reactions post-injection compared to IIV3-SD, but most of these reactions are mild and short-lived. The most common AEs experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. Refer to the relevant subsections of Section IV for additional information.
Less common and serious or severe adverse events Serious adverse events (SAEs) are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some vaccine components. Refer to Section IV.5 below for additional information.
Other reported adverse events and conditions
# Guillain-Barré syndrome
Studies suggest that the absolute risk of Guillain-Barré syndrome (GBS) in the period following seasonal and A(H1N1)pdm09 influenza vaccination is about one excess case per million vaccinations (18,19) , and that the risk of GBS associated with influenza illness is larger (about 17 cases per million influenza-coded health care encounters, which are a proxy for influenza illness) than that associated with influenza vaccination (19) .
Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
# Oculorespiratory syndrome
Oculorespiratory syndrome (ORS), which is defined as the presence of bilateral red eyes and one or more associated respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial oedema, was identified during the 2000-2001 influenza season (20) . Since then, there have been far fewer cases per year reported to CAEFISS (21) . ORS is not considered to be an allergic response. People who have a recurrence of ORS upon vaccination do not necessarily experience further episodes with future vaccinations.
# Allergic reactions to previous vaccine doses
Expert review of the benefits and risks of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent significant allergic reaction to the vaccine, or any other symptoms that could indicate a significant allergic reaction (e.g., throat constriction, difficulty swallowing) that raise concern regarding the safety of revaccination. This advice may be obtained from experts in infectious disease, allergy, and immunology, or public health.
In view of the considerable morbidity and mortality associated with influenza, a diagnosis of influenza vaccine allergy should not be made without confirmation, which may involve consultation with an allergy or immunology expert.
# Drug interactions
Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterollowering actions. Two published studies have found that adults who are regular statin users (at least 65 years of age (22) in one study and 45 years and older in the other (23) had an apparent decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT) (22) or reduced VE against medically attended acute respiratory illness (23) . Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concomitant statin use in adult populations could have implications for influenza VE and how this use is assessed in the measurement of VE. NACI will continue to monitor the literature related to this issue.
# Guidance on reporting adverse events following immunization
To ensure the ongoing safety of influenza vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in most jurisdictions, reporting is mandatory under the law.
An AEFI is any untoward medical occurrence that follows vaccination and that does not necessarily have a causal relationship with the usage of a vaccine. The AE may be any unfavourable or unintended sign, abnormal laboratory finding, symptom, or disease. In general, any AE felt to be temporally related to vaccination and for which there is no other clear cause at the time of reporting should be reported. Of particular interest are those AEFIs which are considered serious or unexpected. A serious AEFI is an AE that is life threatening or results in death, requires hospitalization or prolongation of an existing hospitalization, results in residual disability or causes congenital malformation (24) . An unexpected AEFI is an event that is not listed in the approved product monograph but may be due to the vaccination, or one whose nature, severity, specificity, or outcome is not consistent with the term or description used in the product monograph (24) . Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. If there is any doubt as to whether or not an event should be reported, a conservative approach should be taken and the event should be reported.
For influenza vaccines, the following AEFIs are of particular interest:
- ORS; and GBS within 6 weeks following vaccination.
Refer to Reporting Adverse Events Following Immunization (AEFI) in Canada for additional information about AEFI reporting and to Vaccine Safety in Part 2 of the CIG for general vaccine safety information.
# II.8 Travellers
Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere).
- NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older, including travellers, who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see List 1).
Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination (i.e., boosting) of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity or difference between the Northern and Southern Hemisphere vaccines, the similarity or difference between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination. Refer to Immunization of Travellers in Part 3 of the CIG for additional general information.
This concludes the summary of relevant influenza vaccine information typically found in the Canadian Immunization Guide. Additional technical information related to seasonal influenza vaccine can be found in the remainder of this statement.
# III. PARTICULARLY RECOMMENDED VACCINE RECIPIENTS: ADDITIONAL INFORMATION
The groups for whom influenza vaccination is particularly recommended are presented in List 1 of Section II. Additional information regarding these particularly recommended recipients is provided below.
# III.1 People at High Risk of Influenza-Related Complications or Hospitalization
All pregnant women NACI recommends the inclusion of all pregnant women, at any stage of pregnancy, among the particularly recommended recipients of IIV, due to the risk of influenza-associated morbidity in pregnant women (25)(26)(27)(28)(29) , evidence of adverse neonatal outcomes associated with maternal respiratory hospitalization or influenza during pregnancy (30)(31)(32)(33) , evidence that vaccination of pregnant women protects their newborns from influenza and influenza-related hospitalization (34)(35)(36)(37) , and evidence that infants born during influenza season to vaccinated women are less likely to be premature, small for gestational age, and of low birth weight than if born to women that had not received an influenza vaccine (38)(39)(40)(41) . The risk of influenza-related hospitalization increases with length of gestation (i.e., it is higher in the third trimester than in the second).
The safety of IIV during pregnancy has been reviewed (42) . Active studies of influenza vaccination during pregnancy have not shown evidence of harm to the mother or fetus associated with influenza vaccination (43) . Although the cumulative sample size of active studies of influenza vaccination in pregnant women is relatively small, particularly in the first trimester, passive surveillance has not raised any safety concerns despite widespread use of IIV during pregnancy over several decades (27,28,42,44) . Surveillance following the use of both adjuvanted and unadjuvanted 2009 pandemic influenza A(H1N1) vaccines in more than 100,000 pregnant women in Canada and more than 488,000 pregnant women in Europe (45) has not revealed any safety concerns.
Refer to the Statement on Seasonal Influenza Vaccine for 2011-2012 and the Statement on Seasonal Influenza Vaccine for 2012-2013 for further details on influenza vaccination during pregnancy.
# Adults and children with chronic health conditions
A number of chronic health conditions, as noted in List 1, are associated with increased risk of influenza-related complications, and influenza can lead to exacerbation of the chronic disease. Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected people. Vaccine effectiveness may be lower in people with immune compromising conditions than in healthy adults.
# Neurologic or neurodevelopment conditions
Neurologic or neurodevelopment conditions (NNCs) include neuromuscular, neurovascular, neurodegenerative, neurodevelopment conditions, and seizure disorders (and, for children, include febrile seizures and isolated developmental delay), but exclude migraines and psychiatric conditions without neurological conditions. Based on reviews of evidence and expert opinion, NACI includes adults and children with NNCs among the groups for whom influenza vaccination is particularly recommended. Refer to the NACI Statement on Seasonal Influenza Vaccine for 2018-2019 for a summary of the rationale supporting this decision and the Literature Review on Individuals with Neurologic or Neurodevelopment Conditions and Risk of Serious Influenza-Related Complications for additional details of the evidence reviews.
# People of any age who are residents of nursing homes and other chronic care facilities
Residents of nursing homes and other chronic care facilities often have one or more chronic health conditions and live in institutional environments that may facilitate the spread of influenza.
# Adults 65 years of age and older
Hospitalization attributable to influenza in this age group is estimated at 125-228 per 100,000 healthy people (46) , and influenza-attributed mortality rates increase with increased age (47) .
# All children 6-59 months of age
On the basis of existing data, NACI recommends the inclusion of all children 6-59 months of age among the particularly recommended recipients of influenza vaccine.
# Indigenous peoples
Based on the body of evidence indicating a higher rate of influenza-associated hospitalization and death among Indigenous peoples, NACI recommends the inclusion of this population among the particularly recommended recipients of influenza vaccine.
It has been proposed that the increased risk of severe influenza outcomes in the Indigenous populations is a consequence of many factors, including high prevalence of chronic health conditions (e.g., diabetes, chronic lung disease, end-stage kidney disease, cardiovascular disease) (48) , obesity, delayed access to health care, and increased susceptibility to disease because of poor housing and overcrowding (49)(50)(51) . Refer to the Statement on Seasonal Influenza Vaccine for 2011-2012 for further details.
# III.2 People Capable of Transmitting Influenza to Those at High Risk of Influenza-Related Complications or Hospitalization
People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk individual has been vaccinated. Vaccination of HCWs decreases their own risk of illness (52,53) , as well as the risk of death and other serious outcomes among the individuals for whom they provide care (54)(55)(56)(57) . Vaccination of HCWs and residents of nursing homes is associated with decreased risk of ILI outbreaks (58) .
People who are more likely to transmit influenza to those at high risk of influenza-related complications or hospitalization include: HCWs and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; and Contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated.
Health care workers and other care providers in facilities and community settings
# Vaccination of health care workers and other care providers
For the purposes of this statement, HCWs and other care providers in facilities and community settings refers to HCWs, regular visitors, emergency response workers, and others who have contact with residents of continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. HCWs include any person, paid or unpaid, who provides services, works, volunteers, or trains in a hospital, clinic, or other health care facility.
Transmission of influenza to patients at high risk of influenza-associated complications results in significant morbidity and mortality. Four cluster randomized controlled trials (RCTs) conducted in geriatric long-term care settings have demonstrated that vaccination of HCWs is associated with substantial decreases in influenza-like illness (55)(56)(57) and all-cause mortality (54)(55)(56)(57) in the residents. In addition, due to their occupation and close contact with people at high-risk of influenza-related complications, HCWs are themselves at increased risk of infection (59) .
As previously stated, adults and children with chronic health conditions, adults 65 years of age and older, and children 0-59 months of age are at greater risk of more severe complications from influenza or worsening of their underlying condition. Given the potential for HCWs and other care providers to transmit influenza to individuals at high risk and knowing that vaccination is the most effective way to prevent influenza, NACI recommends that, in the absence of contraindications, HCWs and other care providers in facilities and community settings should be vaccinated against influenza annually. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs and other care providers for their own protection and that of their patients. This group should consider annual influenza vaccination as part of their responsibilities to provide the highest standard of care.
Although current influenza vaccine coverage for HCWs is higher than in the general public (60,61) , it remains below the national goal of 80% coverage for HCWs in Canada (62) . Comprehensive vaccination programs should be adopted that address HCWs' acceptance of the vaccine and facilitate the process of vaccinating HCWs to improve uptake of the influenza vaccine beyond the current level. HCW influenza vaccination programs that have successfully increased vaccine coverage of HCWs have included a combination of education, increased awareness, accessible on-site vaccination delivery options for all HCWs, visible support from senior staff and other leaders, and regular review and improvement of vaccination strategies (63)(64)(65)(66)(67)(68) .
# Outbreak management in health care facilities
As noted in PHAC's Guidance: Infection Prevention and Control Measures for Healthcare Workers in Acute Care and Long-term Care Settings for seasonal influenza, all health care organizations should have a written plan for managing an influenza outbreak in their facilities. Inherent in such plans should be policies and programs to optimize HCW's influenza vaccination (69) . As part of outbreak management, the above-mentioned PHAC guidance suggests consideration of chemoprophylaxis for all unvaccinated HCWs, unless contraindications exist.
Refer to the Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada) website for guidelines regarding the use of antiviral medications for prophylaxis.
# Contacts of individuals at high risk of influenza complications
Vaccination is recommended for contacts, both adults and children, of individuals at high risk of influenza-related complications or hospitalization (see List 1), whether or not the individual at high risk has been vaccinated. These contacts include: household contacts and care providers of individuals at high risk, household contacts and care providers of infants less than 6 months of age (as these infants are at high risk of complications from influenza but cannot receive influenza vaccine), members of a household expecting a newborn during the influenza season, household contacts and care providers (whether in or out of the home) of children 6-59 months of age, and providers of services within closed or relatively closed settings with people at high risk of influenza-related complications (e.g., crew on a ship).
# III.3 Others
People who provide essential community services Vaccination for these individuals should be encouraged to minimize the disruption of services and routine activities during annual influenza epidemics. People who provide essential community services, including healthy working adults, should consider annual influenza vaccination, as this intervention has been shown to decrease work absenteeism due to respiratory and related illnesses (52,53,(70)(71)(72) .
People in direct contact with poultry infected with avian influenza during culling operations
# Poultry workers
Although seasonal influenza vaccination will not prevent avian influenza infection, some countries (73) and provinces have recommended influenza vaccination on a yearly basis for poultry workers, based on the rationale that preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with human and avian influenza viruses (74) .
NACI recommends seasonal influenza vaccination for people in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of avian influenza infection because of exposure during the culling operation (75)(76)(77)(78) . Refer to the Statement on Seasonal Influenza Vaccine for 2013-2014 for further information informing this recommendation.
Direct contact may be defined as sufficient contact with infected poultry to allow transmission of an avian virus to the exposed person. The relevant individuals include those performing the cull, as well as others who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. It is recommended that biosecurity measures such as personal protective equipment and antivirals be used. Refer to Human Health Issues Related to Avian Influenza in Canada for PHAC recommendations on the management of domestic avian influenza outbreaks.
Swine workers NACI has concluded that there is insufficient evidence at this time to recommend routine influenza vaccination specifically for swine workers; however, NACI recommends that influenza vaccination should be offered to anyone 6 months of age and older who does not have contraindications to the vaccine.
Refer to the Statement on Seasonal Influenza Vaccine for 2013-2014 for further information informing this recommendation.
# IV. VACCINE PREPARATIONS AUTHORIZED FOR USE IN CANADA: ADDITIONAL INFORMATION
The following sections describe information on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines that are authorized for use in Canada by type: IIV and LAIV. Refer to Appendix A for a summary of the characteristics of specific influenza vaccine products available in Canada for the 2020-2021 season.
NACI acknowledges that evidence related to influenza vaccine performance, particularly with respect to vaccine efficacy and effectiveness, is constantly evolving with advances in research methodology and accumulation of data over many influenza seasons. Therefore, the evidence summarized in this section may not include the latest studies. However, in accordance with usual practice, NACI continues to closely monitor the emerging evidence on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines to update and to make recommendations when warranted.
# IV.1 Inactivated Influenza Vaccine (IIV)
IIVs contain standardized amounts of the HA protein from representative seed strains of the two human influenza A subtypes (H3N2 and H1N1) and either one (for trivalent vaccines) or both (for quadrivalent vaccines) of the two influenza B lineages (Yamagata or Victoria). IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines, both consisting of disrupted virus particles. Split virus vaccines contain whole inactivated viruses split with detergent, ether, or both, while subunit vaccines are made of purified HA and NA. The amount of NA in the vaccines is not standardized. HA-based serum antibody produced to one influenza A subtype is anticipated to provide little or no protection against strains belonging to the other subtype. The potential for trivalent vaccine to stimulate antibody protection across B lineages requires further evaluation and may be dependent upon factors such as age and prior antigenic experience with the two B lineages (79)(80)(81)(82)(83)(84) .
Because of potential changes in the circulating influenza virus from year to year and waning immunity in vaccine recipients, annual influenza vaccination is recommended. Although NACI is aware of some recent studies that suggest that vaccine induced protection may be greater in individuals who have no recent vaccine history, optimal protection against influenza, season after season, is best achieved through annual influenza vaccination (85,86) . NACI will continue to monitor this issue.
# Immunological considerations related to children
Young children have a high burden of illness and their vaccine-induced immune response is not as robust as older children. However, some studies suggest moderate improvement in antibody response in young children, without an increase in reactogenicity, with the use of a full vaccine dose (0.5 mL) for IIV-SDs (8,9,87) . On the basis of this moderate improvement in antibody response without an increase in reactogenicity, NACI recommends the use of a 0.5 mL dose for all recipients of IIV-SDs, including young children.
# Immunological considerations related to older adults and those with immune compromising conditions
Although the initial antibody response in older adults may be lower to some influenza vaccine components when compared to those in other age groups, a literature review identified no evidence for a subsequent antibody decline that was any more rapid in older adults than in younger age groups (88) .
Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patients (89)(90)(91)(92) .
Most studies have shown that administration of a second dose of influenza vaccine in the same season to older adults or other individuals who may have an altered immune response does not result in a clinically significant antibody boost (11,(93)(94)(95) .
# Standard-dose trivalent inactivated influenza vaccine (IIV3-SD)
Vaccines currently authorized for use:
- Agriflu ® (Seqirus) Fluviral ® (GlaxoSmithKline) *
# Efficacy and effectiveness
The NACI Literature Review on Influenza Vaccination in Healthy 5-18 Year Olds found that VE of IIV3-SD against laboratory-confirmed influenza was variable but was most frequently between 65-85% (96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114) . In the NACI literature review on Influenza Vaccine Effectiveness, Immunogenicity, and Safety in Healthy Adults 19-64 Years Old, efficacy against laboratory-confirmed influenza for IIV3-SD in healthy adults 18-64 years of age ranged widely from as low as 15% to as high as 75%, with the majority of studies estimating efficacy at 50-60%. Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for a more detailed summary of efficacy and effectiveness evidence for IIV3-SD in healthy children 5-18 years of age and healthy adults 19-64 years of age.
In older adults, VE of IIV3-SD is about half of that in healthy adults and varies depending on the outcomes measured and the study population (115,116) . Systematic reviews have demonstrated that influenza vaccine decreases the incidence of pneumonia, hospital admissions, and deaths in older adults (115) and reduces exacerbations in people with chronic obstructive pulmonary disease (117) . The NACI Literature Review on the Comparative Effectiveness and Immunogenicity of Subunit and Split Virus Inactivated Influenza Vaccines in Adults 65 Years of Age and Older found no statistically significant differences in VE of subunit IIV3-SD compared with split virus IIV3-SD in adults 65 years of age and older against infection with any influenza virus strain, or against infection with influenza A(H1N1), A(H3N2), or B virus specifically.
In observational studies, influenza vaccination has been shown to reduce the number of physician visits, hospitalizations, and deaths in adults 18-64 years of age with high-risk medical conditions (118) , hospitalizations for cardiac disease and stroke in adults 65 years of age and older (119) , and hospitalization and deaths in adults 18 years of age and older with diabetes mellitus (120) during influenza epidemics. Observational studies that use non-specific clinical outcomes or that do not take into account differences in functional status or health-related behaviours should be interpreted with caution (121)(122)(123)(124)(125) .
# Immunogenicity
Both humoral and cell-mediated immune responses are thought to play a role in immunity to influenza. While humoral immunity is thought to play a primary role in protection against infection, cell-mediated immunity, notably cytotoxic T lymphocyte responses to internal viral components, is increasingly invoked as important in protecting against severe outcomes of influenza, particularly those associated with subtype HA variations (shift and drift) (126) . The IM administration of IIV3-SD results in the production of circulating immunoglobulin G (IgG) antibodies to the viral HA and NA proteins, as well as a more limited cytotoxic T lymphocyte response.
# Safety
Studies evaluating the safety of IIV3-SDs in healthy children have found a good safety profile with no SAEs of note (127) . The most common solicited local reactions are pain and redness at the injection site, while the most common solicited systemic reactions are irritability, malaise, and headache. Mild injection site reactions, primarily soreness at the vaccination site, have been found to occur in 7% or less of healthy children who are less than 3 years of age (128)(129)(130) . Postvaccination fever may be observed in 12% or less of vaccinated children 1-5 years of age (101,130) .
For adults, IIV3-SDs have been demonstrated to have a good safety profile with acceptable reactogenicity (127) . Common local reactions at injection site include redness, swelling, pain, and induration. These reactions last 2-3 days and rarely interfere with normal activities. Common systemic reactions include headache, malaise, myalgia, fatigue, arthralgia, and fever.
# Adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj)
Vaccines currently authorized for use:
- Fluad ® (Seqirus) Fluad Pediatric ® (Seqirus)
# Fluad (adults 65 years of age and older) Efficacy and effectiveness
There is fair evidence that the MF59-adjuvanted Fluad (IIV3-Adj) may be effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to unvaccinated individuals. However, there is insufficient evidence that IIV3-Adj is more effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to those who received unadjuvanted subunit IIV3-SD. Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for more information on the efficacy and effectiveness of IIV3-Adj in adults 65 years of age and older.
# Immunogenicity
The mechanism of action of MF59 is not fully determined and has primarily been studied using in vitro and mouse models. From these studies, it appears that MF59 may act differently from aluminum-based adjuvants. These studies show that MF59 acts in the muscle fibres to create a local immune-stimulatory environment at the injection site (131) . MF59 allows for an increased influx of phagocytes (e.g., macrophages, monocytes) to the site of injection. The recruited phagocytes are further stimulated by MF59, thereby increasing the production of chemokines to attract more innate immune cells and inducing differentiation of monocytes into dendritic cells (132,133) . MF59 further facilitates the internalization of antigen by these dendritic cells (132,134) . The overall higher number of cells available locally increases the likelihood of interaction between an antigen presenting cell and the antigen, leading to more efficient transport of antigen to the lymph nodes, with resulting improved T cell priming (132) .
There is evidence from RCTs that IIV3-Adj elicits non-inferior immune responses compared to the unadjuvanted subunit and split virus IIV3-SDs; however, superiority of IIV3-Adj to these vaccines by pre-defined criteria has not been consistently demonstrated. Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for more information on the immunogenicity of IIV3-Adj in adults 65 years of age and older.
# Safety
IIV3-Adj produces injection site reactions (pain, erythema, and induration) significantly more frequently than IIV3-SD, but they are classified as mild and transient. Systemic reactions (myalgia, headache, fatigue, and malaise) are comparable or more frequent with IIV3-Adj compared to IIV3-SD and are rated as mild to moderate and transient. SAEs were uncommon and were comparable to IIV3-SD. Refer to the Recommendations on the use of MF59-Adjuvanted Trivalent Influenza Vaccine (Fluad ® ): Supplemental Statement of Seasonal Influenza Vaccine for 2011-2012 for additional information on the safety of IIV3-Adj in adults 65 years of age and older.
# Fluad Pediatric (children 6-23 months of age) Efficacy and effectiveness
A pre-licensure efficacy trial in children 6-71 months of age found a higher relative efficacy for IIV-Adj than the unadjuvanted IIV3-SD (135) . However, the findings of this study should be interpreted with caution. The comparator unadjuvanted IIV3 used in this trial was shown, in an unrelated study, to induce a lower immune response compared to another unadjuvanted IIV3-SD. There were concerns raised by a European Medicines Agency inspection about the quality of diagnostic laboratory testing and validity of ascertainment of influenza cases. The study administered 0.25 mL doses of the comparator unadjuvanted IIV3-SD for children less than 36 months of age, which is lower than the dose of 0.5 mL of unadjuvanted IIV3-SD or IIV4-SD that is recommended for this age group in Canada. Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for more information on the efficacy and effectiveness of IIV3-Adj in children.
# Immunogenicity
In children, there is limited but consistent evidence that IIV3-Adj is more immunogenic than IIV3-SD against both influenza A and B (135)(136)(137)(138)(139)(140) . In particular, a single dose of IIV3-Adj is more immunogenic than a single dose of IIV3-SD, and has been shown in one study to produce greater GMTs than 2 doses of IIV3-SD against influenza A (140) . However, similar to IIV3-SD, IIV3-Adj generally induced a weaker hemagglutination-inhibition antibody response against B strains compared to A strains and therefore 2 doses of IIV3-Adj are still necessary to achieve a satisfactory immune response against influenza B.
Almost all of the pre-licensure pediatric studies used vaccine formulations of 0.25 mL in children 6-35 months of age, both for IIV3-Adj and the comparator unadjuvanted influenza vaccine (NACI recommends 0.5 mL dosage of IIV3-SD or IIV4-SD for all age groups). There is limited immunogenicity evidence comparing IIV3-Adj at 0.25 mL dose to IIV3-SD or IIV4-SD at 0.5 mL dose in the 6-23 month age group. Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for more information on the immunogenicity of IIV3-Adj in children.
# Safety
The safety data in children are consistent with what is known about IIV3-Adj's safety profile in adults. In pediatric trials, IIV3-Adj was more reactogenic than IIV3-SD, with recipients experiencing 10-15% more solicited local and systemic reactions. However, most reactions were mild and resolved quickly. A dose-ranging study of MF59-adjuvanted and unadjuvanted IIV3 and IIV4 did not find an increased risk of AEs associated with increased MF59 dose, antigen dose, or the addition of a second B strain; however, the reactogenicity of 15 µg formulations were slightly higher for both adjuvanted and unadjuvanted vaccines compared to the corresponding 7.5 µg formulations (138) .
There are currently no data on the effects of long-term or repeated administration of adjuvanted influenza vaccines in children. The most significant experience with an adjuvanted influenza vaccine in children was the AS03-adjuvanted A(H1N1) pandemic vaccine that has been associated with an increased risk of narcolepsy. A study comparing two AS03-adjuvanted A(H1N1) vaccine products (Pandemrix and Arepanrix) has suggested that the underlying immune mediated mechanism associated with the increased narcolepsy risk may not be initiated by the adjuvant, but by the A(H1N1) nucleoprotein viral antigen, given that the study found significant antigenic differences between the two A(H1N1) pandemic vaccines (141) . However, the pandemic vaccine was a single strain adjuvanted vaccine administered only during one season, and it is unknown what effects a multi-strain adjuvanted vaccine or an adjuvanted vaccine administered for more than one season may have in young children.
Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for additional information on the safety of IIV3-Adj in children.
# High-dose trivalent inactivated influenza vaccine (IIV3-HD)
Vaccine currently authorized for use:
- Fluzone ® High-Dose (Sanofi Pasteur)
# Efficacy and effectiveness
There is good evidence that Fluzone High-Dose (IIV3-HD) provides better protection compared with IIV3-SD in adults 65 years of age and older. A few studies found that IIV3-HD may provide greater benefit in adults 75 years of age and older compared to adults 65-74 years of age (142)(143) ; however, additional studies are needed to validate this finding. There remain no efficacy or effectiveness studies that compare IIV3-HD with IIV3-Adj or IIV4-SD specifically.
Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for more information on the efficacy and effectiveness of IIV3-HD in adults 65 years of age and older.
# Immunogenicity
Five studies compared the rates of seroconversion for study participants receiving IIV3-HD and IIV3-SD among those 65 years of age and older (145)(146)(147)(148)(149)(150) . Rates of seroconversion were found to be about 19% higher (ranging from 8-39% higher) for those receiving the higher dose vaccine across all three vaccine strains. Similarly, rates of seroconversion were higher for those receiving the high-compared to standard-dose vaccines for participants 75 years of age and older and for a cohort of participants with underlying cardiopulmonary disease.
Eight studies reported higher rates of seroprotection for older adults receiving IIV3-HD compared to those vaccinated with IIV3-SD (145)(146)(147)(148)(149)(150)(151)(152) . Seroprotection was significantly higher for all 3 strains in the vaccine in three of five studies assessing significance. There were different results in the remaining studies. In the study by Couch et al., seroprotection was higher only against A(H1N1), possibly attributed to the fact that 78% of participants were vaccinated against the same influenza strains within 6 months prior to the study (146) . In Nace et al., seroprotection was higher against A(H3N2) and B but not A(H1N1); the lack of higher seroprotection against A(H1N1) may be attributed to strain circulation during the study that made it difficult to assess seroprotection against this subtype (150) .
Geometric mean titre ratios (GMTR) of participants' responses to high-versus standard-dose influenza vaccines were reported in several studies and were calculated for those that provided group-specific, post-vaccination titres for each of the vaccines (145)(146)(147)(148)(149)151,152) . Seroresponse to the B strains in the vaccines was about 1.5 times greater (1.3-1.7) in the IIV3-HD recipients than the IIV3-SD recipients. The GMTR of the A strains was about 1.8 times higher for those receiving IIV3-HD compared to IIV3-SD, ranging from 1.6-2.3.
# Safety
IIV3-HD has been observed to produce a higher rate of some systemic and local reactions than IIV3-SD. Studies have reported higher rates of malaise, myalgia, and moderate to severe fever. Most systemic reactions were mild and resolved within 3 days. SAEs were rare and similar in frequency between standard-dose and high-dose vaccines.
Refer to NACI's A Review of the Literature of High Dose Seasonal Influenza Vaccine for Adults 65 Years and Older for details.
# Standard-dose quadrivalent inactivated influenza vaccine (IIV4-SD)
Vaccines currently authorized for use:
- Afluria ® Tetra (Seqirus) Flulaval ® Tetra (GlaxoSmithKline) Fluzone ® Quadrivalent (Sanofi Pasteur)
- Influvac ® Tetra (BGP Pharma ULC, operating as Mylan)
# Efficacy and effectiveness
In the NACI Literature Review on Quadrivalent Influenza Vaccines, only one study was identified that measured IIV4-SD efficacy. In that study, efficacy was estimated at 59% in children 3-8 years of age, in comparison to children who received hepatitis A vaccine (153) . No literature was found in this review on efficacy or effectiveness directly comparing trivalent and quadrivalent formulations.
# Immunogenicity
In the same review of the literature noted above, NACI reviewed the immunogenicity data for IIV4-SD produced by manufacturers who supplied influenza vaccine in Canada at the time of the literature review: AstraZeneca, GlaxoSmithKline, and Sanofi Pasteur. The results of phase II and III trials that compared trivalent formulations to quadrivalent formulations generally showed noninferiority of the quadrivalent products for the A(H3N2), A(H1N1), and B strain contained in the trivalent formulations. As expected, these studies showed that the immune response to the B strain that was not in the trivalent formulation was better in subjects who received the quadrivalent vaccine, which contained the additional B strain. These findings were consistent across age groups. Refer to the Literature Review on Quadrivalent Influenza Vaccines for additional details.
In the phase III trials, recipients of the trivalent formulations showed, to a lesser degree, some immune response to the B strain not contained in the trivalent formulation. In one study of adults, both the trivalent and quadrivalent vaccines met all the European Medicines Agency Committee for Medicinal Products for Human Use and the United States Food and Drug Administration criteria for evaluation of influenza vaccine immunogenicity, including those for the B strain not in the trivalent vaccine.
In all other studies, the trivalent vaccine failed at least one of the criteria for seroprotection or seroconversion for the missing B strain. It has been hypothesized that there is some level of crossreactivity between B strains. The degree of cross protection against infection with one lineage provided by immunization against the other lineage is uncertain (154) .
# Safety
As IIV4-SD has higher antigenic content than IIV3-SD, increased reactogenicity may be a concern for the quadrivalent vaccine. However, pre-licensure clinical trials (refer to Literature Review on Quadrivalent Influenza Vaccines) and post-marketing surveillance showed that IIV4-SD had a similar safety profile to IIV3-SD (155) .
# IV.2 Live Attenuated Influenza Vaccine (LAIV)
LAIV contains standardized quantities of FFU of live attenuated influenza virus reassortants. The virus strains in LAIV are cold-adapted and temperature sensitive, so they replicate in the nasal mucosa rather than the lower respiratory tract, and they are attenuated, so they do not produce ILI. There have been no reported or documented cases, and no theoretical or scientific basis to suggest transmission of vaccine virus would occur to the individual administering LAIV. As a live replicating whole virus formulation administered intranasally, it elicits mucosal immunity, which may more closely mimic natural infection.
Vaccine currently authorized for use:
- FluMist ® Quadrivalent (AstraZeneca)
# Efficacy and effectiveness
After careful review of the available Canadian and international LAIV VE data over many influenza seasons, NACI concluded that the current evidence is consistent with LAIV providing comparable protection against influenza to that afforded by IIV and does not support a recommendation for the preferential use of LAIV in children 2-17 years of age.
Observational studies from the United States found low effectiveness of LAIV against circulating post-2009 pandemic A(H1N1), or A(H1N1)pdm09, in 2013-2014 and 2015-2016; however, reduced LAIV effectiveness was not observed in Canada or any other countries that have investigated the issue. Manufacturer investigation identified potential reduced replicative fitness of the A(H1N1)pdm09-like LAIV viruses in the nasal mucosa from the two affected A(H1N1)dominant seasons compared to pre-2009 pandemic influenza A(H1N1) LAIV viruses as contributing to the poor LAIV effectiveness against circulating A(H1N1) (156) . This finding led to the manufacturer replacing the A(H1N1)pdm09 component of LAIV with new strains, with the A/Slovenia/2903/2015 being the strain that has been used since the 2017-2018 season. In adults, studies have found IIV-SD to be similarly or more efficacious or effective compared with LAIV.
Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for detailed information supporting this recommendation.
# Immunogenicity
LAIV, which is administered by the intranasal route, is thought to result in an immune response that mimics that induced by natural infection with wild-type viruses, with the development of both mucosal and systemic immunity. Local mucosal antibodies protect the upper respiratory tract and may be more important for protection than serum antibody.
Studies have demonstrated that the presence of a hemagglutination-inhibition antibody response after the administration of LAIV3 is predictive of protection. However, efficacy studies have shown protection in the absence of a significant antibody response as well (157) . In these studies, LAIV3 has generally been shown to be equally, if not more, immunogenic compared to IIV3-SD for all 3 strains in children, whereas IIV3-SD was typically more immunogenic in adults than LAIV3. Greater rates of seroconversion to LAIV3 occurred in baseline seronegative individuals compared to baseline seropositive individuals in both pediatric and adult populations, because pre-existing immunity may interfere with response to a live vaccine. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for further details regarding the immunogenicity of LAIV3.
LAIV4 has shown non-inferiority based on immunogenicity compared to LAIV3 in both children and adults. The immune response to the B strain found only in the quadrivalent formulation was better in children who received the quadrivalent vaccine (158)(159)(160) .
# Safety
The most common AEs experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. In a large efficacy trial, rates of wheezing were statistically higher among children 6-23 months of age for LAIV3 compared to IIV3-SD (157) . This finding is expected to be the same for recipients of LAIV4; however, pre-licensure clinical studies for LAIV4 were conducted only in adults and children 2 years of age and older.
Studies on LAIV3 have shown that vaccine virus can be recovered by nasal swab in children and adults following vaccination (i.e., "shedding"). The frequency of shedding decreases with increasing age and time since vaccination. Shedding is generally below the levels needed to transmit infection, although in rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated people. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for more information on LAIV and viral shedding.
# Considerations related to individuals with HIV infection
Following a review of the literature regarding the use of LAIV in HIV-infected individuals, NACI concluded that LAIV is immunogenic in children with stable HIV infection on HAART and with adequate immune function. In addition, NACI concluded that LAIV appears to have a similar safety profile as IIV in children on HAART and with stable HIV infection with regard to frequency and severity of AEs. As expected, injection site reactions were seen only with IIV and nasal symptoms were more common with LAIV. However, the evidence base is too small to effectively detect uncommon, rare, and very rare AEs related to the use of LAIV in in this population. In addition, nasal spray may be preferable to IM injection for some individuals who are averse to receiving the vaccine by injection. Therefore, NACI recommends that LAIV may be considered as an option for children 2-17 years of age with stable HIV infection on HAART and with adequate immune function. LAIV should be considered only in children with HIV who meet the following criteria:
- Receiving HAART for ≥4 months; CD4 count ≥500/µL if 2-5 years of age, or ≥200/µL if 6-17 years of age (measured within 100 days before administration of LAIV); and HIV plasma RNA <10,000 copies/mL (measured within 100 days before administration of LAIV).
IM influenza vaccination is still considered the standard for children living with HIV by NACI and the Canadian Pediatric and Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e. plasma HIV RNA >40 copies/mL). However, if IM vaccination is not accepted by the patient or substitute decision maker, LAIV would be a reasonable option for children meeting the criteria listed above.
Refer to the NACI Statement on the Use of LAIV in HIV-Infected Individuals for more information on the use of LAIV in this population.
# IV.3 Schedule
The first time that children 6 months to less than 9 years of age receive seasonal influenza vaccination, a two-dose schedule is required to achieve protection (161)(162)(163) . Several studies have looked at whether these two initial doses need to be given in the same season (81,82,164) . Englund et al. reported similar immunogenicity in children 6-23 months of age whether 2 doses were given in the same or separate seasons when there was no change, or only minor vaccine strain change, in vaccine formulation between seasons (81,82) . However, seroprotection rates to the B component were considerably reduced in the subsequent season when there was a major B lineage change, suggesting that the major change in B virus lineage reduced the priming benefit of previous vaccination (80,82) . Issues related to effective prime-boost when there is a major change in influenza B lineage across sequential seasons require further evaluation (165) . Because children 6-23 months of age are less likely to have had prior priming exposure to an influenza virus, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children in this age group.
# IV.4 Simultaneous Administration with Other Vaccines
In general, NACI recommends that two live parenteral vaccines be administered either on the same day or at least 4 weeks apart (166) . This recommendation is based largely on a single study from 1965 that demonstrated immune interference between smallpox vaccine and measles vaccine administered 9-15 days apart. Subsequent studies have revealed conflicting results on immune interference between live vaccines (167)(168)(169)(170) . No studies were found on potential immune interference between LAIV and other live attenuated vaccines (oral or parenteral) administered within 4 weeks. A few studies on concomitant administration of LAIV3 with MMR, varicella, and oral polio vaccines did not find evidence of clinically significant immune interference (10,12,13) . One study reported a statistically significant but not clinically meaningful decrease in seroresponse rates to rubella antigen when administered concomitantly with LAIV.
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Possible immune mechanisms include: the inhibitory and immunomodulatory effects of systemic and locally produced cytokines on B-and T-cell response and viral replication; immunosuppression induced by certain viruses (such as measles); and direct viral interference as a result of competition for a common niche. Mucosal vaccines may have less impact on a parenteral vaccine and vice versa. The immune response with a mucosal vaccine may be compartmentalized to the mucosa while that to a parenteral vaccine is systemic. It is likely that there is some interaction between the systemic and mucosal compartments; however, the extent to which this interaction occurs is not known.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of an inactivated influenza vaccine would avoid this theoretical concern.
# IV.5 Additional Vaccine Safety Considerations
Influenza vaccine is safe and well tolerated. Contraindications, precautions, and common AEs are described in Section II. Additional information regarding egg-allergic individuals and GBS is provided below.
# Egg-allergic individuals
After careful review of clinical and post-licensure safety data, NACI has concluded that eggallergic individuals may be vaccinated against influenza using any appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular consideration, including vaccination setting. The amount of trace ovalbumin allowed in influenza vaccines that are authorized for use in Canada is associated with a low risk of AE. The observation period post-vaccination is as recommended in Vaccine Safety in Part 2 of the CIG. As with all vaccine administration, vaccine providers should be prepared with the necessary equipment, knowledge, and skills to respond to a vaccine emergency at all times.
Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for safety data supporting this recommendation for IIV and LAIV.
# Guillain-Barré syndrome
In a review of studies conducted between 1976 and 2005, the United States Institute of Medicine concluded that the 1976 "swine flu" vaccine was associated with an elevated risk of GBS. However, evidence was inadequate to accept or to reject a causal relation between GBS in adults and seasonal influenza vaccination (171) .
The attributable risk of GBS in the period following seasonal and monovalent 2009 pandemic influenza vaccination is about one excess case per million vaccinations (18,19) . In a self-controlled study that explored the risk of GBS after seasonal influenza vaccination and after influenza health care encounters (a proxy for influenza illness), the attributable risks were 1.03 GBS admissions per million vaccinations compared with 17.2 GBS admissions per million influenza-coded health care encounters (19) . This finding shows that both influenza vaccination and influenza illness are associated with small attributable risks of GBS, but the risk of GBS associated with influenza illness is notably higher than with influenza vaccination. The self-controlled study also found that the risk of GBS after vaccination was highest during weeks 2-4, whereas for influenza illness, the risk was greatest within the first week after a health care encounter and decreased thereafter, but remained significantly elevated for up to 4 weeks. The risk of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and all the other benefits of influenza vaccination (172)(173)(174)(175) .
# V. CHOICE OF SEASONAL INFLUENZA VACCINE: ADDITIONAL INFORMATION
With the recent availability of a number of new influenza vaccines, some of which are designed to enhance immunogenicity in specific age groups, the choice of product is now more complex. Section II.5 summarizes NACI's recommendations on the choice of currently authorized influenza vaccines. This section provides more details for these recommendations.
V.1 Children
# Burden of disease in children
The proportion of disease burden due to influenza B infection is higher in children compared to other age groups. Canadian surveillance data from 2001-2002 to 2012-2013 has shown that influenza B strains accounted for 17% of laboratory-confirmed tests for influenza. Children less than 24 months of age comprise approximately 2% of the Canadian population (176) . (177) .
The IMPACT study also found that the proportion of deaths attributable to influenza was significantly greater for children admitted to hospital with influenza B (1.1%) than for those admitted with influenza A (0.4%). The proportion of hospitalizations due to influenza B relative to all influenza hospitalizations has been generally similar to the proportion of influenza B detections relative to all influenza infections in the general population during the same time period. Additional information can be found in the Statement on Seasonal Influenza Vaccine for 2014-2015.
In Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that a quadrivalent influenza vaccine should be used. If a quadrivalent vaccine is not available, any of the available age-appropriate trivalent vaccines should be used.
There is insufficient evidence to make comparative recommendations on the use of IIV3-Adj over IIV3-SD.
# Efficacy and effectiveness
There was early evidence of superior efficacy of LAIV3 compared with IIV3-SD in children less than 6 years of age from randomized controlled trials, with weaker evidence of superior efficacy in older children. However, later post-marketing and surveillance studies across multiple influenza seasons found comparable protection against influenza for LAIV and IIV, with findings of reduced effectiveness for LAIV against A(H1N1) in some studies.
Like IIV4-SD, LAIV4 is expected to provide additional protection against the influenza B strain not contained in IIV3-SD.
# Immunogenicity
LAIV3 has been shown to be as immunogenic as IIV3-SD, depending on age, with LAIV4 being non-inferior to LAIV3.
# Safety
Rhinitis (runny nose) and nasal congestion are more common with LAIV. Clinical studies and post-marketing studies showed a similar safety profile to IIV.
Contraindications There are vaccine contraindications specific to LAIV. LAIV is contraindicated for children with severe asthma, medically attended wheezing in the 7 days prior to vaccination, and immune compromising conditions (with the exception of children with stable HIV infection on HAART and with adequate immune function), as well as those currently receiving aspirin or aspirin-containing therapy. LAIV is also contraindicated for pregnant adolescents.
# Acceptability
Delivery of LAIV as a nasal spray may be preferable for children who are averse to receiving the vaccine by needle injection.
# V.2 Adults
# Burden of disease in adults
A study focusing on estimates of deaths associated with influenza in the United States has established that the average annual rate of influenza-associated deaths for adults aged 65 years of age and older was 17.0 deaths per 100,000 (range: 2.4-36.7) (178) . The study also states that of deaths coded as being influenza-or pneumonia-related, persons 65 years of age and older accounted for 87.9% of the overall estimated annual average number of influenza-associated deaths. When influenza-related deaths among adults 65 years of age and older were estimated using underlying respiratory and circulatory causes, these estimates increased to 66.1 deaths per 100,000 (range: 8.0-121.1) and 89.4%, respectively. This study described a wide variation in the estimated number of deaths from season to season, which was closely related to the particular influenza virus types and subtypes in circulation. Estimates presented in the study of yearly influenza-associated deaths with underlying pneumonia and influenza causes reveal a large difference between influenza type A and B with a calculated median of greater than 6,000 deaths associated with influenza type A and half of that number for influenza type B (approximately 3,360) for persons 65 years of age and older. During the 22 seasons in which influenza A(H3N2) was the prominent strain, the average influenza-associated mortality rates were 2.7 times higher than for the nine seasons that it was not (all age groups combined), and on average, there were about 37% more annual influenza-associated deaths, regardless of the primary medical cause of death. A higher risk of hospitalization and death was also reported by Cromer et al. in adults 65 years of age and older, compared to younger adults in their assessment of the burden of influenza in England by age and clinical risk group (179) .
Canadian surveillance data show that hospitalization rates among adults 65 years of age and older were higher during the A(H3N2)-predominant 2014-2015 season compared to the previous five influenza seasons and also compared to the 2012-2013 season when A(H3N2) also predominated; 2014-2015 was a season in which there was a vaccine mismatch with the circulating A(H3N2) strain. Similar to the hospitalization rates, death rates among older adults were highest in the 2014-2015 season compared to the previous five seasons and compared to the previous A(H3N2) season in 2012-2013. Mortality rates among other age groups were similar to or lower than the previous five influenza seasons. Laboratory detections over this same time period showed that influenza seasons in which influenza subtype A(H3N2) predominated, disproportionally affected adults 65 years of age and older, while seasons with greater A(H1N1) detections resulted in a higher prevalence of positive cases in younger age groups.
# Adults 65 years of age and older
Four types of influenza vaccine are authorized for use in adults 65 years of age and older: IIV3-SD, IIV3-Adj, IIV3-HD, and IIV4-SD.
# Influenza vaccine type compared with IIV3-SD IIV3-Adj IIV3-HD IIV4-SD Burden of disease
Although influenza-associated morbidity and mortality varies each season, in general there is an increased burden of severe disease in adults 65 years of age and older during influenza seasons when influenza A(H3N2) predominates (178) Efficacy and effectiveness Insufficient evidence compared with IIV3-SD.
Better protection compared with IIV3-SD, particularly in influenza A(H3N2)dominant seasons.
Better protection against the influenza B strain not contained in IIV3.
# Immunogenicity
Non-inferior immune response compared to IIV3-SD. Superiority to IIV3-SD has not been consistently demonstrated.
Superior immune response to influenza A strains and noninferior immune response to B strains compared to IIV3-SD.
Non-inferior immune response to the strains contained in IIV3-SD with superior immune response to the additional B strain.
Contraindications Same contraindications as IIV3-SD.
# Safety
Higher rate of injection site reactions than IIV3-SD. Higher or comparable systemic reactions compared to IIV3-SD; systemic reactions were mild to moderate and transient.
SAEs were comparable to IIV3-SD and were uncommon.
Higher rate of some systemic reactions than IIV3-SD; most systemic reactions were mild and transient.
SAEs were rare and similar in frequency to IIV3-SD.
Pre-licensure clinical trials and postmarketing surveillance showed a similar safety profile to IIV3.
Abbreviations: IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; SAE: serious adverse event.
a NACI has not assessed the comparative cost-effectiveness of available influenza vaccine types for adults 65 years of age and older.
Adults with chronic health conditions NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to adults with chronic health conditions identified in List 1, including those with immune compromising conditions.
Pregnant women NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to pregnant women.
Due to a lack of safety data at this time, LAIV should not be administered to pregnant women due to the theoretical risk to the fetus from administering a live virus vaccine. LAIV can be administered to breastfeeding women.
Health care workers NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to HCWs.
Comparative studies in healthy adults have found IIV to be similarly or more efficacious or effective compared with LAIV (157) . In addition, as a precautionary measure, LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection. Former ex-officio representatives: K Barnes (National Defence and the Canadian Armed Forces).
# Recommendation for individual-level decision making
When available, IIV3-HD should be used over IIV3-SD, given the burden of influenza A(H3N2) disease and the good evidence of better protection compared to IIV3-SD in adults 65 years of age and older. There is insufficient evidence to recommend the use of IIV3-HD over IIV4-SD. However, given the increased burden of disease associated with influenza A(H3N2) in older adults, better protection against influenza A(H3N2) may be more important than better protection against influenza B. At this time, NACI does not make comparative recommendations on the use of IIV3-Adj or IIV4-SD over IIV3-SD or among IIV3-Adj, IIV3-HD, and IIV4-SD.
Any of the available influenza vaccines would be preferable to remaining unvaccinated or requesting individuals to return for vaccine. Therefore, in the absence of a specific product, NACI recommends that any of the available influenza vaccines should be used.
# Recommendation for public health program-level decision making
IIV3-HD is expected to provide better protection compared to IIV3-SD; however, with costeffectiveness assessments having been outside the scope of the evidence review, there is insufficient evidence to make a comparative recommendation on the use of these vaccines at the programmatic level. Therefore, NACI recommends that any of the available influenza vaccines should be used.
Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose (Fluzone ® High-Dose) and MF59-Adjuvanted (Fluad ® ) Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for additional information supporting these recommendations.
# Summary of vaccine characteristics for decision making
There are four types of inactivated influenza vaccines (IIV3-SD, IIV3-Adj, IIV3-HD, and IIV4-SD) authorized for use in Canada for adults 65 years of age and older. The comparison of vaccine characteristics across vaccine types, in Table 5 below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program. Due to a lack of available data directly comparing the performance of IIV3-Adj, IIV3-HD, and IIV4-SD, considerations for these vaccines in Table 5 are compared to IIV3-SD for which comparative data on efficacy, effectiveness, and/or immunogenicity with each of IIV3-Adj, IIV3-HD, and IIV4-SD are available. Abbreviations: FFU: fluorescent focus units; HA: hemagglutinin; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine; NA: neuraminidase.
# LIST OF ABBREVIATIONS
a Full details of the composition of each vaccine authorized for use in Canada, including other non-medicinal ingredients, and a brief description of its manufacturing process can be found in the product monograph. b Neomycin and polymyxin B are only used if gentamicin cannot be used. No trace amounts of neomycin or polymyxin B are present if gentamicin was used. | # PREAMBLE
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflicts of interest.
# I. INTRODUCTION
This document, the "Advisory Committee Statement: Canadian Immunization Guide Chapter on Influenza and National Advisory Committee on Immunization (NACI) Statement on Seasonal Influenza Vaccine for 2020-2021", updates NACI's recommendations regarding the use of seasonal influenza vaccines.
I.1 New or Updated Information for 2020-2021
Updated wording for the recommendation on the vaccination of health care workers and other care providers NACI recently reassessed the wording for the recommendation on the vaccination of health care workers (HCWs) and other care providers as a group for whom influenza vaccination is particularly recommended. The existing evidence on HCW influenza vaccination and the reduction of morbidity associated with influenza in patients being cared for by a HCW in health care settings was considered in the context of ethics and acceptability. NACI continues to recommend that, in the absence of contraindications, HCWs and other care providers in facilities and community settings should be vaccinated annually against influenza, and recommends the inclusion of this group among the particularly recommended recipients of influenza vaccine. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs and other care providers for their own protection and that of their patients. This group should consider annual influenza vaccination as part of their responsibilities to provide the highest standard of care.
# Recommendation on the use of LAIV in HIV-infected individuals
Live attenuated influenza vaccine (LAIV) has been authorized for use in Canada since 2011, and was previously considered contraindicated by NACI in individuals with HIV. Based on a systematic review of the available literature, NACI has concluded that LAIV is immunogenic in children with stable HIV infection on highly active antiretroviral therapy (HAART) and with adequate immune function. NACI also concluded that, while there is insufficient direct evidence to detect uncommon or rare adverse events (AEs) related to the use of LAIV in HIV infected children, LAIV appears to have a similar safety profile to inactivated influenza vaccine (IIV). In addition, some children and their substitute decision makers may prefer that they receive influenza vaccine through an intranasal spray as opposed to an intramuscular (IM) injection, although preferences will vary.
Therefore, NACI recommends that LAIV may be considered as an option for children 2-17 years of age with stable HIV infection on HAART and with adequate immune function (Discretionary NACI Recommendation). LAIV should be considered only in children with HIV who: have been receiving HAART for ≥4 months; have a CD4 count ≥500/µL if 2-5 years of age, or ≥200/µL if 6-17 years of age (measured within 100 days before administration of LAIV); and have HIV plasma ribonucleic acid (RNA) <10,000 copies/mL (measured within 100 days before administration of LAIV).
While IM influenza vaccination still is considered the standard for children living with HIV by NACI and the Canadian Pediatric and Perinatal HIV/AIDS Research Group, LAIV would be reasonable for children meeting the criteria outlined above, if IM vaccination is not accepted by the patient or substitute decision maker. LAIV remains contraindicated in adults with HIV infection due to the lack of evidence for its immunogenicity and safety, and given that LAIV may be less effective than IIV in adults. Refer to the NACI Statement on the Use of LAIV in HIV-Infected Individuals for additional information supporting this recommendation.
# I.2 Abbreviations for Influenza Vaccines
The abbreviations used in this document for the different influenza vaccines authorized in Canada are as follows: Abbreviations: IIV: inactivated influenza vaccine; IIV3: trivalent inactivated influenza vaccine; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standarddose trivalent inactivated influenza vaccine; IIV4: quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV: live attenuated influenza vaccine; LAIV3: trivalent live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine.
a The numeric suffix denotes the number of antigens contained in the vaccine ("3" refers to the trivalent formulation and "4" refers to the quadrivalent formulation). The hyphenated suffix "-SD" is used when referring to IIV products that do not have an adjuvant, contain 15 µg hemagglutinin (HA) per strain and are administered as a 0.5 mL dose by intramuscular injection; "-Adj" refers to an IIV with an adjuvant (e.g., IIV3-Adj for Fluad ® or Fluad Pediatric ® ); and "-HD" refers to an IIV that contains higher antigen content than 15 µg HA per strain (e.g., IIV3-HD for Fluzone ® High-Dose). b 15 µg HA per strain. c 7.5 µg (in 0.25 mL) or 15 µg (in 0.5 mL) HA per strain. d 60 µg HA per strain.
# I.3 Background
The World Health Organization's (WHO) recommendations on the composition of influenza virus vaccines are typically available in February of each year for the upcoming season in the Northern Hemisphere. The WHO recommends that three influenza strains be included in the trivalent seasonal influenza vaccine: one influenza A(H1N1), one influenza A(H3N2), and one influenza B. Quadrivalent seasonal influenza vaccines should contain the three strains recommended for the trivalent vaccine, as well as an influenza B virus from the lineage that is not included in the trivalent vaccine.
Annual recommendations on the use of influenza vaccine in Canada are developed by the NACI Influenza Working Group (IWG) for consideration by NACI. Recommendations are developed based on a review of a variety of issues, which can include: the burden of influenza illness and the target populations for vaccination; efficacy, effectiveness, immunogenicity, and safety of influenza vaccines; vaccine schedules; and other aspects of influenza immunization. In addition, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing their recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels. These programmatic factors include economics, ethics, equity, feasibility, and acceptability. Details regarding NACI's evidence-based process for developing a statement are outlined in Evidence-based Recommendations for Immunization − Methods of the National Advisory Committee on Immunization.
Health care providers in Canada should offer the seasonal influenza vaccine as soon as feasible after it becomes available in the fall, since seasonal influenza activity may start as early as October in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing, and intensity), opportune moments for vaccination, as well as programmatic considerations. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local public health agencies.
Although vaccination before the onset of the influenza season is strongly preferred, influenza vaccine may still be administered up until the end of the season. Delayed administration may result in lost opportunities to prevent infection from exposures that occur prior to vaccination, and patients should be informed that vaccine administered during an outbreak may not provide optimum protection. Vaccine providers should use every opportunity to administer influenza vaccine to individuals at risk who have not already been vaccinated during the current season, even after influenza activity has been documented in the community.
# II. CANADIAN IMMUNIZATION GUIDE CHAPTER ON INFLUENZA: CLINICAL INFORMATION FOR VACCINE PROVIDERS
The Canadian Immunization Guide (CIG) is written primarily for health care providers (frontline clinicians and public health practitioners) but it is also used by policy makers, program planners, and the general public. The CIG has been a trusted, reader-friendly summary of the vaccine statements provided by NACI since 1979.
The information in this section replaces the influenza chapter of the CIG and is adapted for inclusion in the NACI Statement on Seasonal Influenza Vaccine. With a new NACI Statement on Seasonal Influenza Vaccine required each year, readers will have quick access to the information that they require within one document, whether it is the relevant influenza vaccine information written primarily for frontline vaccine providers as is found in this section, or the more detailed technical information that is found in the rest of this statement, commencing in Section III.
# II.1 Key Information
The following highlights key information for vaccine providers. Please refer to the remainder of this statement for additional details.
# What
Influenza is a respiratory infection caused primarily by influenza A and B viruses. Seasonal influenza epidemics occur annually in Canada, generally in the late fall and winter months. Influenza occurs globally with an annual attack rate estimated at 5-10% in adults and 20-30% in children (1) .
Symptoms of influenza typically include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week to 10 days, but some people are at greater risk of severe complications, such as pneumonia or death. Influenza infection can also worsen certain chronic conditions, such as heart disease (2) .
Both inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) are authorized for use in Canada; some protect against 3 strains of influenza (i.e., trivalent formulation, IIV3) and some protect against 4 strains of influenza (i.e., quadrivalent formulation, IIV4 or LAIV4).
The influenza vaccine is safe and well-tolerated. The influenza vaccine cannot cause influenza illness because inactivated influenza vaccines do not contain live virus and live attenuated influenza vaccines contain weakened viruses.
# Who
NACI makes the following recommendations for individual-level and public health program-level decision making. Individual-level recommendations are intended for people wishing to protect themselves from influenza or for vaccine providers wishing to advise individual patients about preventing influenza. Program-level recommendations are intended for provinces and territories responsible for making decisions on publicly funded immunization programs. Individual-level and program-level recommendations may differ, as the important factors to consider when recommending a vaccine for a population (e.g., population demographics, economic considerations) may be different than for an individual.
# Recommendation for individual-level decision making
NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see List 1). These groups include:
-people at high risk of influenza-related complications or hospitalization; -people capable of transmitting influenza to those at high risk; -people who provide essential community services; and -people in direct contact with poultry infected with avian influenza during culling operations.
Influenza vaccine is less immunogenic in infants less than 6 months of age than in older children and adults and does not confer sufficient protection to make the vaccine useful before 6 months of age (3) . Currently authorized influenza vaccines are not indicated for use in infants less than 6 months of age. For these reasons, NACI recommends that influenza vaccine should not be offered to infants less than 6 months of age. However, infants less than 6 months of age are at high risk of influenza-related illness; therefore the influenza vaccine should be offered to their household contacts, care providers, and pregnant women (see List 1).
# Recommendation for public health program-level decision-making
The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors.
NACI recommends that influenza vaccine should be offered as a priority to the groups for whom influenza vaccination is particularly recommended (see List 1 in the section below).
# People for whom influenza vaccination is particularly recommended
# People capable of transmitting influenza to those at high risk
Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated: -household contacts of individuals at high risk; -household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine; -members of a household expecting a newborn during the influenza season; Those providing regular child care to children 0-59 months of age, whether in or out of the home; and Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a ship).
# Others
People who provide essential community services; and People who are in direct contact with poultry infected with avian influenza during culling operations.
a Refer to Immunization of Persons with Chronic Diseases and Immunization of Immunocompromised Persons in Part 3 of the CIG for additional information about vaccination of people with chronic diseases.
# How
The benefits and risks of influenza vaccination should be discussed prior to vaccination, including the risks of not being immunized.
# Choice of influenza vaccine
A variety of influenza vaccines are authorized for use in Canada, some of which are authorized for use only in specific age groups. Therefore, the choice of influenza vaccine has become more complex. Refer to Section II.5 for recommendations on the choice of influenza vaccine by age group.
# Dose and route of administration
The dose and route of administration varies by product (see Section II.6 for details).
Unadjuvanted IIVs are administered as a 0.5 mL intramuscular (IM) injection for everyone 6 months of age and older;
MF59-adjuvanted trivalent inactivated influenza vaccine (Fluad ® ) is administered as a 0.5 mL IM injection for adults 65 years of age and older. A pediatric formulation is also available (Fluad Pediatric ® ), and is administered as a 0.25 mL IM injection for children 6-23 months of age;
LAIV (FluMist ® Quadrivalent) is administered as 0.2 mL given intranasally (0.1 mL in each nostril) for individuals 2-59 years of age.
# Schedule
# NACI recommends that:
Adults and children 9 years of age and older should receive 1 dose of influenza vaccine each year; and Children 6 months to less than 9 years of age who have never received the seasonal influenza vaccine in a previous influenza season should be given 2 doses of influenza vaccine in the current season, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in any previous season should receive 1 dose of influenza vaccine per season thereafter.
# Contraindications
For all influenza vaccines (IIV and LAIV), NACI recommends that influenza vaccination should not be given to:
People who have had an anaphylactic reaction to a previous dose of influenza vaccine;
People who have had an anaphylactic reaction to any of the components of that specific influenza vaccine, with the exception of egg (refer to Section II.7 for more information); -If an individual is found to have an anaphylactic reaction to a component in one influenza vaccine, consideration may be given to offering another influenza vaccine that does not contain the implicated component, in consultation with an allergy expert. Individuals who have an allergy to substances that are not components of the influenza vaccine are not at increased risk of allergy to influenza vaccine. -Egg allergy is not a contraindication for influenza vaccination, as there is a low risk of AEs associated with the trace amounts of ovalbumin allowed in influenza vaccines manufactured using eggs. Egg-allergic individuals may be vaccinated against influenza using any age-appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg, and in any setting where vaccines are routinely administered. -As with any vaccine product, vaccine providers should be prepared for and have the necessary equipment to respond to a vaccine emergency at all times.
People who have developed Guillain-Barré Syndrome (GBS) within 6 weeks of a previous influenza vaccination (refer to Section II.7 for more information).
-The potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
For LAIV, in addition to the above-mentioned contraindications, NACI also recommends that LAIV should not be given to:
People with immune compromising conditions, with the exception of children with stable HIV infection on HAART and with adequate immune function (see Section IV.2 for more information); -Immune compromising conditions may be due to underlying disease, therapy, or both;
People with severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing) or medically attended wheezing in the 7 days prior to the proposed date of vaccination, due to increased risk of wheezing following administration of LAIV; -LAIV is not contraindicated for people with a history of stable asthma or recurrent wheeze.
Children less than 24 months of age, due to increased risk of wheezing following administration of LAIV;
Children 2-17 years of age currently receiving aspirin or aspirin-containing therapy, because of the association of Reye's syndrome with aspirin and wild-type influenza infection; -In addition, aspirin-containing products in children less than 18 years of age should be delayed for 4 weeks after receipt of LAIV.
Pregnant women, because it is a live attenuated vaccine and there is a lack of safety data at this time; -LAIV is not contraindicated in breastfeeding mothers.
Receipt of an anti-influenza antiviral drug in the previous 48 hours.
Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 of the CIG for a list of all vaccines authorized for use in Canada and their contents and to Vaccine Safety in Part 2 of the CIG for information regarding the management of AEs, including anaphylaxis.
# Precautions
# NACI recommends that:
Influenza vaccination should usually be postponed in people with serious acute illnesses until their symptoms have abated; -Vaccination should not be delayed because of minor or moderate acute illness, with or without fever.
If significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa, IIV can be administered or LAIV can be deferred until resolution of the congestion;
LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection; and LAIV should not be administered until 48 hours after antiviral agents active against influenza (e.g., oseltamivir, zanamivir) are stopped, and those antiviral agents, unless medically indicated, should not be administered until 2 weeks after receipt of LAIV so that the antiviral agents do not kill the replicating vaccine virus.
-If antiviral agents are administered within this time frame (i.e., from 48 hours prevaccination with LAIV to 2 weeks post-vaccination), revaccination should take place at least 48 hours after the antivirals are stopped, or IIV could be given at any time.
LAIV recipients who are less than 18 years of age should avoid the use of aspirincontaining products for at least 4 weeks after receipt of LAIV.
Refer to Section II.7 for additional information on influenza vaccine-related precautions.
# Simultaneous administration with other vaccines
# NACI recommends that:
All seasonal influenza vaccines, including LAIV, may be considered for administration at the same time as, or at any time before or after, administration of any other live attenuated or inactivated vaccines (see Section II.6 below for details); -It should be noted that no studies have been conducted on the co-administration of recombinant zoster vaccine (RZV) with adjuvanted or high-dose influenza vaccine. No immune response interference or safety concerns have been demonstrated when RZV is administered concomitantly with standard dose, unadjuvanted vaccine (4) .
Different injection sites and separate needles and syringes should be used for concomitant parenteral injections.
# Why
Vaccination is the most effective way to prevent influenza and its complications. Vaccinated individuals who are protected from influenza will not pass infection to others. Although most people will recover fully from influenza infection in 7-10 days, influenza can lead to severe complications, including hospitalization and death.
Annual vaccination is required because the specific strains in the vaccine are reviewed each year by WHO and are often changed to provide a better match against the viruses expected to circulate in that given year, and because the body's immune response to influenza vaccination is transient and may not persist beyond a year.
# II.2 Epidemiology Disease description
Influenza is a respiratory illness caused by the influenza A and B viruses and can cause mild to severe illness, which can result in hospitalization or death. Certain populations, such as young children, older adults, and those with chronic health conditions, may be at higher risk for serious influenza complications such as viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions.
# Infectious agent
There are two main types of influenza virus that cause seasonal epidemics: Over time, antigenic variation (antigenic drift) of strains occurs within an influenza A subtype or a B lineage. The ever-present possibility of antigenic drift, which may occur in one or more influenza virus strains, requires seasonal influenza vaccines to be reformulated annually, with one or more vaccine strains changing in most seasons.
A
# Transmission
Influenza is primarily transmitted by droplets spread through coughing or sneezing and through direct or indirect contact with respiratory secretions. The incubation period of seasonal influenza is usually 2 days but can range from 1-4 days. Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.
# Risk factors
The people at greatest risk of influenza-related complications are adults and children with chronic health conditions (see List 1), residents of nursing homes and other chronic care facilities, adults 65 years of age and older, children 0-59 months of age, pregnant women, and Indigenous peoples.
# Seasonal and temporal patterns
Influenza activity in Canada is usually low in the late spring and summer, begins to increase over the fall, and peaks in the winter months. Depending on the year, the peak may occur as early as fall or as late as spring. Influenza season in Canada can last from a few weeks to many months, and more than one influenza strain typically circulates each season.
# Spectrum of clinical illness
Symptoms typically include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week or 10 days. However, adults and children with chronic health conditions, adults 65 years of age and older, children 0-59 months of age, residents of long-term care facilities, pregnant women, and Indigenous peoples are at greater risk of more severe complications or worsening of their underlying condition.
# Disease incidence
Global Worldwide, annual epidemics result in approximately one billion cases of influenza, three to five million cases of severe illness, and 290,000 to 650,000 deaths. The global annual attack rate is estimated to be 5-10% in adults and 20-30% in children (1) . For current international influenza activity information, refer to WHO's FluNet website.
# National
Together, influenza and pneumonia are ranked among the top 10 leading causes of death in Canada (5) .The FluWatch program is Canada's national surveillance system, which monitors the spread of influenza and influenza-like illnesses (ILI) continually throughout the year. Since the 2010-2011 season, an average of 30,000 laboratory-confirmed cases of influenza have been reported to FluWatch each year. Although the burden of influenza can vary from year to year, it is estimated that there are an average of 12,200 hospitalizations related to influenza and approximately 3,500 deaths attributable to influenza annually (6,7) . Current influenza activity information can be found on the FluWatch website.
It should be noted that the incidence of influenza is often underreported since the illness may be confused with other viral illnesses and many people with ILI do not seek medical care or have viral diagnostic testing done.
# II.3 Vaccine Products Authorized for Use in Canada
This section describes the influenza vaccine products that are authorized for use in Canada for the 2020-2021 season. All influenza vaccines available in Canada have been authorized by Health Canada. However, not all products authorized for use are necessarily available in the marketplace. The vaccine manufacturers determine whether they will make any or all of their products available in a given market. Provincial and territorial health authorities then determine which of the products available for purchase will be used in their respective publicly funded influenza immunization programs and for which population groups.
The antigenic characteristics of circulating influenza virus strains provide the basis for selecting the strains included in each year's vaccine. Vaccine selection by the WHO generally occurs more than 6 months prior to the start of the influenza season to allow time for the vaccine manufacturers to produce the required quantity of vaccine. All manufacturers that distribute influenza vaccine products in Canada confirm to Health Canada that the vaccines to be marketed in Canada for the upcoming influenza season contain the WHO's recommended antigenic strains for the Northern Hemisphere. Vaccine producers may use antigenically equivalent strains because of their growth properties.
There are two categories of influenza vaccine authorized for use in Canada: inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV). Trivalent (3 strain) vaccines contain one A(H1N1) strain, one A(H3N2) strain, and one influenza B strain from one of the two lineages. Quadrivalent (4 strain) vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage. All influenza vaccines currently authorized for use in Canada are made from influenza viruses grown in eggs.
A summary of the characteristics of influenza vaccines available in Canada during the 2020-2021 influenza season can be found in Appendix A. For complete prescribing information, readers should consult the product monographs available through Health Canada's Drug Product Database.
# Standard-dose inactivated influenza vaccine (IIV-SD)
The standard-dose inactivated influenza vaccines (IIV-SDs) currently authorized for use in Canada are a mix of split virus and subunit vaccines. In split virus vaccines, the virus has been disrupted by a detergent. In subunit vaccines, HA and NA have been further purified by removal of other viral components. These vaccines are unadjuvanted, contain 15 µg HA per strain, and are administered as a 0.5 mL dose by IM injection. Refer to Basic Immunology and Vaccinology in Part 1 of the CIG for more information about inactivated vaccines.
Both trivalent (IIV3-SD: Agriflu ® , Fluviral ® , Influvac ® , and Vaxigrip ® ) and quadrivalent (IIV4-SD: Afluria ® Tetra, Flulaval ® Tetra, Fluzone ® Quadrivalent, and Influvac ® Tetra) products are authorized for use in Canada.
# Adjuvanted inactivated influenza vaccine (IIV-Adj)
The adjuvanted inactivated influenza vaccine (IIV-Adj) currently authorized for use in Canada is a trivalent subunit IIV that contains the adjuvant MF59, which is an oil-in-water emulsion composed of squalene as the oil phase that is stabilized with the surfactants polysorbate 80 and sorbitan triolate in citrate buffer. IIV-Adj contains 7.5 µg HA per strain administered as a 0.25 mL dose by IM injection for children 6-23 months of age (Fluad Pediatric ® ) or 15 µg HA per strain administered as a 0.5 mL dose by IM injection for adults 65 years of age and older (Fluad ® ). Other IIVs do not contain an adjuvant.
# High-dose inactivated influenza vaccine (IIV-HD)
The high-dose inactivated influenza vaccine (IIV-HD) currently authorized for use in Canada is a trivalent unadjuvanted, split virus IIV that contains 60 µg HA per strain and is administered as a 0.5 mL dose by IM injection (Fluzone ® High-Dose).
# Live attenuated influenza vaccine (LAIV)
LAIV is given as an intranasal spray. The influenza viruses contained in LAIV are attenuated so that they do not cause influenza and are cold-adapted and temperature sensitive, so that they replicate in the nasal mucosa rather than the lower respiratory tract. LAIV contains standardized quantities of fluorescent focus units (FFU) of live attenuated reassortants and is given as a 0.2 mL dose (0.1 mL in each nostril).
A quadrivalent product (LAIV4; FluMist ® Quadrivalent) is authorized for use in Canada for children 2-17 years of age and adults 18-59 years of age. The trivalent formulation (LAIV3) is no longer available in Canada.
# II.4 Efficacy, Effectiveness, and Immunogenicity
Efficacy and effectiveness
Influenza vaccine has been shown in randomized controlled clinical trials to be efficacious in providing protection against influenza infection and illness. However, the effectiveness of the vaccine-that is, how it performs in settings that are more reflective of usual health care practicecan vary from season to season and by influenza vaccine strain type and subtype. Influenza vaccine effectiveness (VE) depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype, as well as the health and age of the individual receiving the vaccine. Even when there is a less-than-ideal match or lower effectiveness against one strain, the possibility of lower VE should not preclude vaccination, particularly for people at high risk of influenza-related complications and hospitalization, since vaccinated individuals are still more likely to be protected compared to those who are unvaccinated.
# Immunogenicity
Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are generally achieved by 2 weeks after vaccination; however, there may be some protection afforded before that time.
# II.5 Choice of Seasonal Influenza Vaccine
The decision to include specific influenza vaccines as part of publicly funded provincial and territorial programs depends on several factors, such as cost-effectiveness evaluation and other programmatic and operational factors, such as implementation strategies. Not all products will be made available in all jurisdictions and availability of some products may be limited; therefore, officials in individual provinces and territories should be consulted regarding the products available in individual jurisdictions.
With the availability of influenza vaccines that are designed to enhance immunogenicity in specific age groups or given through a different route of administration, the choice of product has become more complex.
# Choice of influenza vaccine by age group
Recommendations for individual-level decision making NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine. Table 2 provides age group-specific recommendations for the age-appropriate influenza vaccine types authorized for use in Canada.
Recommendations for public health program-level decision making NACI recommends that any of the age-appropriate influenza vaccine types available for use may be considered for people without contraindications to the vaccine. Table 2 provides age group-specific recommendations for the age-appropriate influenza vaccine types authorized in Canada.
# II.6 Vaccine Administration
Dose, route of administration, and schedule
With the variety of influenza vaccines available for use in Canada, it is important for vaccine providers to note the specific differences in age indication, route of administration, dosage, and schedule for the products that they will be using (see Table 3). Key relevant details and differences between vaccine products are also highlighted in Appendix A.
For influenza vaccines given by the IM route, the anterolateral thigh muscle is the recommended site in infants 6-12 months of age. The anterolateral thigh or the deltoid muscle can be used for toddlers and older children. The deltoid muscle of the arm is the preferred injection site in adolescents and adults. For more information on vaccine administration, please refer to Vaccine Administration Practices in Part 1 of the CIG. f Evidence suggests moderate improvement in antibody response in infants, without an increase in reactogenicity, with the use of full vaccine doses (0.5 mL) for unadjuvanted inactivated influenza vaccines (8,9) . This moderate improvement in antibody response without an increase in reactogenicity is the basis for the full dose recommendation for unadjuvanted inactivated vaccine for all ages. For more information, refer to Statement on Seasonal Influenza Vaccine for 2011-2012. g Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.
# Booster doses and revaccination
Booster doses are not required within the same influenza season. However, children 6 months to less than 9 years of age who have not previously received the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses (see Table 3). Only one dose of influenza vaccine per season is recommended for everyone else. Two doses of seasonal influenza vaccine in older adults do not appear to improve the immune response to the vaccine compared to one dose (11) .
# Serological testing
Serologic testing is not necessary before or after receiving seasonal influenza vaccine.
# Storage requirements
Influenza vaccine should be stored at +2°C to +8°C and should not be frozen. Refer to the individual product monographs for further details. Refer to Storage and Handling of Immunizing Agents in Part 1 of the CIG for additional information.
# Simultaneous administration with other vaccines
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Studies have been done showing no interference when administering LAIV3 concomitantly with: measles, mumps, rubella (MMR); measles, mumps, rubella, varicella (MMRV); or oral polio live vaccines (10,12,13) . No studies have been done to assess the possibility of interference between LAIV and other live vaccines, or on LAIV given before or after other live vaccines. Additional information regarding simultaneous administration with other vaccines can be found in Section IV.4 of this statement.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of an inactivated influenza vaccine would avoid this theoretical concern. Note that the timing rules related to two parenteral live vaccines (e.g., MMR and varicella vaccines) still apply. For more information regarding vaccination administration timing rules, please refer to Timing of Vaccine Administration in Part 1 of the CIG.
When more than one injection is given at a single clinic visit, it is preferable to administer them in different limbs. If it is not possible to do so, injections given in one limb should be separated by a distance of at least 2.5 cm (1 inch). A separate needle and syringe should be used for each injection.
The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. Vaccine providers should take the opportunity to vaccinate eligible people against pneumococcal disease when influenza vaccine is given.
# Simultaneous administration with recombinant zoster vaccine
RZV is a recombinant adjuvanted subunit herpes zoster vaccine (Shingrix ® , GlaxoSmithKline) that is authorized for use in Canada in adults 50 years of age and older; therefore, the target age group for herpes zoster vaccine and influenza vaccine overlap. RZV has been shown to be safe and effective when given concomitantly with unadjuvanted, standard dose influenza vaccines (4) . However, no studies have been conducted that have assessed the co-administration of RZV with adjuvanted or high dose influenza vaccine (14) . It should be noted that that the RZV and IIV-adj currently authorized for use in Canada contain the adjuvants AS01B and MF59 respectively. How these adjuvants may interact when RZV and IIV-adj are administered concomitantly is not known.
# II.7 Vaccine Safety and Adverse Events
Post-marketing surveillance of influenza vaccines in Canada has shown that seasonal influenza vaccines have a safe and stable profile. In addition to routine surveillance, every year during the seasonal influenza vaccination campaigns, PHAC and the Federal/Provincial/Territorial Vaccine Vigilance Working Group (VVWG) of the Canadian Immunization Committee conduct weekly expedited surveillance of AEFIs for current influenza vaccines in order to identify vaccine safety signals in a timely manner. Refer to the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) web page for more information on post-marketing surveillance and AEFIs in Canada.
All influenza vaccines currently authorized for use in Canada are considered safe for use in people with latex allergies. The multi-dose vial formulations of inactivated influenza vaccine that are authorized for use in Canada contain minute quantities of thimerosal, which is used as a preservative (15,16) to keep the product sterile. Large cohort studies of administrative health databases have found no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders (17) . All single dose formulations of IIV and LAIV are thimerosal-free. Refer to Vaccine Safety in Part 2 of the CIG for additional information.
# Common adverse events
With IM administered influenza vaccines, injection site reactions are common but are generally classified as mild and transient. IIV3-Adj tends to produce more extensive injection site reactions than unadjuvanted IIV3, but these reactions are also generally mild and resolve spontaneously within a few days. IIV3-HD tends to induce higher rates of systemic reactions post-injection compared to IIV3-SD, but most of these reactions are mild and short-lived. The most common AEs experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. Refer to the relevant subsections of Section IV for additional information.
Less common and serious or severe adverse events Serious adverse events (SAEs) are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some vaccine components. Refer to Section IV.5 below for additional information.
Other reported adverse events and conditions
# Guillain-Barré syndrome
Studies suggest that the absolute risk of Guillain-Barré syndrome (GBS) in the period following seasonal and A(H1N1)pdm09 influenza vaccination is about one excess case per million vaccinations (18,19) , and that the risk of GBS associated with influenza illness is larger (about 17 cases per million influenza-coded health care encounters, which are a proxy for influenza illness) than that associated with influenza vaccination (19) .
Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
# Oculorespiratory syndrome
Oculorespiratory syndrome (ORS), which is defined as the presence of bilateral red eyes and one or more associated respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial oedema, was identified during the 2000-2001 influenza season (20) . Since then, there have been far fewer cases per year reported to CAEFISS (21) . ORS is not considered to be an allergic response. People who have a recurrence of ORS upon vaccination do not necessarily experience further episodes with future vaccinations.
# Allergic reactions to previous vaccine doses
Expert review of the benefits and risks of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent significant allergic reaction to the vaccine, or any other symptoms that could indicate a significant allergic reaction (e.g., throat constriction, difficulty swallowing) that raise concern regarding the safety of revaccination. This advice may be obtained from experts in infectious disease, allergy, and immunology, or public health.
In view of the considerable morbidity and mortality associated with influenza, a diagnosis of influenza vaccine allergy should not be made without confirmation, which may involve consultation with an allergy or immunology expert.
# Drug interactions
Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterollowering actions. Two published studies have found that adults who are regular statin users (at least 65 years of age (22) in one study and 45 years and older in the other (23) had an apparent decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT) (22) or reduced VE against medically attended acute respiratory illness (23) . Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concomitant statin use in adult populations could have implications for influenza VE and how this use is assessed in the measurement of VE. NACI will continue to monitor the literature related to this issue.
# Guidance on reporting adverse events following immunization
To ensure the ongoing safety of influenza vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in most jurisdictions, reporting is mandatory under the law.
An AEFI is any untoward medical occurrence that follows vaccination and that does not necessarily have a causal relationship with the usage of a vaccine. The AE may be any unfavourable or unintended sign, abnormal laboratory finding, symptom, or disease. In general, any AE felt to be temporally related to vaccination and for which there is no other clear cause at the time of reporting should be reported. Of particular interest are those AEFIs which are considered serious or unexpected. A serious AEFI is an AE that is life threatening or results in death, requires hospitalization or prolongation of an existing hospitalization, results in residual disability or causes congenital malformation (24) . An unexpected AEFI is an event that is not listed in the approved product monograph but may be due to the vaccination, or one whose nature, severity, specificity, or outcome is not consistent with the term or description used in the product monograph (24) . Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. If there is any doubt as to whether or not an event should be reported, a conservative approach should be taken and the event should be reported.
For influenza vaccines, the following AEFIs are of particular interest:
ORS; and GBS within 6 weeks following vaccination.
Refer to Reporting Adverse Events Following Immunization (AEFI) in Canada for additional information about AEFI reporting and to Vaccine Safety in Part 2 of the CIG for general vaccine safety information.
# II.8 Travellers
Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere).
NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older, including travellers, who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see List 1).
Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination (i.e., boosting) of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity or difference between the Northern and Southern Hemisphere vaccines, the similarity or difference between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination. Refer to Immunization of Travellers in Part 3 of the CIG for additional general information.
This concludes the summary of relevant influenza vaccine information typically found in the Canadian Immunization Guide. Additional technical information related to seasonal influenza vaccine can be found in the remainder of this statement.
# III. PARTICULARLY RECOMMENDED VACCINE RECIPIENTS: ADDITIONAL INFORMATION
The groups for whom influenza vaccination is particularly recommended are presented in List 1 of Section II. Additional information regarding these particularly recommended recipients is provided below.
# III.1 People at High Risk of Influenza-Related Complications or Hospitalization
All pregnant women NACI recommends the inclusion of all pregnant women, at any stage of pregnancy, among the particularly recommended recipients of IIV, due to the risk of influenza-associated morbidity in pregnant women (25)(26)(27)(28)(29) , evidence of adverse neonatal outcomes associated with maternal respiratory hospitalization or influenza during pregnancy (30)(31)(32)(33) , evidence that vaccination of pregnant women protects their newborns from influenza and influenza-related hospitalization (34)(35)(36)(37) , and evidence that infants born during influenza season to vaccinated women are less likely to be premature, small for gestational age, and of low birth weight than if born to women that had not received an influenza vaccine (38)(39)(40)(41) . The risk of influenza-related hospitalization increases with length of gestation (i.e., it is higher in the third trimester than in the second).
The safety of IIV during pregnancy has been reviewed (42) . Active studies of influenza vaccination during pregnancy have not shown evidence of harm to the mother or fetus associated with influenza vaccination (43) . Although the cumulative sample size of active studies of influenza vaccination in pregnant women is relatively small, particularly in the first trimester, passive surveillance has not raised any safety concerns despite widespread use of IIV during pregnancy over several decades (27,28,42,44) . Surveillance following the use of both adjuvanted and unadjuvanted 2009 pandemic influenza A(H1N1) vaccines in more than 100,000 pregnant women in Canada and more than 488,000 pregnant women in Europe (45) has not revealed any safety concerns.
Refer to the Statement on Seasonal Influenza Vaccine for 2011-2012 and the Statement on Seasonal Influenza Vaccine for 2012-2013 for further details on influenza vaccination during pregnancy.
# Adults and children with chronic health conditions
A number of chronic health conditions, as noted in List 1, are associated with increased risk of influenza-related complications, and influenza can lead to exacerbation of the chronic disease. Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected people. Vaccine effectiveness may be lower in people with immune compromising conditions than in healthy adults.
# Neurologic or neurodevelopment conditions
Neurologic or neurodevelopment conditions (NNCs) include neuromuscular, neurovascular, neurodegenerative, neurodevelopment conditions, and seizure disorders (and, for children, include febrile seizures and isolated developmental delay), but exclude migraines and psychiatric conditions without neurological conditions. Based on reviews of evidence and expert opinion, NACI includes adults and children with NNCs among the groups for whom influenza vaccination is particularly recommended. Refer to the NACI Statement on Seasonal Influenza Vaccine for 2018-2019 for a summary of the rationale supporting this decision and the Literature Review on Individuals with Neurologic or Neurodevelopment Conditions and Risk of Serious Influenza-Related Complications for additional details of the evidence reviews.
# People of any age who are residents of nursing homes and other chronic care facilities
Residents of nursing homes and other chronic care facilities often have one or more chronic health conditions and live in institutional environments that may facilitate the spread of influenza.
# Adults 65 years of age and older
Hospitalization attributable to influenza in this age group is estimated at 125-228 per 100,000 healthy people (46) , and influenza-attributed mortality rates increase with increased age (47) .
# All children 6-59 months of age
On the basis of existing data, NACI recommends the inclusion of all children 6-59 months of age among the particularly recommended recipients of influenza vaccine.
# Indigenous peoples
Based on the body of evidence indicating a higher rate of influenza-associated hospitalization and death among Indigenous peoples, NACI recommends the inclusion of this population among the particularly recommended recipients of influenza vaccine.
It has been proposed that the increased risk of severe influenza outcomes in the Indigenous populations is a consequence of many factors, including high prevalence of chronic health conditions (e.g., diabetes, chronic lung disease, end-stage kidney disease, cardiovascular disease) (48) , obesity, delayed access to health care, and increased susceptibility to disease because of poor housing and overcrowding (49)(50)(51) . Refer to the Statement on Seasonal Influenza Vaccine for 2011-2012 for further details.
# III.2 People Capable of Transmitting Influenza to Those at High Risk of Influenza-Related Complications or Hospitalization
People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk individual has been vaccinated. Vaccination of HCWs decreases their own risk of illness (52,53) , as well as the risk of death and other serious outcomes among the individuals for whom they provide care (54)(55)(56)(57) . Vaccination of HCWs and residents of nursing homes is associated with decreased risk of ILI outbreaks (58) .
People who are more likely to transmit influenza to those at high risk of influenza-related complications or hospitalization include: HCWs and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; and Contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated.
Health care workers and other care providers in facilities and community settings
# Vaccination of health care workers and other care providers
For the purposes of this statement, HCWs and other care providers in facilities and community settings refers to HCWs, regular visitors, emergency response workers, and others who have contact with residents of continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. HCWs include any person, paid or unpaid, who provides services, works, volunteers, or trains in a hospital, clinic, or other health care facility.
Transmission of influenza to patients at high risk of influenza-associated complications results in significant morbidity and mortality. Four cluster randomized controlled trials (RCTs) conducted in geriatric long-term care settings have demonstrated that vaccination of HCWs is associated with substantial decreases in influenza-like illness (55)(56)(57) and all-cause mortality (54)(55)(56)(57) in the residents. In addition, due to their occupation and close contact with people at high-risk of influenza-related complications, HCWs are themselves at increased risk of infection (59) .
As previously stated, adults and children with chronic health conditions, adults 65 years of age and older, and children 0-59 months of age are at greater risk of more severe complications from influenza or worsening of their underlying condition. Given the potential for HCWs and other care providers to transmit influenza to individuals at high risk and knowing that vaccination is the most effective way to prevent influenza, NACI recommends that, in the absence of contraindications, HCWs and other care providers in facilities and community settings should be vaccinated against influenza annually. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs and other care providers for their own protection and that of their patients. This group should consider annual influenza vaccination as part of their responsibilities to provide the highest standard of care.
Although current influenza vaccine coverage for HCWs is higher than in the general public (60,61) , it remains below the national goal of 80% coverage for HCWs in Canada (62) . Comprehensive vaccination programs should be adopted that address HCWs' acceptance of the vaccine and facilitate the process of vaccinating HCWs to improve uptake of the influenza vaccine beyond the current level. HCW influenza vaccination programs that have successfully increased vaccine coverage of HCWs have included a combination of education, increased awareness, accessible on-site vaccination delivery options for all HCWs, visible support from senior staff and other leaders, and regular review and improvement of vaccination strategies (63)(64)(65)(66)(67)(68) .
# Outbreak management in health care facilities
As noted in PHAC's Guidance: Infection Prevention and Control Measures for Healthcare Workers in Acute Care and Long-term Care Settings for seasonal influenza, all health care organizations should have a written plan for managing an influenza outbreak in their facilities. Inherent in such plans should be policies and programs to optimize HCW's influenza vaccination (69) . As part of outbreak management, the above-mentioned PHAC guidance suggests consideration of chemoprophylaxis for all unvaccinated HCWs, unless contraindications exist.
Refer to the Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada) website for guidelines regarding the use of antiviral medications for prophylaxis.
# Contacts of individuals at high risk of influenza complications
Vaccination is recommended for contacts, both adults and children, of individuals at high risk of influenza-related complications or hospitalization (see List 1), whether or not the individual at high risk has been vaccinated. These contacts include: household contacts and care providers of individuals at high risk, household contacts and care providers of infants less than 6 months of age (as these infants are at high risk of complications from influenza but cannot receive influenza vaccine), members of a household expecting a newborn during the influenza season, household contacts and care providers (whether in or out of the home) of children 6-59 months of age, and providers of services within closed or relatively closed settings with people at high risk of influenza-related complications (e.g., crew on a ship).
# III.3 Others
People who provide essential community services Vaccination for these individuals should be encouraged to minimize the disruption of services and routine activities during annual influenza epidemics. People who provide essential community services, including healthy working adults, should consider annual influenza vaccination, as this intervention has been shown to decrease work absenteeism due to respiratory and related illnesses (52,53,(70)(71)(72) .
People in direct contact with poultry infected with avian influenza during culling operations
# Poultry workers
Although seasonal influenza vaccination will not prevent avian influenza infection, some countries (73) and provinces have recommended influenza vaccination on a yearly basis for poultry workers, based on the rationale that preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with human and avian influenza viruses (74) .
NACI recommends seasonal influenza vaccination for people in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of avian influenza infection because of exposure during the culling operation (75)(76)(77)(78) . Refer to the Statement on Seasonal Influenza Vaccine for 2013-2014 for further information informing this recommendation.
Direct contact may be defined as sufficient contact with infected poultry to allow transmission of an avian virus to the exposed person. The relevant individuals include those performing the cull, as well as others who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. It is recommended that biosecurity measures such as personal protective equipment and antivirals be used. Refer to Human Health Issues Related to Avian Influenza in Canada for PHAC recommendations on the management of domestic avian influenza outbreaks.
Swine workers NACI has concluded that there is insufficient evidence at this time to recommend routine influenza vaccination specifically for swine workers; however, NACI recommends that influenza vaccination should be offered to anyone 6 months of age and older who does not have contraindications to the vaccine.
Refer to the Statement on Seasonal Influenza Vaccine for 2013-2014 for further information informing this recommendation.
# IV. VACCINE PREPARATIONS AUTHORIZED FOR USE IN CANADA: ADDITIONAL INFORMATION
The following sections describe information on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines that are authorized for use in Canada by type: IIV and LAIV. Refer to Appendix A for a summary of the characteristics of specific influenza vaccine products available in Canada for the 2020-2021 season.
NACI acknowledges that evidence related to influenza vaccine performance, particularly with respect to vaccine efficacy and effectiveness, is constantly evolving with advances in research methodology and accumulation of data over many influenza seasons. Therefore, the evidence summarized in this section may not include the latest studies. However, in accordance with usual practice, NACI continues to closely monitor the emerging evidence on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines to update and to make recommendations when warranted.
# IV.1 Inactivated Influenza Vaccine (IIV)
IIVs contain standardized amounts of the HA protein from representative seed strains of the two human influenza A subtypes (H3N2 and H1N1) and either one (for trivalent vaccines) or both (for quadrivalent vaccines) of the two influenza B lineages (Yamagata or Victoria). IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines, both consisting of disrupted virus particles. Split virus vaccines contain whole inactivated viruses split with detergent, ether, or both, while subunit vaccines are made of purified HA and NA. The amount of NA in the vaccines is not standardized. HA-based serum antibody produced to one influenza A subtype is anticipated to provide little or no protection against strains belonging to the other subtype. The potential for trivalent vaccine to stimulate antibody protection across B lineages requires further evaluation and may be dependent upon factors such as age and prior antigenic experience with the two B lineages (79)(80)(81)(82)(83)(84) .
Because of potential changes in the circulating influenza virus from year to year and waning immunity in vaccine recipients, annual influenza vaccination is recommended. Although NACI is aware of some recent studies that suggest that vaccine induced protection may be greater in individuals who have no recent vaccine history, optimal protection against influenza, season after season, is best achieved through annual influenza vaccination (85,86) . NACI will continue to monitor this issue.
# Immunological considerations related to children
Young children have a high burden of illness and their vaccine-induced immune response is not as robust as older children. However, some studies suggest moderate improvement in antibody response in young children, without an increase in reactogenicity, with the use of a full vaccine dose (0.5 mL) for IIV-SDs (8,9,87) . On the basis of this moderate improvement in antibody response without an increase in reactogenicity, NACI recommends the use of a 0.5 mL dose for all recipients of IIV-SDs, including young children.
# Immunological considerations related to older adults and those with immune compromising conditions
Although the initial antibody response in older adults may be lower to some influenza vaccine components when compared to those in other age groups, a literature review identified no evidence for a subsequent antibody decline that was any more rapid in older adults than in younger age groups (88) .
Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patients (89)(90)(91)(92) .
Most studies have shown that administration of a second dose of influenza vaccine in the same season to older adults or other individuals who may have an altered immune response does not result in a clinically significant antibody boost (11,(93)(94)(95) .
# Standard-dose trivalent inactivated influenza vaccine (IIV3-SD)
Vaccines currently authorized for use:
Agriflu ® (Seqirus) Fluviral ® (GlaxoSmithKline) *
# Efficacy and effectiveness
The NACI Literature Review on Influenza Vaccination in Healthy 5-18 Year Olds found that VE of IIV3-SD against laboratory-confirmed influenza was variable but was most frequently between 65-85% (96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114) . In the NACI literature review on Influenza Vaccine Effectiveness, Immunogenicity, and Safety in Healthy Adults 19-64 Years Old, efficacy against laboratory-confirmed influenza for IIV3-SD in healthy adults 18-64 years of age ranged widely from as low as 15% to as high as 75%, with the majority of studies estimating efficacy at 50-60%. Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for a more detailed summary of efficacy and effectiveness evidence for IIV3-SD in healthy children 5-18 years of age and healthy adults 19-64 years of age.
In older adults, VE of IIV3-SD is about half of that in healthy adults and varies depending on the outcomes measured and the study population (115,116) . Systematic reviews have demonstrated that influenza vaccine decreases the incidence of pneumonia, hospital admissions, and deaths in older adults (115) and reduces exacerbations in people with chronic obstructive pulmonary disease (117) . The NACI Literature Review on the Comparative Effectiveness and Immunogenicity of Subunit and Split Virus Inactivated Influenza Vaccines in Adults 65 Years of Age and Older found no statistically significant differences in VE of subunit IIV3-SD compared with split virus IIV3-SD in adults 65 years of age and older against infection with any influenza virus strain, or against infection with influenza A(H1N1), A(H3N2), or B virus specifically.
In observational studies, influenza vaccination has been shown to reduce the number of physician visits, hospitalizations, and deaths in adults 18-64 years of age with high-risk medical conditions (118) , hospitalizations for cardiac disease and stroke in adults 65 years of age and older (119) , and hospitalization and deaths in adults 18 years of age and older with diabetes mellitus (120) during influenza epidemics. Observational studies that use non-specific clinical outcomes or that do not take into account differences in functional status or health-related behaviours should be interpreted with caution (121)(122)(123)(124)(125) .
# Immunogenicity
Both humoral and cell-mediated immune responses are thought to play a role in immunity to influenza. While humoral immunity is thought to play a primary role in protection against infection, cell-mediated immunity, notably cytotoxic T lymphocyte responses to internal viral components, is increasingly invoked as important in protecting against severe outcomes of influenza, particularly those associated with subtype HA variations (shift and drift) (126) . The IM administration of IIV3-SD results in the production of circulating immunoglobulin G (IgG) antibodies to the viral HA and NA proteins, as well as a more limited cytotoxic T lymphocyte response.
# Safety
Studies evaluating the safety of IIV3-SDs in healthy children have found a good safety profile with no SAEs of note (127) . The most common solicited local reactions are pain and redness at the injection site, while the most common solicited systemic reactions are irritability, malaise, and headache. Mild injection site reactions, primarily soreness at the vaccination site, have been found to occur in 7% or less of healthy children who are less than 3 years of age (128)(129)(130) . Postvaccination fever may be observed in 12% or less of vaccinated children 1-5 years of age (101,130) .
For adults, IIV3-SDs have been demonstrated to have a good safety profile with acceptable reactogenicity (127) . Common local reactions at injection site include redness, swelling, pain, and induration. These reactions last 2-3 days and rarely interfere with normal activities. Common systemic reactions include headache, malaise, myalgia, fatigue, arthralgia, and fever.
# Adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj)
Vaccines currently authorized for use:
Fluad ® (Seqirus) Fluad Pediatric ® (Seqirus)
# Fluad (adults 65 years of age and older) Efficacy and effectiveness
There is fair evidence that the MF59-adjuvanted Fluad (IIV3-Adj) may be effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to unvaccinated individuals. However, there is insufficient evidence that IIV3-Adj is more effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to those who received unadjuvanted subunit IIV3-SD. Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for more information on the efficacy and effectiveness of IIV3-Adj in adults 65 years of age and older.
# Immunogenicity
The mechanism of action of MF59 is not fully determined and has primarily been studied using in vitro and mouse models. From these studies, it appears that MF59 may act differently from aluminum-based adjuvants. These studies show that MF59 acts in the muscle fibres to create a local immune-stimulatory environment at the injection site (131) . MF59 allows for an increased influx of phagocytes (e.g., macrophages, monocytes) to the site of injection. The recruited phagocytes are further stimulated by MF59, thereby increasing the production of chemokines to attract more innate immune cells and inducing differentiation of monocytes into dendritic cells (132,133) . MF59 further facilitates the internalization of antigen by these dendritic cells (132,134) . The overall higher number of cells available locally increases the likelihood of interaction between an antigen presenting cell and the antigen, leading to more efficient transport of antigen to the lymph nodes, with resulting improved T cell priming (132) .
There is evidence from RCTs that IIV3-Adj elicits non-inferior immune responses compared to the unadjuvanted subunit and split virus IIV3-SDs; however, superiority of IIV3-Adj to these vaccines by pre-defined criteria has not been consistently demonstrated. Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for more information on the immunogenicity of IIV3-Adj in adults 65 years of age and older.
# Safety
IIV3-Adj produces injection site reactions (pain, erythema, and induration) significantly more frequently than IIV3-SD, but they are classified as mild and transient. Systemic reactions (myalgia, headache, fatigue, and malaise) are comparable or more frequent with IIV3-Adj compared to IIV3-SD and are rated as mild to moderate and transient. SAEs were uncommon and were comparable to IIV3-SD. Refer to the Recommendations on the use of MF59-Adjuvanted Trivalent Influenza Vaccine (Fluad ® ): Supplemental Statement of Seasonal Influenza Vaccine for 2011-2012 for additional information on the safety of IIV3-Adj in adults 65 years of age and older.
# Fluad Pediatric (children 6-23 months of age) Efficacy and effectiveness
A pre-licensure efficacy trial in children 6-71 months of age found a higher relative efficacy for IIV-Adj than the unadjuvanted IIV3-SD (135) . However, the findings of this study should be interpreted with caution. The comparator unadjuvanted IIV3 used in this trial was shown, in an unrelated study, to induce a lower immune response compared to another unadjuvanted IIV3-SD. There were concerns raised by a European Medicines Agency inspection about the quality of diagnostic laboratory testing and validity of ascertainment of influenza cases. The study administered 0.25 mL doses of the comparator unadjuvanted IIV3-SD for children less than 36 months of age, which is lower than the dose of 0.5 mL of unadjuvanted IIV3-SD or IIV4-SD that is recommended for this age group in Canada. Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for more information on the efficacy and effectiveness of IIV3-Adj in children.
# Immunogenicity
In children, there is limited but consistent evidence that IIV3-Adj is more immunogenic than IIV3-SD against both influenza A and B (135)(136)(137)(138)(139)(140) . In particular, a single dose of IIV3-Adj is more immunogenic than a single dose of IIV3-SD, and has been shown in one study to produce greater GMTs than 2 doses of IIV3-SD against influenza A (140) . However, similar to IIV3-SD, IIV3-Adj generally induced a weaker hemagglutination-inhibition antibody response against B strains compared to A strains and therefore 2 doses of IIV3-Adj are still necessary to achieve a satisfactory immune response against influenza B.
Almost all of the pre-licensure pediatric studies used vaccine formulations of 0.25 mL in children 6-35 months of age, both for IIV3-Adj and the comparator unadjuvanted influenza vaccine (NACI recommends 0.5 mL dosage of IIV3-SD or IIV4-SD for all age groups). There is limited immunogenicity evidence comparing IIV3-Adj at 0.25 mL dose to IIV3-SD or IIV4-SD at 0.5 mL dose in the 6-23 month age group. Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for more information on the immunogenicity of IIV3-Adj in children.
# Safety
The safety data in children are consistent with what is known about IIV3-Adj's safety profile in adults. In pediatric trials, IIV3-Adj was more reactogenic than IIV3-SD, with recipients experiencing 10-15% more solicited local and systemic reactions. However, most reactions were mild and resolved quickly. A dose-ranging study of MF59-adjuvanted and unadjuvanted IIV3 and IIV4 did not find an increased risk of AEs associated with increased MF59 dose, antigen dose, or the addition of a second B strain; however, the reactogenicity of 15 µg formulations were slightly higher for both adjuvanted and unadjuvanted vaccines compared to the corresponding 7.5 µg formulations (138) .
There are currently no data on the effects of long-term or repeated administration of adjuvanted influenza vaccines in children. The most significant experience with an adjuvanted influenza vaccine in children was the AS03-adjuvanted A(H1N1) pandemic vaccine that has been associated with an increased risk of narcolepsy. A study comparing two AS03-adjuvanted A(H1N1) vaccine products (Pandemrix and Arepanrix) has suggested that the underlying immune mediated mechanism associated with the increased narcolepsy risk may not be initiated by the adjuvant, but by the A(H1N1) nucleoprotein viral antigen, given that the study found significant antigenic differences between the two A(H1N1) pandemic vaccines (141) . However, the pandemic vaccine was a single strain adjuvanted vaccine administered only during one season, and it is unknown what effects a multi-strain adjuvanted vaccine or an adjuvanted vaccine administered for more than one season may have in young children.
Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for additional information on the safety of IIV3-Adj in children.
# High-dose trivalent inactivated influenza vaccine (IIV3-HD)
Vaccine currently authorized for use:
Fluzone ® High-Dose (Sanofi Pasteur)
# Efficacy and effectiveness
There is good evidence that Fluzone High-Dose (IIV3-HD) provides better protection compared with IIV3-SD in adults 65 years of age and older. A few studies found that IIV3-HD may provide greater benefit in adults 75 years of age and older compared to adults 65-74 years of age (142)(143) ; however, additional studies are needed to validate this finding. There remain no efficacy or effectiveness studies that compare IIV3-HD with IIV3-Adj or IIV4-SD specifically.
Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for more information on the efficacy and effectiveness of IIV3-HD in adults 65 years of age and older.
# Immunogenicity
Five studies compared the rates of seroconversion for study participants receiving IIV3-HD and IIV3-SD among those 65 years of age and older (145)(146)(147)(148)(149)(150) . Rates of seroconversion were found to be about 19% higher (ranging from 8-39% higher) for those receiving the higher dose vaccine across all three vaccine strains. Similarly, rates of seroconversion were higher for those receiving the high-compared to standard-dose vaccines for participants 75 years of age and older and for a cohort of participants with underlying cardiopulmonary disease.
Eight studies reported higher rates of seroprotection for older adults receiving IIV3-HD compared to those vaccinated with IIV3-SD (145)(146)(147)(148)(149)(150)(151)(152) . Seroprotection was significantly higher for all 3 strains in the vaccine in three of five studies assessing significance. There were different results in the remaining studies. In the study by Couch et al., seroprotection was higher only against A(H1N1), possibly attributed to the fact that 78% of participants were vaccinated against the same influenza strains within 6 months prior to the study (146) . In Nace et al., seroprotection was higher against A(H3N2) and B but not A(H1N1); the lack of higher seroprotection against A(H1N1) may be attributed to strain circulation during the study that made it difficult to assess seroprotection against this subtype (150) .
Geometric mean titre ratios (GMTR) of participants' responses to high-versus standard-dose influenza vaccines were reported in several studies and were calculated for those that provided group-specific, post-vaccination titres for each of the vaccines (145)(146)(147)(148)(149)151,152) . Seroresponse to the B strains in the vaccines was about 1.5 times greater (1.3-1.7) in the IIV3-HD recipients than the IIV3-SD recipients. The GMTR of the A strains was about 1.8 times higher for those receiving IIV3-HD compared to IIV3-SD, ranging from 1.6-2.3.
# Safety
IIV3-HD has been observed to produce a higher rate of some systemic and local reactions than IIV3-SD. Studies have reported higher rates of malaise, myalgia, and moderate to severe fever. Most systemic reactions were mild and resolved within 3 days. SAEs were rare and similar in frequency between standard-dose and high-dose vaccines.
Refer to NACI's A Review of the Literature of High Dose Seasonal Influenza Vaccine for Adults 65 Years and Older for details.
# Standard-dose quadrivalent inactivated influenza vaccine (IIV4-SD)
Vaccines currently authorized for use:
Afluria ® Tetra (Seqirus) Flulaval ® Tetra (GlaxoSmithKline) Fluzone ® Quadrivalent (Sanofi Pasteur)
Influvac ® Tetra (BGP Pharma ULC, operating as Mylan)
# Efficacy and effectiveness
In the NACI Literature Review on Quadrivalent Influenza Vaccines, only one study was identified that measured IIV4-SD efficacy. In that study, efficacy was estimated at 59% in children 3-8 years of age, in comparison to children who received hepatitis A vaccine (153) . No literature was found in this review on efficacy or effectiveness directly comparing trivalent and quadrivalent formulations.
# Immunogenicity
In the same review of the literature noted above, NACI reviewed the immunogenicity data for IIV4-SD produced by manufacturers who supplied influenza vaccine in Canada at the time of the literature review: AstraZeneca, GlaxoSmithKline, and Sanofi Pasteur. The results of phase II and III trials that compared trivalent formulations to quadrivalent formulations generally showed noninferiority of the quadrivalent products for the A(H3N2), A(H1N1), and B strain contained in the trivalent formulations. As expected, these studies showed that the immune response to the B strain that was not in the trivalent formulation was better in subjects who received the quadrivalent vaccine, which contained the additional B strain. These findings were consistent across age groups. Refer to the Literature Review on Quadrivalent Influenza Vaccines for additional details.
In the phase III trials, recipients of the trivalent formulations showed, to a lesser degree, some immune response to the B strain not contained in the trivalent formulation. In one study of adults, both the trivalent and quadrivalent vaccines met all the European Medicines Agency Committee for Medicinal Products for Human Use and the United States Food and Drug Administration criteria for evaluation of influenza vaccine immunogenicity, including those for the B strain not in the trivalent vaccine.
In all other studies, the trivalent vaccine failed at least one of the criteria for seroprotection or seroconversion for the missing B strain. It has been hypothesized that there is some level of crossreactivity between B strains. The degree of cross protection against infection with one lineage provided by immunization against the other lineage is uncertain (154) .
# Safety
As IIV4-SD has higher antigenic content than IIV3-SD, increased reactogenicity may be a concern for the quadrivalent vaccine. However, pre-licensure clinical trials (refer to Literature Review on Quadrivalent Influenza Vaccines) and post-marketing surveillance showed that IIV4-SD had a similar safety profile to IIV3-SD (155) .
# IV.2 Live Attenuated Influenza Vaccine (LAIV)
LAIV contains standardized quantities of FFU of live attenuated influenza virus reassortants. The virus strains in LAIV are cold-adapted and temperature sensitive, so they replicate in the nasal mucosa rather than the lower respiratory tract, and they are attenuated, so they do not produce ILI. There have been no reported or documented cases, and no theoretical or scientific basis to suggest transmission of vaccine virus would occur to the individual administering LAIV. As a live replicating whole virus formulation administered intranasally, it elicits mucosal immunity, which may more closely mimic natural infection.
Vaccine currently authorized for use:
FluMist ® Quadrivalent (AstraZeneca)
# Efficacy and effectiveness
After careful review of the available Canadian and international LAIV VE data over many influenza seasons, NACI concluded that the current evidence is consistent with LAIV providing comparable protection against influenza to that afforded by IIV and does not support a recommendation for the preferential use of LAIV in children 2-17 years of age.
Observational studies from the United States found low effectiveness of LAIV against circulating post-2009 pandemic A(H1N1), or A(H1N1)pdm09, in 2013-2014 and 2015-2016; however, reduced LAIV effectiveness was not observed in Canada or any other countries that have investigated the issue. Manufacturer investigation identified potential reduced replicative fitness of the A(H1N1)pdm09-like LAIV viruses in the nasal mucosa from the two affected A(H1N1)dominant seasons compared to pre-2009 pandemic influenza A(H1N1) LAIV viruses as contributing to the poor LAIV effectiveness against circulating A(H1N1) (156) . This finding led to the manufacturer replacing the A(H1N1)pdm09 component of LAIV with new strains, with the A/Slovenia/2903/2015 being the strain that has been used since the 2017-2018 season. In adults, studies have found IIV-SD to be similarly or more efficacious or effective compared with LAIV.
Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for detailed information supporting this recommendation.
# Immunogenicity
LAIV, which is administered by the intranasal route, is thought to result in an immune response that mimics that induced by natural infection with wild-type viruses, with the development of both mucosal and systemic immunity. Local mucosal antibodies protect the upper respiratory tract and may be more important for protection than serum antibody.
Studies have demonstrated that the presence of a hemagglutination-inhibition antibody response after the administration of LAIV3 is predictive of protection. However, efficacy studies have shown protection in the absence of a significant antibody response as well (157) . In these studies, LAIV3 has generally been shown to be equally, if not more, immunogenic compared to IIV3-SD for all 3 strains in children, whereas IIV3-SD was typically more immunogenic in adults than LAIV3. Greater rates of seroconversion to LAIV3 occurred in baseline seronegative individuals compared to baseline seropositive individuals in both pediatric and adult populations, because pre-existing immunity may interfere with response to a live vaccine. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for further details regarding the immunogenicity of LAIV3.
LAIV4 has shown non-inferiority based on immunogenicity compared to LAIV3 in both children and adults. The immune response to the B strain found only in the quadrivalent formulation was better in children who received the quadrivalent vaccine (158)(159)(160) .
# Safety
The most common AEs experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. In a large efficacy trial, rates of wheezing were statistically higher among children 6-23 months of age for LAIV3 compared to IIV3-SD (157) . This finding is expected to be the same for recipients of LAIV4; however, pre-licensure clinical studies for LAIV4 were conducted only in adults and children 2 years of age and older.
Studies on LAIV3 have shown that vaccine virus can be recovered by nasal swab in children and adults following vaccination (i.e., "shedding"). The frequency of shedding decreases with increasing age and time since vaccination. Shedding is generally below the levels needed to transmit infection, although in rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated people. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for more information on LAIV and viral shedding.
# Considerations related to individuals with HIV infection
Following a review of the literature regarding the use of LAIV in HIV-infected individuals, NACI concluded that LAIV is immunogenic in children with stable HIV infection on HAART and with adequate immune function. In addition, NACI concluded that LAIV appears to have a similar safety profile as IIV in children on HAART and with stable HIV infection with regard to frequency and severity of AEs. As expected, injection site reactions were seen only with IIV and nasal symptoms were more common with LAIV. However, the evidence base is too small to effectively detect uncommon, rare, and very rare AEs related to the use of LAIV in in this population. In addition, nasal spray may be preferable to IM injection for some individuals who are averse to receiving the vaccine by injection. Therefore, NACI recommends that LAIV may be considered as an option for children 2-17 years of age with stable HIV infection on HAART and with adequate immune function. LAIV should be considered only in children with HIV who meet the following criteria:
Receiving HAART for ≥4 months; CD4 count ≥500/µL if 2-5 years of age, or ≥200/µL if 6-17 years of age (measured within 100 days before administration of LAIV); and HIV plasma RNA <10,000 copies/mL (measured within 100 days before administration of LAIV).
IM influenza vaccination is still considered the standard for children living with HIV by NACI and the Canadian Pediatric and Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e. plasma HIV RNA >40 copies/mL). However, if IM vaccination is not accepted by the patient or substitute decision maker, LAIV would be a reasonable option for children meeting the criteria listed above.
Refer to the NACI Statement on the Use of LAIV in HIV-Infected Individuals for more information on the use of LAIV in this population.
# IV.3 Schedule
The first time that children 6 months to less than 9 years of age receive seasonal influenza vaccination, a two-dose schedule is required to achieve protection (161)(162)(163) . Several studies have looked at whether these two initial doses need to be given in the same season (81,82,164) . Englund et al. reported similar immunogenicity in children 6-23 months of age whether 2 doses were given in the same or separate seasons when there was no change, or only minor vaccine strain change, in vaccine formulation between seasons (81,82) . However, seroprotection rates to the B component were considerably reduced in the subsequent season when there was a major B lineage change, suggesting that the major change in B virus lineage reduced the priming benefit of previous vaccination (80,82) . Issues related to effective prime-boost when there is a major change in influenza B lineage across sequential seasons require further evaluation (165) . Because children 6-23 months of age are less likely to have had prior priming exposure to an influenza virus, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children in this age group.
# IV.4 Simultaneous Administration with Other Vaccines
In general, NACI recommends that two live parenteral vaccines be administered either on the same day or at least 4 weeks apart (166) . This recommendation is based largely on a single study from 1965 that demonstrated immune interference between smallpox vaccine and measles vaccine administered 9-15 days apart. Subsequent studies have revealed conflicting results on immune interference between live vaccines (167)(168)(169)(170) . No studies were found on potential immune interference between LAIV and other live attenuated vaccines (oral or parenteral) administered within 4 weeks. A few studies on concomitant administration of LAIV3 with MMR, varicella, and oral polio vaccines did not find evidence of clinically significant immune interference (10,12,13) . One study reported a statistically significant but not clinically meaningful decrease in seroresponse rates to rubella antigen when administered concomitantly with LAIV.
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Possible immune mechanisms include: the inhibitory and immunomodulatory effects of systemic and locally produced cytokines on B-and T-cell response and viral replication; immunosuppression induced by certain viruses (such as measles); and direct viral interference as a result of competition for a common niche. Mucosal vaccines may have less impact on a parenteral vaccine and vice versa. The immune response with a mucosal vaccine may be compartmentalized to the mucosa while that to a parenteral vaccine is systemic. It is likely that there is some interaction between the systemic and mucosal compartments; however, the extent to which this interaction occurs is not known.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of an inactivated influenza vaccine would avoid this theoretical concern.
# IV.5 Additional Vaccine Safety Considerations
Influenza vaccine is safe and well tolerated. Contraindications, precautions, and common AEs are described in Section II. Additional information regarding egg-allergic individuals and GBS is provided below.
# Egg-allergic individuals
After careful review of clinical and post-licensure safety data, NACI has concluded that eggallergic individuals may be vaccinated against influenza using any appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular consideration, including vaccination setting. The amount of trace ovalbumin allowed in influenza vaccines that are authorized for use in Canada is associated with a low risk of AE. The observation period post-vaccination is as recommended in Vaccine Safety in Part 2 of the CIG. As with all vaccine administration, vaccine providers should be prepared with the necessary equipment, knowledge, and skills to respond to a vaccine emergency at all times.
Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for safety data supporting this recommendation for IIV and LAIV.
# Guillain-Barré syndrome
In a review of studies conducted between 1976 and 2005, the United States Institute of Medicine concluded that the 1976 "swine flu" vaccine was associated with an elevated risk of GBS. However, evidence was inadequate to accept or to reject a causal relation between GBS in adults and seasonal influenza vaccination (171) .
The attributable risk of GBS in the period following seasonal and monovalent 2009 pandemic influenza vaccination is about one excess case per million vaccinations (18,19) . In a self-controlled study that explored the risk of GBS after seasonal influenza vaccination and after influenza health care encounters (a proxy for influenza illness), the attributable risks were 1.03 GBS admissions per million vaccinations compared with 17.2 GBS admissions per million influenza-coded health care encounters (19) . This finding shows that both influenza vaccination and influenza illness are associated with small attributable risks of GBS, but the risk of GBS associated with influenza illness is notably higher than with influenza vaccination. The self-controlled study also found that the risk of GBS after vaccination was highest during weeks 2-4, whereas for influenza illness, the risk was greatest within the first week after a health care encounter and decreased thereafter, but remained significantly elevated for up to 4 weeks. The risk of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and all the other benefits of influenza vaccination (172)(173)(174)(175) .
# V. CHOICE OF SEASONAL INFLUENZA VACCINE: ADDITIONAL INFORMATION
With the recent availability of a number of new influenza vaccines, some of which are designed to enhance immunogenicity in specific age groups, the choice of product is now more complex. Section II.5 summarizes NACI's recommendations on the choice of currently authorized influenza vaccines. This section provides more details for these recommendations.
V.1 Children
# Burden of disease in children
The proportion of disease burden due to influenza B infection is higher in children compared to other age groups. Canadian surveillance data from 2001-2002 to 2012-2013 has shown that influenza B strains accounted for 17% of laboratory-confirmed tests for influenza. Children less than 24 months of age comprise approximately 2% of the Canadian population (176) . (177) .
The IMPACT study also found that the proportion of deaths attributable to influenza was significantly greater for children admitted to hospital with influenza B (1.1%) than for those admitted with influenza A (0.4%). The proportion of hospitalizations due to influenza B relative to all influenza hospitalizations has been generally similar to the proportion of influenza B detections relative to all influenza infections in the general population during the same time period. Additional information can be found in the Statement on Seasonal Influenza Vaccine for 2014-2015.
In Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that a quadrivalent influenza vaccine should be used. If a quadrivalent vaccine is not available, any of the available age-appropriate trivalent vaccines should be used.
There is insufficient evidence to make comparative recommendations on the use of IIV3-Adj over IIV3-SD.
# Efficacy and effectiveness
There was early evidence of superior efficacy of LAIV3 compared with IIV3-SD in children less than 6 years of age from randomized controlled trials, with weaker evidence of superior efficacy in older children. However, later post-marketing and surveillance studies across multiple influenza seasons found comparable protection against influenza for LAIV and IIV, with findings of reduced effectiveness for LAIV against A(H1N1) in some studies.
Like IIV4-SD, LAIV4 is expected to provide additional protection against the influenza B strain not contained in IIV3-SD.
# Immunogenicity
LAIV3 has been shown to be as immunogenic as IIV3-SD, depending on age, with LAIV4 being non-inferior to LAIV3.
# Safety
Rhinitis (runny nose) and nasal congestion are more common with LAIV. Clinical studies and post-marketing studies showed a similar safety profile to IIV.
Contraindications There are vaccine contraindications specific to LAIV. LAIV is contraindicated for children with severe asthma, medically attended wheezing in the 7 days prior to vaccination, and immune compromising conditions (with the exception of children with stable HIV infection on HAART and with adequate immune function), as well as those currently receiving aspirin or aspirin-containing therapy. LAIV is also contraindicated for pregnant adolescents.
# Acceptability
Delivery of LAIV as a nasal spray may be preferable for children who are averse to receiving the vaccine by needle injection.
# V.2 Adults
# Burden of disease in adults
A study focusing on estimates of deaths associated with influenza in the United States has established that the average annual rate of influenza-associated deaths for adults aged 65 years of age and older was 17.0 deaths per 100,000 (range: 2.4-36.7) (178) . The study also states that of deaths coded as being influenza-or pneumonia-related, persons 65 years of age and older accounted for 87.9% of the overall estimated annual average number of influenza-associated deaths. When influenza-related deaths among adults 65 years of age and older were estimated using underlying respiratory and circulatory causes, these estimates increased to 66.1 deaths per 100,000 (range: 8.0-121.1) and 89.4%, respectively. This study described a wide variation in the estimated number of deaths from season to season, which was closely related to the particular influenza virus types and subtypes in circulation. Estimates presented in the study of yearly influenza-associated deaths with underlying pneumonia and influenza causes reveal a large difference between influenza type A and B with a calculated median of greater than 6,000 deaths associated with influenza type A and half of that number for influenza type B (approximately 3,360) for persons 65 years of age and older. During the 22 seasons in which influenza A(H3N2) was the prominent strain, the average influenza-associated mortality rates were 2.7 times higher than for the nine seasons that it was not (all age groups combined), and on average, there were about 37% more annual influenza-associated deaths, regardless of the primary medical cause of death. A higher risk of hospitalization and death was also reported by Cromer et al. in adults 65 years of age and older, compared to younger adults in their assessment of the burden of influenza in England by age and clinical risk group (179) .
Canadian surveillance data show that hospitalization rates among adults 65 years of age and older were higher during the A(H3N2)-predominant 2014-2015 season compared to the previous five influenza seasons and also compared to the 2012-2013 season when A(H3N2) also predominated; 2014-2015 was a season in which there was a vaccine mismatch with the circulating A(H3N2) strain. Similar to the hospitalization rates, death rates among older adults were highest in the 2014-2015 season compared to the previous five seasons and compared to the previous A(H3N2) season in 2012-2013. Mortality rates among other age groups were similar to or lower than the previous five influenza seasons. Laboratory detections over this same time period showed that influenza seasons in which influenza subtype A(H3N2) predominated, disproportionally affected adults 65 years of age and older, while seasons with greater A(H1N1) detections resulted in a higher prevalence of positive cases in younger age groups.
# Adults 65 years of age and older
Four types of influenza vaccine are authorized for use in adults 65 years of age and older: IIV3-SD, IIV3-Adj, IIV3-HD, and IIV4-SD.
# Influenza vaccine type compared with IIV3-SD IIV3-Adj IIV3-HD IIV4-SD Burden of disease
Although influenza-associated morbidity and mortality varies each season, in general there is an increased burden of severe disease in adults 65 years of age and older during influenza seasons when influenza A(H3N2) predominates (178) Efficacy and effectiveness Insufficient evidence compared with IIV3-SD.
Better protection compared with IIV3-SD, particularly in influenza A(H3N2)dominant seasons.
Better protection against the influenza B strain not contained in IIV3.
# Immunogenicity
Non-inferior immune response compared to IIV3-SD. Superiority to IIV3-SD has not been consistently demonstrated.
Superior immune response to influenza A strains and noninferior immune response to B strains compared to IIV3-SD.
Non-inferior immune response to the strains contained in IIV3-SD with superior immune response to the additional B strain.
Contraindications Same contraindications as IIV3-SD.
# Safety
Higher rate of injection site reactions than IIV3-SD. Higher or comparable systemic reactions compared to IIV3-SD; systemic reactions were mild to moderate and transient.
SAEs were comparable to IIV3-SD and were uncommon.
Higher rate of some systemic reactions than IIV3-SD; most systemic reactions were mild and transient.
SAEs were rare and similar in frequency to IIV3-SD.
Pre-licensure clinical trials and postmarketing surveillance showed a similar safety profile to IIV3.
Abbreviations: IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; SAE: serious adverse event.
a NACI has not assessed the comparative cost-effectiveness of available influenza vaccine types for adults 65 years of age and older.
Adults with chronic health conditions NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to adults with chronic health conditions identified in List 1, including those with immune compromising conditions.
Pregnant women NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to pregnant women.
Due to a lack of safety data at this time, LAIV should not be administered to pregnant women due to the theoretical risk to the fetus from administering a live virus vaccine. LAIV can be administered to breastfeeding women.
Health care workers NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to HCWs.
Comparative studies in healthy adults have found IIV to be similarly or more efficacious or effective compared with LAIV (157) . In addition, as a precautionary measure, LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection. Former ex-officio representatives: K Barnes (National Defence and the Canadian Armed Forces).
# Recommendation for individual-level decision making
When available, IIV3-HD should be used over IIV3-SD, given the burden of influenza A(H3N2) disease and the good evidence of better protection compared to IIV3-SD in adults 65 years of age and older. There is insufficient evidence to recommend the use of IIV3-HD over IIV4-SD. However, given the increased burden of disease associated with influenza A(H3N2) in older adults, better protection against influenza A(H3N2) may be more important than better protection against influenza B. At this time, NACI does not make comparative recommendations on the use of IIV3-Adj or IIV4-SD over IIV3-SD or among IIV3-Adj, IIV3-HD, and IIV4-SD.
Any of the available influenza vaccines would be preferable to remaining unvaccinated or requesting individuals to return for vaccine. Therefore, in the absence of a specific product, NACI recommends that any of the available influenza vaccines should be used.
# Recommendation for public health program-level decision making
IIV3-HD is expected to provide better protection compared to IIV3-SD; however, with costeffectiveness assessments having been outside the scope of the evidence review, there is insufficient evidence to make a comparative recommendation on the use of these vaccines at the programmatic level. Therefore, NACI recommends that any of the available influenza vaccines should be used.
Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose (Fluzone ® High-Dose) and MF59-Adjuvanted (Fluad ® ) Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for additional information supporting these recommendations.
# Summary of vaccine characteristics for decision making
There are four types of inactivated influenza vaccines (IIV3-SD, IIV3-Adj, IIV3-HD, and IIV4-SD) authorized for use in Canada for adults 65 years of age and older. The comparison of vaccine characteristics across vaccine types, in Table 5 below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program. Due to a lack of available data directly comparing the performance of IIV3-Adj, IIV3-HD, and IIV4-SD, considerations for these vaccines in Table 5 are compared to IIV3-SD for which comparative data on efficacy, effectiveness, and/or immunogenicity with each of IIV3-Adj, IIV3-HD, and IIV4-SD are available. Abbreviations: FFU: fluorescent focus units; HA: hemagglutinin; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine; NA: neuraminidase.
# LIST OF ABBREVIATIONS
a Full details of the composition of each vaccine authorized for use in Canada, including other non-medicinal ingredients, and a brief description of its manufacturing process can be found in the product monograph. b Neomycin and polymyxin B are only used if gentamicin cannot be used. No trace amounts of neomycin or polymyxin B are present if gentamicin was used. | None | None |
971a2e2adc369db2ea4ded8832204e53e39ccffc | cma | None | In Canada, recreational use of cannabis was legalized in October 2018. This policy change along with recent publications evaluating the efficacy of cannabis for the medical treatment of epilepsy and media awareness about its use have increased the public interest about this agent. The Canadian League Against Epilepsy Medical Therapeutics Committee, along with a multidisciplinary group of experts and Canadian Epilepsy Alliance representatives, has developed a position statement about the use of medical cannabis for epilepsy. This article addresses the current Canadian legal framework, recent publications about its efficacy and safety profile, and our understanding of the clinical issues that should be considered when contemplating cannabis use for medical purposes. RÉSUMÉ: Énoncé de position quant à l'utilisation du cannabis médical dans le traitement de l'épilepsie. L'utilisation du cannabis à des fins récréatives a été légalisée au Canada en octobre 2018. Parallèlement à ce changement de politique, de récentes publication visant à évaluer l'efficacité du cannabis dans le traitement de l'épilepsie, de même qu'une sensibilisation médiatique accrue en ce qui concerne son utilisation, ont eu pour effet d'augmenter l'intérêt du grand public à son égard. Le Comité médical thérapeutique de la Ligue canadienne contre l'épilepsie (LCCE), de concert avec un groupe multidisciplinaire d'experts et des représentants de l'Alliance canadienne de l'épilepsie, a ainsi élaboré un énoncé de position en ce qui regarde# INTRODUCTION
The marijuana plant, Cannabis sativa, Cannabis indica, and Cannabis ruderalis (for some considered a subspecies of C. sativa), contains more than 500 chemical species with more than 100 different phytocannabinoid (i.e. derived from the plant) compounds. 1 Two of these compounds -Δ-9-tetrahydrocannabiniol (THC) and cannabidiol (CBD)have generated the most interest in terms of their putative effectiveness as an anti-seizure agent. Most of the psychoactive properties of marijuana are mediated by THC. CBD is the most abundant nonpsychoactive cannabinoid in the marijuana plant. As a plant-derived oral solution, both CBD and THC have shown some anti-seizure effects in a number of laboratory models of seizures and epilepsy 2,3 and in both open-label and randomized control trials (RCTs) in Dravet syndrome and Lennox-Gastaut syndrome. However, other studies have failed to replicate THC anti-seizure effect and a few showed pro-convulsant effects. 3 There is some evidence that THC (recreational use) causes cognitive impairment and chronic psychiatric disturbances in adolescents and adults. For these reasons, the focus of most research and clinical use has been on another cannabinoid, namely, CBD. 3 The potential beneficial effects of nonpurified medical marijuana with a high CBD-THC ratio has motivated discussions in recent years, leading to an increased demand for the high CBD and low THC cannabis herbal extract oil (CBD-THC oil) for both adults and children with drug-resistant epilepsy. This increased demand and specific issues about the use of cannabinoids in Canada 11 has prompted the Canadian League Against Epilepsy (CLAE) to develop a formal statement about its current position regarding the use of CBD-THC, particularly the oil formulation, for epilepsy. As the Canadian government uses the term cannabis to refer to regulated marijuana (for recreational or medical use), for the purpose of this statement, the term cannabis will refer to both regulated marijuana and its derivatives within the framework of federal, provincial, and territorial regulations for recreational or medical purpose. We have purposely avoided the term "hemp" as it is loosely used by the media, creating some confusion. According to the Industrial Hemp Regulations (SOR/2018-145, ), "industrial hemp" means a cannabis plant or any part of that plant in which the concentration of THC is 0.3% or less in the flowering heads and leaves. However, some commercially available high CBD-THC ratio hemp oils may not meet this specific legal criterion.
This position statement is based on a literature search, expert opinion, and consumer (epilepsy) representatives' input with final approval by the CLAE Board of Directors and Executive Committee; however, it may not necessarily represent the opinion of all CLAE members. It addresses three key elements: (1) the current legal framework for cannabis medical use, (2) the published evidence for the anti-seizure efficacy of CBD-derived products, and (3) our current understanding of its utilization, doses, and safety with regard to both the short-and the long-term effects of cannabis use for medical purposes.
# LEGAL CONSIDERATIONS OF CANNABIS FOR MEDICAL USE
The use of recreational cannabis in adults (defined as 18-year-old or older) was legalized in Canada on October 17, 2018. As per the Department of Justice website (/ cannabis/) and subject to provincial or territorial restrictions, the current legal framework (legalization and regulation) for cannabis use in adults is addressed in the Cannabis Act (S.C. 2018, c.16) and summarized in Table 1.
The Government of Canada has several online resources for the general public. A detailed explanation on how to access cannabis for medical purposes from a licensed producer can be found at . General information about the consumption of cannabis can be accessed at .
The process to access cannabis and its derivatives for medical purposes for Canadian patients was recently summarized by the Canadian Pediatric Society (CPS) 12 and by the Government of Canada (/ publications/drugs-health-products/understanding-new-accessto-cannabis-for-medical-purposes-regulations.html). Cannabis for medical use was sanctioned by Health Canada in 2001. Since then multiple revisions occurred. The most up-to-date version of the Access to Cannabis for Medical Purposes Regulations (ACMPR, last amended on January 15, 2019) is available at under Part 14. 13 The process to obtain cannabis for medical purposes is summarized in Table 2.
Despite the legalization of the consumption of medical cannabis in Canada, there are no regulations regarding when it is appropriate to use medical cannabis. This leaves the final decision to the discretion of physicians in consultation with the person living with epilepsy and/or their care partners/parents. Table 3 includes a list of resources for physicians practicing in different provinces or territories in Canada with links to access provincial regulatory policies. These regulations do not apply to out-of-country utilization where the use of cannabis could be considered a criminal offense.
Of note, the Canadian Medical Association submitted a proposal to Health Canada to unify the cannabis regulations system for medical and recreational cannabis. If this were to happen, the maximum monthly cannabis supply allowed may need to be modified as some medical doses may require larger amounts of cannabis (/ News/proposed-approach-regulation-cannabis-e.pdf).
# THERAPEUTIC CONSIDERATIONS
A pharmacological review of the anticonvulsant activity of the cannabinoids is beyond the scope of this document. For a detailed review we recommend the following references: Gaston and Friedman 14 and Reddy and Golub. 15 In addition, we refer the reader to Dow-Edwards and Silva 16 for a review of the endocannabinoid system and its effects on brain plasticity during development.
A Cochrane review 17 and a systematic review by the American Academy of Neurology 18 (both published in 2014) concluded that there was a lack of adequate data from randomized, controlled trials of THC, CBD, or any other cannabinoid to support the use of these compounds in the treatment of epilepsy. Since these publications however, there have been four published randomized placebo-controlled clinical trials using a purified CBD oil (Epidiolex ® ) to treat two well-recognized and very specific drug-resistant pediatric epilepsy syndromes, namely, Dravet syndrome 7,8 and Lennox-Gastaut syndrome. 9,10 Epidiolex ® is a CBD solution with a concentration of 100 mg/ml. Results to date show CBD to be beneficial in treating drug-resistant epilepsy, with a reasonable safety profile for short-term use in the above syndromes. When compared to placebo, there was an overall relative improvement in seizure frequency of 20%-25% for all seizure types. 19 The first study in Dravet syndrome showed a statistically significant reduction only of convulsive seizures reported by the parents of affected children but not in other seizure types. 8 Furthermore, 5% of all patients were seizure free on CBD treatment and 57% of patients had a seizure reduction of less than 50%. Common side effects were noted in more than 30% of patients, in particular gastrointestinal disturbance and somnolence. 8 CBD can increase the serum levels of some anti-seizure medications, particularly clobazam and its metabolite, which may have resulted in somnolence, at times severe, in some patients. Elevations in liver enzymes have also been reported. Clinical trials in patients with Lennox-Gastaut syndrome showed a statistically significant improvement in the frequency of parent-reported drop seizures and overall seizures. 9,10 Despite the statistically significant improvement, clinical significance is not clear since the median number of drop seizures decreased from 85 to 50 per month (from 3 to 2 seizures a day). CBD doses trialed were 10 and 20 mg/kg/day. Study limitations included the lack of blinding due to noteworthy side effects in the Epidiolex ® group. There was also a relatively high incidence of seizure worsening, including status epilepticus (up to 15%) in patients on Epidiolex ® when compared to placebo. 9,10 The results of the RCTs published to date do not readily translate to the Canadian experience as Epidiolex ® (GW Pharmaceuticals, Cambridge, UK) is not available in Canada. In these studies, the maintenance dose used was between 10 and 20 mg/kg/day and only as an add-on therapy with other anti-seizure medication(s). The wide spectrum of CBD-containing products manufactured for medical purposes in Canada further precludes the ability to make any conclusions. Canadians mainly use oil formulations with a wide range of CBD-THC ratios. A recent, prospective open-label study in Dravet syndrome, using a cannabis oil product with a CBD-THC (50:1) performed in Canada, 6 resulted in a median motor seizure reduction of 70.6%, a statistically significant improvement in quality of life, and a reduction in electroencephalographic spike activity over a 20-week period. The small sample size of 19 patients and unblinded intervention, however, were significant study limitations. 6 Relatively long-term efficacy and safety was reported in an open-label ongoing expanded-access program study for the use of Epidiolex ® . 4 Of the 607 enrolled patients, 89 (15%) withdrew due to lack of efficacy and 32 (5%) withdrew due to adverse events. Only 138 (23%) patients were followed until week 96. The 50%, 75%, and 100% reduction in convulsive seizures rates by week 12 of treatment were 52%, 31%, and 11%, respectively. These differences remained similar throughout until week 96 in those patients with available data. However, 23%-29% of patients had increased convulsive seizure frequency and 24%-27% had an increase in total seizures by the last visit at week 96 of those with available data. 4 Thus, about 50% of patients with drug-resistant epilepsy (mainly Dravet syndrome or Lennox-Gastaut syndrome) will have a 50% or greater seizure reduction, 25% will not improve or will not tolerate the intervention, and 25% will have an increase in seizure frequency.
In Canada, the current commercially available CBD-THC cannabis oil for the treatment of epilepsy ranges from 12.5:1 to 50:1, with variable concentrations of milligram per milliliter. In the authors' experience, management decisions cannot simply be made by only considering a ratio. For instance, when comparing two different oil products with CBD-THC of 20:1 ratio, one product may contain 100:5 mg/ml of CBD-THC, while another may have 10:0.5 mg/ml. In both samples, the ratio is the same, 20:1 but the milligram amount of CBD and THC per ml is different. Due to these differences, CBD-THC cannabis oil products also have variable dried cannabis content. A recent - Possess no more than 30 g of legal cannabis, dried or equivalent nondried form in public.
- Share no more than 30 g of legal cannabis with other adults - Buy dried or fresh cannabis and cannabis oil from a provincially licensed retailer - Be able to purchase cannabis online from federally licensed producers in provinces and territories without a regulated retail framework
- Grow, from licensed seed or seedlings, up to four cannabis plants per residence for personal use
- Make cannabis products, such as food and drinks, at home as long as organic solvents are not used to create concentrated products.
- Equivalents for 1 g of dried cannabis are the following:
○ 5 g of fresh cannabis ○ 15 g of edible product ○ 70 g of liquid product ○ 0.25 g of concentrates (solid or liquid) ○ 1 cannabis plant seed
- Not sell or provide cannabis for recreational use to any person under the age of 18 years or use a youth to commit a cannabis-related offense; doing so could result in criminal charges with a maximum penalty of 14 years in jail. ○ The health-care practitioner's given name, surname, profession, business address and telephone number and, if applicable, their facsimile number and e-mail address. ○ The province in which the health-care practitioner is authorized to practice their profession and the number assigned by the province to that authorization. ○ The given name, surname, and date of birth of the individual who is under the professional treatment of the health-care practitioner.
○ The address of the location at which the individual consulted with the health-care practitioner.
○ The daily quantity of dried cannabis, expressed in grams, that the health-care practitioner authorizes for the individual. ○ A period of use, specified as a number of days, weeks or months. ○ A medical document must be signed and dated by the health-care practitioner who is providing it and must include a statement confirming that the information in the document is correct and complete.
- The physician can prescribe in the document up to 1 year of treatment. 4. The document is then presented by the practitioner to a licensed producer by regular mail of by fax. An updated list of current licensed producers for medical and recreational purposes can be found here . 5. The producer can provide the patient with up to 30-day supply or up to a maximum weight of 150 g of dried cannabis or the equivalent amount if in another form. 6. A patient is able to request that a licensed producer transfers the medical document to another licensed producer. A patient does not have to obtain a new medical document in order to switch between two licensed producers; however, each licensed producer used must have a Medical Document or a faxed copy.
European study comparing the reported and the actual concentration in commercially available CBD oils supports this observation. In this study, authors carried an in-depth chemical profiling of cannabinoids, terpenes, and oxidation products of 14 commercially available CBD oils. Nine (64%) samples had concentrations differing from the declared amount with only five maintaining the optimal limits. 20 The maintenance dose (as used in the four RCTs) was 10-20 mg/kg/day. Depending on the patient's weight and the product used, this maintenance dose may require more than 150 g of dried cannabis per month, exceeding the legally allowed possession limit. In such cases, the practitioner may still authorize the appropriate dose, but the patient or parent/caregiver would have to order multiple batches of supply from the licensed producer, so that they do not possess more than 150 g at any one time.
The variability between cannabis oil products is also a major topic of confusion as it has a direct impact on doses, costs, and side effects, particularly when switching suppliers. Of note, according to a published paper in Canada, a combination of CBD-THC (50:1 with 50:1 mg/ml) was used, tapering to smaller doses by the end of the 20-week period, achieving a mean dose of 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/ day of THC (range 0.14-0.32 mg/kg/day) 6 which could potentially support the use of a smaller daily dose of CBD (and THC). The cost of an appropriate daily CBD dose could range from CAD $800 to $1500 per month; regarding Epidiolex ® , the cost for 100 ml is US$1297.84 () and the yearly cost could be up to US$32,500. At present, cannabis oil is not covered by any medical insurance companies, and the cost must be borne out of pocket by the patient or family/care partners. This situation is unlikely to change, unless more evidence is obtained to support the use of medical cannabis.
# SAFETY CONSIDERATIONS
Much of the available data regarding the safety and side effect profile of cannabinoids, especially with long-term use, are obtained from studies examining the effects of recreational marijuana, which contains high levels of THC. Few studies assessed the long-term effects of purified CBD. In studies of pediatric patients with severe epilepsy, the short-term side effects of cannabis included diarrhea, gastrointestinal intolerance, fatigue, and severe somnolence. In an open-label study of purified CBD, status epilepticus was observed in 6% of patients. 21 More chronic side effects, particularly of THC include impairment of memory, judgment, cognition and motor performance, and psychosis. 22 The use of CBD alone seems to have a minor to moderate impairment effect on driving. Combining CBD with alcohol, however, is a major concern. 23 Cannabis use during pregnancy, especially on a daily basis, has been associated with adverse neonatal outcomes leading to neurophysiological and behavioral abnormalities. 24,25 The potential exposure to pesticides, which are used to keep the marijuana plant healthy, is also of concern during pregnancy. 26 It is unknown whether cannabis for medical use could produce similar results.
An important point to consider is the pharmacological interactions between CBD and commonly used anti-seizure medications. It is important to be aware of potentially important and concerning serum level increases in anti-seizure medications, particularly N-desmethylclobazam, eslicarbazepine, rufinamide, topiramate, and zonisamide. Altered liver enzyme levels are common when combining CBD and valproic acid; thus, close monitoring of liver function is key. 27 High levels of the biologically active clobazam metabolite (N-desmethylclobazam) were reported when given concomitantly with CBD. Patients on this combination reported an over twofold increase in somnolence as compared to patients not on clobazam. 4 Careful monitoring of this interaction is therefore essential to avoid the complications of excessive somnolence, particularly respiratory failure and accidents. Measuring clobazam and N-desmethylclobazam levels in serum should be considered when side effects are noticed as CBD or THC levels in blood are not reliable indicators of toxicity. Currently there is no reliable serum level assay for CBD.
An additional important issue is the lack of consistency in CBD-THC concentrations from one batch of product to another as each marijuana plant possesses different concentrations of CBD and THC. The current regulations from Health Canada are attempting to address good production practices. However, there are no CBD-based products related to epilepsy treatment with a drug identification number at the present time (. ca/en/health-canada/services/drugs-medication/cannabis/licensedproducers/additional-information-licensed-producers-under-accesscannabis-medical-purposes-regulations.html#a2).
Information about the long-term side effects of purified CBD or combinations at different ratios of CBD-THC is lacking even when these products are appropriately dosed and medically supervised. Furthermore, the effect of CBD and/or THC on the developing brains of neonates, infants and children is not clear. Well-designed studies investigating the long-term side effects of CBD and/or THC are lacking.
# SUMMARY
Due to social media, patient and family advocacy groups, and Internet activity, there is significant public interest in cannabis as an alternative treatment of those living with epilepsy. CBD therapy offers a potentially promising alternative for patients who have failed to respond to many traditional anti-seizure medications, the ketogenic diet and/or surgical interventions. At present, the best data are available for two specific epilepsy syndromes: Dravet syndrome and Lennox-Gastaut syndrome. The extrapolation of these data to all seizure types or other epilepsy syndromes is difficult and not recommendable. The cost of treatment with reported maintenance doses is high. This therapy is not covered by medical insurance companies, provincial health programs, or the Ministry of Health and may place financial distress on already strained patients and their care partners/families. Although few RCTs are published, the reported findings are encouraging for Dravet and Lennox-Gastaut syndromes, showing significant improvements in seizure frequency in 20%-50% of patients. However, there exists a 20%-25% potential risk of significant side effects severe enough to warrant discontinuation. Furthermore, 15%-20% of patients do not show a decrease in seizure frequency. Information regarding the side effects of long-term use in humans and the risk in pregnancy is limited. Notably, the purified CBD oil (Epidiolex ® ) tested in the above described RCTs is not currently available in Canada. Canada remains dependent on a variety of products of differing quality and consistency.
# RECOMMENDATIONS
We recognize that recent publications herein examined show some benefits of purified CBD oil (Epidiolex ® ) in patients with Dravet syndrome and Lennox-Gastaut syndrome with daily seizures. In our opinion, purified CBD oil without THC may be considered as an add-on treatment of patients with these two specific epilepsy syndromes and daily seizure frequency utilizing the reported dose (10-20 mg/kg/day) only when those patients have failed two appropriately prescribed and utilized anti-seizure medications. However, evidence is lacking for the remaining epilepsy syndromes and epilepsies not otherwise classified as well as for the other products currently available in Canada, containing a combination of CBD-THC (i.e. vaporizing, edibles, smoking, and others including CBD-THC oil).
Should a patient or a parent/guardian opt to use cannabis, we strongly recommend that this decision be made in consultation with their health-care provider to ensure their safety. We recommend that the treatment with CBD-THC cannabis oil be managed by a physician knowledgeable and experienced with epilepsy care and anti-seizure medications, preferably with experience in CBD-THC cannabis oil. The product should be procured from a Health Canada-approved licensed producer. It is important that physicians carry out an appropriate baseline assessment of the patient, ensuring no contraindications prior to starting the therapy and that potential drug interactions are monitored for, and appropriate laboratory evaluations are obtained. Physicians involved in the care of these patients should also be equipped | In Canada, recreational use of cannabis was legalized in October 2018. This policy change along with recent publications evaluating the efficacy of cannabis for the medical treatment of epilepsy and media awareness about its use have increased the public interest about this agent. The Canadian League Against Epilepsy Medical Therapeutics Committee, along with a multidisciplinary group of experts and Canadian Epilepsy Alliance representatives, has developed a position statement about the use of medical cannabis for epilepsy. This article addresses the current Canadian legal framework, recent publications about its efficacy and safety profile, and our understanding of the clinical issues that should be considered when contemplating cannabis use for medical purposes. RÉSUMÉ: Énoncé de position quant à l'utilisation du cannabis médical dans le traitement de l'épilepsie. L'utilisation du cannabis à des fins récréatives a été légalisée au Canada en octobre 2018. Parallèlement à ce changement de politique, de récentes publication visant à évaluer l'efficacité du cannabis dans le traitement de l'épilepsie, de même qu'une sensibilisation médiatique accrue en ce qui concerne son utilisation, ont eu pour effet d'augmenter l'intérêt du grand public à son égard. Le Comité médical thérapeutique de la Ligue canadienne contre l'épilepsie (LCCE), de concert avec un groupe multidisciplinaire d'experts et des représentants de l'Alliance canadienne de l'épilepsie, a ainsi élaboré un énoncé de position en ce qui regarde# INTRODUCTION
The marijuana plant, Cannabis sativa, Cannabis indica, and Cannabis ruderalis (for some considered a subspecies of C. sativa), contains more than 500 chemical species with more than 100 different phytocannabinoid (i.e. derived from the plant) compounds. 1 Two of these compounds -Δ-9-tetrahydrocannabiniol (THC) and cannabidiol (CBD)have generated the most interest in terms of their putative effectiveness as an anti-seizure agent. Most of the psychoactive properties of marijuana are mediated by THC. CBD is the most abundant nonpsychoactive cannabinoid in the marijuana plant. As a plant-derived oral solution, both CBD and THC have shown some anti-seizure effects in a number of laboratory models of seizures and epilepsy 2,3 and in both open-label and randomized control trials (RCTs) in Dravet syndrome and Lennox-Gastaut syndrome. [4][5][6][7][8][9][10] However, other studies have failed to replicate THC anti-seizure effect and a few showed pro-convulsant effects. 3 There is some evidence that THC (recreational use) causes cognitive impairment and chronic psychiatric disturbances in adolescents and adults. For these reasons, the focus of most research and clinical use has been on another cannabinoid, namely, CBD. 3 The potential beneficial effects of nonpurified medical marijuana with a high CBD-THC ratio has motivated discussions in recent years, leading to an increased demand for the high CBD and low THC cannabis herbal extract oil (CBD-THC oil) for both adults and children with drug-resistant epilepsy. This increased demand and specific issues about the use of cannabinoids in Canada 11 has prompted the Canadian League Against Epilepsy (CLAE) to develop a formal statement about its current position regarding the use of CBD-THC, particularly the oil formulation, for epilepsy. As the Canadian government uses the term cannabis to refer to regulated marijuana (for recreational or medical use), for the purpose of this statement, the term cannabis will refer to both regulated marijuana and its derivatives within the framework of federal, provincial, and territorial regulations for recreational or medical purpose. We have purposely avoided the term "hemp" as it is loosely used by the media, creating some confusion. According to the Industrial Hemp Regulations (SOR/2018-145, https://laws-lois.justice.gc.ca/PDF/SOR-2018-145.pdf), "industrial hemp" means a cannabis plant or any part of that plant in which the concentration of THC is 0.3% or less in the flowering heads and leaves. However, some commercially available high CBD-THC ratio hemp oils may not meet this specific legal criterion.
This position statement is based on a literature search, expert opinion, and consumer (epilepsy) representatives' input with final approval by the CLAE Board of Directors and Executive Committee; however, it may not necessarily represent the opinion of all CLAE members. It addresses three key elements: (1) the current legal framework for cannabis medical use, (2) the published evidence for the anti-seizure efficacy of CBD-derived products, and (3) our current understanding of its utilization, doses, and safety with regard to both the short-and the long-term effects of cannabis use for medical purposes.
# LEGAL CONSIDERATIONS OF CANNABIS FOR MEDICAL USE
The use of recreational cannabis in adults (defined as 18-year-old or older) was legalized in Canada on October 17, 2018. As per the Department of Justice website (https://www.justice.gc.ca/eng/cj-jp/ cannabis/) and subject to provincial or territorial restrictions, the current legal framework (legalization and regulation) for cannabis use in adults is addressed in the Cannabis Act (S.C. 2018, c.16) and summarized in Table 1.
The Government of Canada has several online resources for the general public. A detailed explanation on how to access cannabis for medical purposes from a licensed producer can be found at https://www.canada.ca/en/health-canada/services/getting-cannabisfrom-licensed-producer/accessing-from-licensed-producer.html. General information about the consumption of cannabis can be accessed at https://www.canada.ca/en/health-canada/services/drugsmedication/cannabis/licensed-producers/consumer-informationcannabis.html.
The process to access cannabis and its derivatives for medical purposes for Canadian patients was recently summarized by the Canadian Pediatric Society (CPS) 12 and by the Government of Canada (https://www.canada.ca/en/health-canada/services/ publications/drugs-health-products/understanding-new-accessto-cannabis-for-medical-purposes-regulations.html). Cannabis for medical use was sanctioned by Health Canada in 2001. Since then multiple revisions occurred. The most up-to-date version of the Access to Cannabis for Medical Purposes Regulations (ACMPR, last amended on January 15, 2019) is available at https://laws-lois.justice.gc.ca/PDF/SOR-2018-144.pdf under Part 14. 13 The process to obtain cannabis for medical purposes is summarized in Table 2.
Despite the legalization of the consumption of medical cannabis in Canada, there are no regulations regarding when it is appropriate to use medical cannabis. This leaves the final decision to the discretion of physicians in consultation with the person living with epilepsy and/or their care partners/parents. Table 3 includes a list of resources for physicians practicing in different provinces or territories in Canada with links to access provincial regulatory policies. These regulations do not apply to out-of-country utilization where the use of cannabis could be considered a criminal offense.
Of note, the Canadian Medical Association submitted a proposal to Health Canada to unify the cannabis regulations system for medical and recreational cannabis. If this were to happen, the maximum monthly cannabis supply allowed may need to be modified as some medical doses may require larger amounts of cannabis (https://www.cma.ca/sites/default/files/pdf/ News/proposed-approach-regulation-cannabis-e.pdf).
# THERAPEUTIC CONSIDERATIONS
A pharmacological review of the anticonvulsant activity of the cannabinoids is beyond the scope of this document. For a detailed review we recommend the following references: Gaston and Friedman 14 and Reddy and Golub. 15 In addition, we refer the reader to Dow-Edwards and Silva 16 for a review of the endocannabinoid system and its effects on brain plasticity during development.
A Cochrane review 17 and a systematic review by the American Academy of Neurology 18 (both published in 2014) concluded that there was a lack of adequate data from randomized, controlled trials of THC, CBD, or any other cannabinoid to support the use of these compounds in the treatment of epilepsy. Since these publications however, there have been four published randomized placebo-controlled clinical trials using a purified CBD oil (Epidiolex ® ) to treat two well-recognized and very specific drug-resistant pediatric epilepsy syndromes, namely, Dravet syndrome 7,8 and Lennox-Gastaut syndrome. 9,10 Epidiolex ® is a CBD solution with a concentration of 100 mg/ml. Results to date show CBD to be beneficial in treating drug-resistant epilepsy, with a reasonable safety profile for short-term use in the above syndromes. When compared to placebo, there was an overall relative improvement in seizure frequency of 20%-25% for all seizure types. [7][8][9][10]19 The first study in Dravet syndrome showed a statistically significant reduction only of convulsive seizures reported by the parents of affected children but not in other seizure types. 8 Furthermore, 5% of all patients were seizure free on CBD treatment and 57% of patients had a seizure reduction of less than 50%. Common side effects were noted in more than 30% of patients, in particular gastrointestinal disturbance and somnolence. 8 CBD can increase the serum levels of some anti-seizure medications, particularly clobazam and its metabolite, which may have resulted in somnolence, at times severe, in some patients. Elevations in liver enzymes have also been reported. [8][9][10] Clinical trials in patients with Lennox-Gastaut syndrome showed a statistically significant improvement in the frequency of parent-reported drop seizures and overall seizures. 9,10 Despite the statistically significant improvement, clinical significance is not clear since the median number of drop seizures decreased from 85 to 50 per month (from 3 to 2 seizures a day). CBD doses trialed were 10 and 20 mg/kg/day. Study limitations included the lack of blinding due to noteworthy side effects in the Epidiolex ® group. There was also a relatively high incidence of seizure worsening, including status epilepticus (up to 15%) in patients on Epidiolex ® when compared to placebo. 9,10 The results of the RCTs published to date do not readily translate to the Canadian experience as Epidiolex ® (GW Pharmaceuticals, Cambridge, UK) is not available in Canada. In these studies, the maintenance dose used was between 10 and 20 mg/kg/day and only as an add-on therapy with other anti-seizure medication(s). The wide spectrum of CBD-containing products manufactured for medical purposes in Canada further precludes the ability to make any conclusions. Canadians mainly use oil formulations with a wide range of CBD-THC ratios. A recent, prospective open-label study in Dravet syndrome, using a cannabis oil product with a CBD-THC (50:1) performed in Canada, 6 resulted in a median motor seizure reduction of 70.6%, a statistically significant improvement in quality of life, and a reduction in electroencephalographic spike activity over a 20-week period. The small sample size of 19 patients and unblinded intervention, however, were significant study limitations. 6 Relatively long-term efficacy and safety was reported in an open-label ongoing expanded-access program study for the use of Epidiolex ® . 4 Of the 607 enrolled patients, 89 (15%) withdrew due to lack of efficacy and 32 (5%) withdrew due to adverse events. Only 138 (23%) patients were followed until week 96. The 50%, 75%, and 100% reduction in convulsive seizures rates by week 12 of treatment were 52%, 31%, and 11%, respectively. These differences remained similar throughout until week 96 in those patients with available data. However, 23%-29% of patients had increased convulsive seizure frequency and 24%-27% had an increase in total seizures by the last visit at week 96 of those with available data. 4 Thus, about 50% of patients with drug-resistant epilepsy (mainly Dravet syndrome or Lennox-Gastaut syndrome) will have a 50% or greater seizure reduction, 25% will not improve or will not tolerate the intervention, and 25% will have an increase in seizure frequency.
In Canada, the current commercially available CBD-THC cannabis oil for the treatment of epilepsy ranges from 12.5:1 to 50:1, with variable concentrations of milligram per milliliter. In the authors' experience, management decisions cannot simply be made by only considering a ratio. For instance, when comparing two different oil products with CBD-THC of 20:1 ratio, one product may contain 100:5 mg/ml of CBD-THC, while another may have 10:0.5 mg/ml. In both samples, the ratio is the same, 20:1 but the milligram amount of CBD and THC per ml is different. Due to these differences, CBD-THC cannabis oil products also have variable dried cannabis content. A recent • Possess no more than 30 g of legal cannabis, dried or equivalent nondried form in public.
• Share no more than 30 g of legal cannabis with other adults • Buy dried or fresh cannabis and cannabis oil from a provincially licensed retailer • Be able to purchase cannabis online from federally licensed producers in provinces and territories without a regulated retail framework
• Grow, from licensed seed or seedlings, up to four cannabis plants per residence for personal use
• Make cannabis products, such as food and drinks, at home as long as organic solvents are not used to create concentrated products.
• Equivalents for 1 g of dried cannabis are the following:
○ 5 g of fresh cannabis ○ 15 g of edible product ○ 70 g of liquid product ○ 0.25 g of concentrates (solid or liquid) ○ 1 cannabis plant seed
• Not sell or provide cannabis for recreational use to any person under the age of 18 years or use a youth to commit a cannabis-related offense; doing so could result in criminal charges with a maximum penalty of 14 years in jail. ○ The health-care practitioner's given name, surname, profession, business address and telephone number and, if applicable, their facsimile number and e-mail address. ○ The province in which the health-care practitioner is authorized to practice their profession and the number assigned by the province to that authorization. ○ The given name, surname, and date of birth of the individual who is under the professional treatment of the health-care practitioner.
○ The address of the location at which the individual consulted with the health-care practitioner.
○ The daily quantity of dried cannabis, expressed in grams, that the health-care practitioner authorizes for the individual. ○ A period of use, specified as a number of days, weeks or months. ○ A medical document must be signed and dated by the health-care practitioner who is providing it and must include a statement confirming that the information in the document is correct and complete.
3. The physician can prescribe in the document up to 1 year of treatment. 4. The document is then presented by the practitioner to a licensed producer by regular mail of by fax. An updated list of current licensed producers for medical and recreational purposes can be found here https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/industry-licenseesapplicants/licensed-cultivators-processors-sellers.html. 5. The producer can provide the patient with up to 30-day supply or up to a maximum weight of 150 g of dried cannabis or the equivalent amount if in another form. 6. A patient is able to request that a licensed producer transfers the medical document to another licensed producer. A patient does not have to obtain a new medical document in order to switch between two licensed producers; however, each licensed producer used must have a Medical Document or a faxed copy.
European study comparing the reported and the actual concentration in commercially available CBD oils supports this observation. In this study, authors carried an in-depth chemical profiling of cannabinoids, terpenes, and oxidation products of 14 commercially available CBD oils. Nine (64%) samples had concentrations differing from the declared amount with only five maintaining the optimal limits. 20 The maintenance dose (as used in the four RCTs) was 10-20 mg/kg/day. Depending on the patient's weight and the product used, this maintenance dose may require more than 150 g of dried cannabis per month, exceeding the legally allowed possession limit. In such cases, the practitioner may still authorize the appropriate dose, but the patient or parent/caregiver would have to order multiple batches of supply from the licensed producer, so that they do not possess more than 150 g at any one time.
The variability between cannabis oil products is also a major topic of confusion as it has a direct impact on doses, costs, and side effects, particularly when switching suppliers. Of note, according to a published paper in Canada, a combination of CBD-THC (50:1 with 50:1 mg/ml) was used, tapering to smaller doses by the end of the 20-week period, achieving a mean dose of 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/ day of THC (range 0.14-0.32 mg/kg/day) 6 which could potentially support the use of a smaller daily dose of CBD (and THC). The cost of an appropriate daily CBD dose could range from CAD $800 to $1500 per month; regarding Epidiolex ® , the cost for 100 ml is US$1297.84 (https://www.drugs.com/price-guide/epidiolex) and the yearly cost could be up to US$32,500. At present, cannabis oil is not covered by any medical insurance companies, and the cost must be borne out of pocket by the patient or family/care partners. This situation is unlikely to change, unless more evidence is obtained to support the use of medical cannabis.
# SAFETY CONSIDERATIONS
Much of the available data regarding the safety and side effect profile of cannabinoids, especially with long-term use, are obtained from studies examining the effects of recreational marijuana, which contains high levels of THC. Few studies assessed the long-term effects of purified CBD. In studies of pediatric patients with severe epilepsy, the short-term side effects of cannabis included diarrhea, gastrointestinal intolerance, fatigue, and severe somnolence. In an open-label study of purified CBD, status epilepticus was observed in 6% of patients. 21 More chronic side effects, particularly of THC include impairment of memory, judgment, cognition and motor performance, and psychosis. 22 The use of CBD alone seems to have a minor to moderate impairment effect on driving. Combining CBD with alcohol, however, is a major concern. 23 Cannabis use during pregnancy, especially on a daily basis, has been associated with adverse neonatal outcomes leading to neurophysiological and behavioral abnormalities. 24,25 The potential exposure to pesticides, which are used to keep the marijuana plant healthy, is also of concern during pregnancy. 26 It is unknown whether cannabis for medical use could produce similar results.
An important point to consider is the pharmacological interactions between CBD and commonly used anti-seizure medications. It is important to be aware of potentially important and concerning serum level increases in anti-seizure medications, particularly N-desmethylclobazam, eslicarbazepine, rufinamide, topiramate, and zonisamide. Altered liver enzyme levels are common when combining CBD and valproic acid; thus, close monitoring of liver function is key. 27 High levels of the biologically active clobazam metabolite (N-desmethylclobazam) were reported when given concomitantly with CBD. Patients on this combination reported an over twofold increase in somnolence as compared to patients not on clobazam. 4 Careful monitoring of this interaction is therefore essential to avoid the complications of excessive somnolence, particularly respiratory failure and accidents. Measuring clobazam and N-desmethylclobazam levels in serum should be considered when side effects are noticed as CBD or THC levels in blood are not reliable indicators of toxicity. Currently there is no reliable serum level assay for CBD.
An additional important issue is the lack of consistency in CBD-THC concentrations from one batch of product to another as each marijuana plant possesses different concentrations of CBD and THC. The current regulations from Health Canada are attempting to address good production practices. However, there are no CBD-based products related to epilepsy treatment with a drug identification number at the present time (https://www.canada. ca/en/health-canada/services/drugs-medication/cannabis/licensedproducers/additional-information-licensed-producers-under-accesscannabis-medical-purposes-regulations.html#a2).
Information about the long-term side effects of purified CBD or combinations at different ratios of CBD-THC is lacking even when these products are appropriately dosed and medically supervised. Furthermore, the effect of CBD and/or THC on the developing brains of neonates, infants and children is not clear. Well-designed studies investigating the long-term side effects of CBD and/or THC are lacking.
# SUMMARY
Due to social media, patient and family advocacy groups, and Internet activity, there is significant public interest in cannabis as an alternative treatment of those living with epilepsy. CBD therapy offers a potentially promising alternative for patients who have failed to respond to many traditional anti-seizure medications, the ketogenic diet and/or surgical interventions. At present, the best data are available for two specific epilepsy syndromes: Dravet syndrome and Lennox-Gastaut syndrome. The extrapolation of these data to all seizure types or other epilepsy syndromes is difficult and not recommendable. The cost of treatment with reported maintenance doses is high. This therapy is not covered by medical insurance companies, provincial health programs, or the Ministry of Health and may place financial distress on already strained patients and their care partners/families. Although few RCTs are published, the reported findings are encouraging for Dravet and Lennox-Gastaut syndromes, showing significant improvements in seizure frequency in 20%-50% of patients. However, there exists a 20%-25% potential risk of significant side effects severe enough to warrant discontinuation. Furthermore, 15%-20% of patients do not show a decrease in seizure frequency. Information regarding the side effects of long-term use in humans and the risk in pregnancy is limited. Notably, the purified CBD oil (Epidiolex ® ) tested in the above described RCTs is not currently available in Canada. Canada remains dependent on a variety of products of differing quality and consistency.
# RECOMMENDATIONS
We recognize that recent publications herein examined show some benefits of purified CBD oil (Epidiolex ® ) in patients with Dravet syndrome and Lennox-Gastaut syndrome with daily seizures. In our opinion, purified CBD oil without THC may be considered as an add-on treatment of patients with these two specific epilepsy syndromes and daily seizure frequency utilizing the reported dose (10-20 mg/kg/day) only when those patients have failed two appropriately prescribed and utilized anti-seizure medications. However, evidence is lacking for the remaining epilepsy syndromes and epilepsies not otherwise classified as well as for the other products currently available in Canada, containing a combination of CBD-THC (i.e. vaporizing, edibles, smoking, and others including CBD-THC oil).
Should a patient or a parent/guardian opt to use cannabis, we strongly recommend that this decision be made in consultation with their health-care provider to ensure their safety. We recommend that the treatment with CBD-THC cannabis oil be managed by a physician knowledgeable and experienced with epilepsy care and anti-seizure medications, preferably with experience in CBD-THC cannabis oil. The product should be procured from a Health Canada-approved licensed producer. It is important that physicians carry out an appropriate baseline assessment of the patient, ensuring no contraindications prior to starting the therapy and that potential drug interactions are monitored for, and appropriate laboratory evaluations are obtained. Physicians involved in the care of these patients should also be equipped
# ACKNOWLEDGEMENT
The authors would like to recognize and thank Suzanne Nurse, MD, who was a crucial initial advocate of this statement.
#
with or have rapid access to the necessary medical infrastructure and personnel to manage potential complications should they arise.
We encourage clinicians and researchers to continue to seek further knowledge and education about this therapeutic approach. The authors also encourage government and not-for-profit entities to support and fund research in this area to reduce the potential biases associated with industry-sponsored trials. 28 The recent US Food and Drug Administration approval of Epidiolex ® in the USA for its use in certain epilepsy syndromes is noted.
The authors recognize that further clinical studies are underway to address the aforementioned limitations in Canada. This statement will be reviewed and modified in the future as more data and knowledge become available.
# CONFLICT OF INTEREST DISCLOSURES
Dr. Appendino has nothing to disclose. Dr. Boelman has nothing to disclose. Dr. Brna has nothing to disclose. Dr. Burneo reports supports for educational and research activities from Jack Cowin Chair in Epilepsy Research, from Eisai Canada, and from Sunovion Canada, outside the submitted work. RPh. Curtis Claassen has nothing to disclose. Dr. Connolly is a co-investigator for the Cannabidiol in Children with Refractory Epileptic Encephalopathy study. For this study, it is used Cannimed's 1:20 THC-CBD Cannabis herbal extract. Dr. Connolly receives no financial support from Cannimed and purchases the product used in the study from Cannimed at the cost of production. She has nothing to disclose. RPh. De Guzman has nothing to disclose. Dr. Federico has nothing to disclose. Mrs. Floyd has nothing to disclose. Dr. Huntsman is the lead investigator for the Cannabidiol in Children with Refractory Epileptic Encephalopathy study. For this study, it is used Cannimed's 1:20 THC-CBD Cannabis herbal extract. Dr. Hunstman received no financial support from Cannimed and purchased the product used in the study from them at the cost of production. Dr. Javidan has nothing to disclose. Dr. Jette received grant funding paid to her institution for grants unrelated to this work from NINDS (NIH U24NS107201, NIH IU54NS100064), PCORI, and Alberta Health. She also received an honorarium for her work as an associate editor of Epilepsia. NP. Jurasek has nothing to disclose. Dr. Keezer reports personal fees from Elsevier, personal fees from Sunovion, personal fees from Novartis, personal fees from Sage Therapeutics, grants and personal fees from UCB, grants and personal fees from Eisai, outside the submitted work. Dr. Lau has nothing to disclose. Dr. McCoy is a PI in a study of cannabinoids in resistant epilepsy, which was part funded by study drug vendor. Dr. McLachlan has nothing to disclose. Dr. Ng has nothing to disclose. Dr. Nguyen reports grants and personal fees from UCB; personal fees from Sunovion and personal fees from Eisai outside the submitted work. Dr. Reid has nothing to disclose. Dr. Rho reports other from Dr. Robert Haslam Chair in Child Neurology, personal fees from UCB Pharma, personal fees from Danone Nutricia, personal fees from Accera Pharma, outside the submitted work. Dr. Snead , Dr. Tellez-Zenteno, and RPh. Wang have nothing to disclose. NP Maria Zak was a co-investigator of a CBD Study in Children with Dravet Syndrome in which the CBD was provided in kind by Tilray.
# STATEMENT OF AUTHORSHIP
JPA, compiled all feedbacks from co-authors, wrote the first draft of the manuscript and produced the final version of the manuscript after revisions and editing were made. CB, PMB, JGB, CSC, MBC, MDG, PF, DF, RH, MJ, NJ, LLJ, MK, JCL, BMC, RML, MCN, DN, AR, JMR, CS, JFT-Z, LW, and MZ equally discussed the topic and provided themes to be considered for the generation of the first draft, reviewed the manuscript at different stages, provided constant feedback, and collaborated with manuscript editing. | None | None |
1c63c76c7df0e91d2073c13cee5e3690a7467f33 | cma | None | # Introduction
The current document summarizes the state-of-the-art knowledge as it relates to management of male lower urinary tract symptoms (MLUTS) secondary to benign prostatic hyperplasia (BPH) by updating the 2018 Canadian Urological Association (CUA) BPH guideline. 1 The process continues to highlight the essential diagnostic and therapeutic information in a Canadian context. The information included in this document includes that reviewed for the 2010 guideline and further information obtained from an updated MEDLINE search of the Englishlanguage literature (search terms included BPH, alpha-blockers, 5-alpha reductase inhibitor, anti-cholinergic, beta3 agonist, phosphodiesterase type 5 inhibitor , transurethral resection of the prostate , monopolar, bipolar, open simple prostatectomy, enucleation, GreenLight, photoselective vaporization of the prostate , Aquablation, Rezum, UroLift, temporarily implanted nitinol device ), as well as review of the most recent American Urological Association (AUA) 2 and European Association of Urology (EAU) guidelines. 3 References include those of historical importance, but management recommendations are based on literature published between 2000 and 2021. When information and data is available from multiple sources, the most relevant (usually most recent) article is cited based on committee opinion.
These guidelines are directed toward the typical male patient over 50 years of age presenting with LUTS and benign prostatic enlargement (BPE) and/or benign prostatic obstruction (BPO). It is recognized that men with LUTS associated with causes other than BPO may require more extensive diagnostic workup and different treatment considerations. We acknowledge that not all patients identify as male. These guidelines should also be applicable to non-binary people, transwomen, and any patients who may have anatomical features of a cis-male genitourinary tract, such as a prostate. It is our intent to make these guidelines inclusive to all persons experiencing LUTS or an enlarged prostate.
In this document, we will address both diagnostic and treatment issues. Diagnostic guidelines are described in the following terms as: mandatory, recommended, optional, or not recommended. The recommendations for diagnostic guidelines and principles of treatment were developed on the basis of clinical principle (widely agreed upon by Canadian urologists) and/or expert opinion (consensus of committee and reviewers). The grade of recommendation will not be offered for diagnostic recommendations. Guidelines for treatment are described using the GRADE approach 4 for summarizing the evidence and making recommendations.
# Diagnostic guidelines
The committee recommended minor revisions in regard to diagnostic considerations as outlined in the 2018 CUA BPH guideline. 1
# Mandatory
# Mandatory evaluations include:
-History -Physical examination, including DRE -Urinalysis In the initial evaluation of a man presenting with LUTS, the evaluation of symptom severity and bother is essential. Medical history should include relevant prior and current illnesses, as well as prior surgery and trauma. Current medication, including over-the-counter drugs and phyto-Dean Elterman 1 , Mélanie Aubé-Peterkin 2 , Howard Evans 3 , Hazem Elmansy 4 , Malek Meskawi 5 , Kevin C. Zorn 5
# Recommended
# Symptom inventory (should include bother assessment)
A formal symptom inventory (e.g., International Prostate Symptom Score or AUA Symptom Index ) is recommended for an objective assessment of symptoms at initial consultation, for followup of symptom evolution for those on watchful waiting, and for evaluation of response to treatment.
# Prostate-specific antigen
Testing of prostate-specific antigen (PSA) should be offered to patients who have at least a 10-year life expectancy and for whom knowledge of the presence of prostate cancer would change management, as well as those for whom PSA measurement may change the management of their voiding symptoms (i.e., estimate for prostate volume that may lead to more precise measurements). Among patients without prostate cancer, serum PSA may also be a useful surrogate marker of prostate size and may also predict risk of BPH progression. 12,13
# Optional
In cases where the physician feels diagnostic uncertainty exists, it is reasonable to proceed with one or more of the following:
# Not recommended
The following diagnostic modalities are not recommended in the routine initial evaluation of a typical patient with BPHassociated LUTS. These investigations may be required in patients with another indication, such as hematuria, diagnostic uncertainty, DRE abnormalities, poor response to medical therapy, or for surgical planning:
# Further diagnostic considerations for surgery
# Indications for surgery
Indications for MLUTS/BPH surgery 1-3 include 1) recurrent or refractory urinary retention; 2) recurrent urinary tract infections (UTIs); 3) bladder stones; 4) recurrent hematuria; 5) renal dysfunction secondary to BPH; 6) symptom deterioration despite medical therapy; and 7) patient preference. The presence of a bladder diverticulum is not an absolute indication for surgery unless associated with recurrent UTI or progressive bladder dysfunction.
# Preoperative testing
Determination of prostate size and extent of median lobe are related to procedure-specific indications (see section on Surgical Treatment). For patients in whom surgery is being considered, cystoscopy should be performed to evaluate prostate size, as well as presence or absence of significant middle/median lobe and/or bladder calculi. Ultrasound (US) (either by transrectal ultrasound or transabdominal US) is recommended to determine the volume of the prostate and the extent of median lobe presence in order to select appropriate modality of surgical therapy. This information
# Treatment guidelines
# Principles of treatment
Therapeutic decision-making should be guided by the severity of the symptoms, the degree of bother, and patient preference. Information on the risks and benefits of BPH treatment options should be explained to all patients who are bothered enough to consider therapy. Patients should be invited to participate as much as possible using a shared decisionmaking approach to determine the best treatment selection for them. This can be facilitated with the use of the CUA surgical BPH decision aid. 14 The patient's therapeutic goal of management should be discussed and documented.
Patients with mild symptoms (e.g., IPSS <7) should be counselled about a combination of lifestyle modification and watchful waiting. Patients with mild symptoms and severe bother should undergo further assessment.
Treatment options for patients with bothersome moderate (e.g., and severe (e.g., IPSS 19-35) symptoms of BPH include watchful waiting/lifestyle modification, as well as medical, minimally invasive, or surgical therapies.
Physicians should use baseline age, LUTS severity, and prostate volume to advise patients of their individual risk of symptom progression, acute urinary retention (AUR) or future need for BPH-related surgery (these risk factors identify patients at risk for progression).
A variety of lifestyle changes may be suggested for patients with non-bothersome symptoms. These can include:
-Fluid restriction, particularly prior to bedtime -Avoidance of caffeinated beverages, alcohol, and spicy foods -Avoidance/monitoring of some drugs (e.g., diuretics, decongestants, antihistamines, antidepressants) -Timed or organized voiding (bladder retraining) -Avoidance or treatment of constipation -Weight loss and prevention or treatment of conditions associated with metabolic syndrome -Pelvic floor physical therapy (PFPT) in cases of suspected non-relaxing pelvic floor dysfunction (causing LUTS, pelvic and or genital pain, bowel and sexual dysfunction, etc.) or overactive bladder and/or urinary incontinence (Kegel exercises, urge suppression, etc.)
# Post-treatment followup
# Watchful waiting
Patients on watchful waiting should have periodic physicianmonitored visits to monitor for any complications associated with their BPO. Physicians should assess either progression of bother, i.e., validated questionnaire such as IPSS (subjective) or worsening urinary function, i.e., uroflowmetry or PVR (objective).
# Medical therapy
Patients started on medical therapy should have followup visit(s) to assess for efficacy and safety (side effects) of medications. If the patient-directed therapeutic goal is achieved, the patient may be followed by the primary care physician as part of a shared-care approach. The primary care physician should be counselled with clear instructions on followup and re-referral as necessary.
# Surgical therapy
Patients who receive prostate surgery for BPH should be reviewed 4-6 weeks after catheter removal to evaluate treatment response (with symptom assessment , and if indicated, uroflowmetry and PVR volume). Side effects and adverse events should also be screened for. The individual patient's circumstances and type of surgical procedure employed will determine the need for and type of further followup required by the urologist and/or primary care physician.
# Medical therapy
The committee recommended few changes in the recommendations for the primary medical management of BPH and MLUTS with alpha-blockers and/or 5-alpha-reductase inhibitors (5ARIs) since 2018. Since the 2018 guideline publication, new evidence is available in regard to other medical therapy, namely beta-3 agonists, for the treatment of MLUTS.
# Alpha-blockers
Alfuzosin, doxazosin, tamsulosin, terazosin, and silodosin are appropriate treatment options for LUTS secondary to BPH. Doxazosin and terazosin require dose titration and blood pressure monitoring. Alpha-blockers do not alter the natural progression of BPH (little impact on prostate growth, risk of urinary retention, or the need for BPH-related surgery). The most common adverse effect associated with alpha-blockers is dizziness (2-10%, with the highest rates for terazosin and doxazosin), while ejaculatory disturbances are most often reported with tamsulosin and silodosin. Floppy iris syndrome has been reported in patients on alpha-blockers, particularly tamsulosin, but this does not appear to be an issue in men with no planned cataract surgery and can be managed by the ophthalmologist, who is aware that the patient is on the medication. 24 Although there are differences in the adverse event profiles of these agents, all five agents appear to have equal clinical effectiveness. The choice of agent should depend on the patient's comorbidities, side effect profile, and tolerance.
# elterman et al
We recommend alpha-blockers as an excellent first-line therapeutic option for men with symptomatic bother due to BPH who desire treatment (strong recommendation, evidence level A).
# 5-ARIs
Several studies have demonstrated that 5-ARI therapy, in addition to improving symptoms and causing a modest (25-30%) shrinkage of the prostate, can alter the natural history of BPH through a reduction in the risk of AUR and the need for surgical intervention. 25,26 Efficacy is noted in patients with a prostate volume >30 cc (and/or PSA levels >1.5 ng/ml). 5-ARI treatment is associated with erectile dysfunction, decreased libido, ejaculation disorders, and rarely, gynecomastia and post-finasteride syndrome. 27 We recommend 5-ARIs (dutasteride and finasteride) as appropriate and effective treatment for patients with LUTS associated with demonstrable prostatic enlargement (strong recommendation, evidence level A).
# Combination therapy (alpha-blocker and 5-ARI)
Prognostic factors suggesting the potential for BPH progression risk 28,29 include: serum PSA >1.4 ng/mL, age >50 years, and gland volume >30 cc. Clinical trial results have shown that combination therapy significantly improves symptom score and peak urinary flow compared with either of the monotherapy options. Combination medical therapy is associated with decreased risk of urinary retention and/or prostate surgery, but also the additive side effects of dual therapy (in particular, ejaculatory disturbances). 30,31 We recommend the combination of an alpha-adrenergic receptor blocker and a 5-ARI as an appropriate and effective treatment strategy for patients with symptomatic LUTS associated with prostatic enlargement (>30 cc) (strong recommendation, evidence level B).
It may be appropriate to consider discontinuing the alphablockers in patients successfully managed with combination therapy after 6-9 months of combination therapy. 32,33 We suggest that patients successfully treated with combination therapy may be given the option of discontinuing the alpha-blocker. If symptoms recur, the alpha-blocker should be restarted (conditional recommendation, evidence level B).
# Antimuscarinic and beta-3 agonist medications
Storage symptoms (urgency, frequency, nocturia) are a bothersome component of MLUTS associated with BPH. Antimuscarinics (anticholinergics) and the beta-3 agonists have demonstrated improvements in male storage LUTS (with and without BPH), including reductions in frequency, urgency, and urgency incontinence episodes. 34,35 Studies of contemporary antimuscarinics, such as tolterodine and fesoterodine, and the beta-3 agonist, mirabegron, have shown low rates of urinary retention, although caution should be exercised in elderly men and those with significant bladder outlet obstruction (BOO) (with PVR >250-300 cc since there is little evidence of safety in men with high PVRs).
We suggest that antimuscarinics or beta-3 agonists may be useful in predominately storage symptoms and BPH, and used with caution in those with significant BOO and/or an elevated PVR (conditional recommendation, evidence level C).
# Antimuscarinic or beta-3 agonists in combination with alpha-blockers
Mixed LUTS (storage and voiding symptoms) can be managed safely with alpha-blockers in combination with antimuscarinics or beta-3-agonists. Clinical trials studied the following drug combinations: tamsulosin 0.4 mg plus solifenacin 5 mg, tamsulosin plus tolterodine ER 4 mg, and tamsulosin 0.4 mg plus mirabegron 50 mg. Evidence showed that combination therapies provide significant improvement in storage symptoms without clinical or statistical evidence of decreased maximum flow rate on uroflowmetry (Qmax) or increased risk of retention. Patients with high PVR >200 ml or previous history of AUR were excluded.
We suggest that an alpha-blocker combined with an antimuscarinic or beta-3 agonist may be useful to treat LUTS/ BPH in men with both voiding and storage symptoms and failure of alpha-blocker monotherapy (conditional recommendation, evidence level B).
# Phosphodiesterase inhibitors
PDE5Is have been shown to not only improve erectile function, but also are an effective treatment for male LUTS. Tadalafil 5 mg daily, due to its longer half-life, is approved for MLUTS. Studies have shown improvements in IPSS, storage and voiding symptoms, and quality of life. 42 Evidence shows that combination therapy with PDE5I and alpha-blockers is superior to alpha-blockers alone in men with voiding symptoms and erectile dysfunction. 43 We recommend long-acting PDE5Is as monotherapy for men with LUTS/BPH, particularly in men with both LUTS and erectile dysfunction (strong recommendation, evidence level B).
# Desmopressin
Nocturnal polyuria (NP) often coexists with MLUTS and BPH but may not respond to typical BPH pharmacotherapies. NP is a major contributing factor of nocturia and is defined by the International Continence Society (ICS) as an abnormally cua guideline: luTs/BPh large volume of urine during sleep. More specifically, 33% of the total daily urine volume occurs at night, while the daily total urine output remains normal. Desmopressin is a synthetic analogue of the antidiuretic hormone, arginine vasopressin (AVP). Desmopressin reduces total nocturnal voids and increases hours of undisturbed sleep by reducing urine production in men with NP. 44 While the risk of hyponatremia is low in men with normal baseline serum sodium, sodium must be checked at baseline in all men, as well as 4-8 days and 30 days after initiation of treatment in men taking desmopressin melts or men ≥65 years taking 50 μg oral disintegrating tablet. In men whose predominant symptom is bothersome nocturia and who do not respond to conservative measures or other monotherapies, desmopressin should be considered.
We recommend desmopressin as a therapeutic option in men with LUTS/BPH with nocturia as result of NP (conditional recommendation, evidence level B).
# Phytotherapies
Plant-based herbal preparations may appeal to some patients. Common formulations include Serenoa repens (saw palmetto), Pygeum africanum (African plum bark), and Urtica dioica (stinging nettle). Phytotherapies lack consistent formulation, predictable pharmacokinetics, and regulatory oversight. Numerous studies and Cochrane meta-analyses report no significant difference between phytotherapies and placebo, as measured by AUA-SI, peak flow rates, prostate volume, residual urine volume, PSA, or quality of life. There are few side effects associated with phytotherapies but there are important potential drug interactions.
We do not recommend phytotherapies as standard treatment for MLUTS/BPH (strong recommendation, evidence level B).
# Surgical therapy
# TURP
# Monopolar TURP
Monopolar TURP (M-TURP) remains the primary, standard-reference surgical treatment option for moderate-tosevere LUTS due to BPH in patients with prostate volume 30-80 cc. 49 Perioperative mortality has decreased over time and is currently approximately 0.1%, while morbidity is related to prostate volume (particularly >60 cc). 50 Contemporary series have reported the following complications: bleeding (2-9%), capsule perforation with significant extravasation (2%), TUR syndrome (0.8%), urinary retention (4.5-13%), infection (3-4%; sepsis 1.5%), incontinence (<1%), bladder neck contracture (3-5%), retrograde ejaculation (65%), erectile dysfunction (6.5%), and need for surgical retreatment (2%/year). 51,52 We recommend M-TURP as a standard first-line surgical therapy for men with moderate-to-severe LUTS/BPH with prostate volume of 30-80 cc (strong recommendation, evidence level A).
# Bipolar TURP (including bipolar plasma kinetic vaporization)
Bipolar TURP (B-TURP) offers a resection alternative to M-TURP in men with moderate to-severe LUTS secondary to BPH with similar efficacy, but lower perioperative morbidity. The predominant difference between M-TURP and B-TURP is the decreased risk of perioperative bleeding and TUR syndrome. The choice of B-TURP should be based on equipment availability, surgeon experience, and patient preference.
We recommend B-TURP as a standard first-line surgical therapy for men with moderate-to-severe LUTS/BPS with prostate volume of 30-80 cc (strong recommendation, evidence level B).
# Open simple prostatectomy
Open simple prostatectomy (OSP) is an effective treatment alternative for men with moderate-to-severe LUTS with substantially enlarged prostates >80 cc and who are significantly bothered by symptoms. 55 Other indications for OSP include plans for concurrent bladder procedure, such as diverticulectomy or cystolithotomy (for very large bladder calculi) and in men who are unable to be placed in dorsal lithotomy position due to severe hip disease. 56 OSP is the most invasive surgical method requiring longer hospitalization and catheterization. The estimated transfusion rate has been reported as 7-14%. 55,56 Complications include transient urinary incontinence (8-10%), bladder neck contracture, and urethral stricture (5-6%). 55,56 We recommend OSP as a first-line surgical therapy when anatomic endoscopic enucleation of the prostate (AEEP) (see below) is unavailable for men with moderate-to-severe LUTS/BPS and enlarged prostate volume >80 cc (strong recommendation, evidence level A).
# Minimally invasive simple prostatectomy
With the advent of minimally invasive surgery, starting with laparoscopy and proceeding to robotic-assisted laparoscopy, the natural evolution came to the OSP as well. These techniques are still relatively new.
Laparoscopic simple prostatectomy (LSP) and robot-assisted simple prostatectomy (RASP), like OSP, are indicated in patients with significantly enlarged prostates (>80-100cc) and bothersome LUTS. 57,58 They are also beneficial when elterman et al performed due to concomitant pathology, such as large bladder stones or bladder diverticulum. There are no randomized controlled trials comparing LSP and RASP to OSP or to any other enucleation procedure. The largest retrospective series includes both techniques and has shown both to be safe and effective. 59 A recent systematic review found that RASP showed similar improvements in IPSS, PVR, Qmax, and quality of life, while having similar complication rates and estimated blood loss (EBL) to laser vaporization and enucleation of the prostate. 60 In comparison to OSP, the length of stay (LOS) and EBL are significantly lower for RASP. 61 Finally, catheterization time and LOS are longer with RASP compared to laser enucleation of the prostate. 60 We recommend LSP or RASP as alternative surgical therapies for men with moderate-to-severe LUTS/BPS and enlarged prostate volume >80 cc in centers where there are surgeons with high-level expertise in robotics or laparoscopy (conditional recommendation, evidence level B).
# AEEP
AEEP adopts the principle of open prostatectomy (OP) using different energy sources and instruments. The holmium laser (HoLEP) with or without Moses technology, GreenLight laser (GreenLEP), monopolar enucleation (MonolEP), bipolar enucleation (BipolEP), diode laser (DiLEP), thulium laser (ThuLEP), and thulium fiber laser (ThuFLEP) are among the available energy sources. The efficacy and safety of AEEP, regardless of the energy source used, have been widely demonstrated. 62 When compared to TURP and OSP, AEEP was associated with greater improvements in IPSS, Qmax, and PVR. AEEP resulted in greater prostate tissue removal, reduced hemoglobin loss, shorter catheterization time, and shorter LOS. 63 Recent evidence supports the use of AEEP in patients with BPH on anticoagulant (AC) or antiplatelet (AP) therapy. AEEP has demonstrated durable results, with a low reoperation rate of 0-3.7% (attributed to adenoma regrowth) on long-term followup of up to 18 years. The procedure requires a steep learning curve (estimated >20-50 cases). 72 We recommend AEEP as an alternative to TURP or OSP in men with moderate-to-severe LUTS and any size prostate >30 cc if performed by an AEEP-trained surgeon. AEEP can be safely performed in patients on AC/AP therapy (strong recommendation, evidence level A).
# PVP
GreenLight-PVP (180W XPS and 120W HPS systems) provides comparable outcomes to TURP in terms of durable improvements in IPSS and Qmax, with similar overall complication rate. 73 Five-year mid-term durability of XPS reported a 1.1% retreatment rate in prostates with volumes of an average 80 g. 74 In the GOLIATH international, multicenter, randomized controlled trial comparing the 180W XPS PVP to TURP for prostate volumes 30-80cc, there was a statistically significant difference in early adverse events, notably bleeding-related one, within the first 30 days favoring XPS PVP. 68,75 Compared to TURP, PVP has better perioperative safety, shorter catheterization time, and shorter hospitalization. 76 Multiple studies have demonstrated that PVP is safe and effective for elderly men, with significant medical comorbidities, 77 large median lobes, 78 and in patients who continue their AC/AP therapy, with negligible transfusion rates. Further to GreenLight safety profile, PVP has been shown to be a cost-effective alternative to TURP in the Canadian setting. 82 There exists no size or shape limitation to PVP; only surgeon expertise and clinical judgement dictate size limitations.
# We recommend PVP as an alternative to M-TURP or B-TURP in men with moderate-to-severe LUTS (strong recommendation based on high-quality evidence).
We also suggest GreenLight PVP therapy as an alternate surgical approach in men on anticoagulation or with a high cardiovascular risk (conditional recommendation, evidence level B).
# Transurethral incision of the prostate
Transurethral incision of the prostate (TUIP) is an appropriate therapy for men with a small prostate size <30 cc without a middle lobe. 83 Symptoms and voiding parameters are improved and the risk of retrograde ejaculation and TUR syndrome is reduced (18.2% and 0%, respectively) compared to TURP; however, the risk of surgical retreatment for LUTS related to BPH are significantly higher for TUIP (18.4%) than after TURP (7.2%).
We recommend TUIP to treat moderate-to-severe LUTS in men with prostate volume <30 cc without a middle lobe. Patients should be made aware of the high retreatment rate (strong recommendation, evidence level B).
# Minimally invasive techniques
# Transurethral microwave therapy
Transurethral microwave therapy (TUMT) is an option for elderly patients with significant comorbidities or greater anesthesia risks, as this procedure can be performed under local ansthesia. 84,85 Although short-term success for LUTS improvement has been reported, the long-term durability of TUMT is limited, with five-year cumulative retreatment rates from 42-59%. 86 TUMT should not be performed in patients with a significant median lobe.
We suggest TUMT therapy as a consideration for treatment of carefully selected, well-informed men (conditional recommendation, evidence level C). cua guideline: luTs/BPh
# Prostatic stents
Temporary stents can provide short-term relief from BPO in patients temporarily unfit for surgery. 87 In general, stents are subject to misplacement, migration, and poor tolerability because of exacerbation of LUTS and encrustation. Given these common side effects, prostatic stents have a limited role in the treatment of moderate-to-severe LUTS. A newer generation of stents are currently being evaluated and may provide an alternative surgical option for the management of BPH/LUTS in the future.
We suggest prostatic stents only as an alternative to catheterization in men unfit for surgery with a functional detrusor (conditional recommendation, evidence level C).
# Prostatic urethral lift
The prostatic urethral lift procedure, or UroLift ® , (small, permanent, suture-based nitinol tabbed implants compress encroaching lateral lobes delivered under cystoscopic guidance), provides less effective but adequate and durable improvements in IPSS and QMax compared to TURP while preserving sexual function (no reported retrograde ejaculation observed at 12 months). 88 Most complications are mild and resolve within four weeks but include dysuria (34%), hematuria (26%), pelvic pain (19%), urge incontinence (7%), and UTI (3%). Surgical retreatment was 13.6% over five years. 89 A recent study (MedLift study) reported on the use of prostatic urethral lift in patients with a median lobe. For middle lobe deployment, the intravesical tissue is pulled into the prostatic fossa and affixed to either side of the urethra. Fort-four patients underwent this technique and results are very similar to the pivotal L.I.F.T. trial regarding improved IPSS and IPSS quality of life, while preserving ejaculatory function. It should be noted that followup for this study was only 12 months. 90 We suggest that prostatic urethral lift (UroLift) may be considered as an alternative treatment for men with LUTS interested in preserving ejaculatory function with prostates <80 cc. Prostatic urethral lift can also be be offered to patients with a small-to-moderate median lobe and bothersome LUTS. Patients (with or without a median lobe) should be made aware of the higher retreatment rate at five years (conditional recommendation, evidence level C).
# Convective water vapor energy ablation
Ablations using the Rezum ® system (uses the thermodynamic principle of convective energy transfer) report significant improvement of IPSS and Qmax at three months and sustained until 12 months, 91 with preservation of erectile and ejaculatory function. 92 Recent five-year results have confirmed durability of the positive clinical outcomes, with a 57% reduction in IPSS, 45% increase in quality of life, and 44% increase in Qmax. Surgical retreatment rate is 4.4% at five years. 93 We suggest that the Rezum system of convective water vapor energy ablation may be considered an alternative treatment for men with LUTS interested in preserving ejaculatory function with prostates <80 cc, including those with a median lobe (conditional recommendation, evidence level C).
# Image-guided robotic waterjet ablation
Aquablation (robotic-guided hydrodissection ablates prostatic parenchyma while sparing collagenous structures such as blood vessels and the surgical capsule) 94 has shown comparable improvements in efficacy and safety compared to TURP in men with <80 cc prostates. 95 Additional studies have also demonstrated efficacy and safety in glands 80-150 cc. Aquablation preserves erectile and ejaculatory function in nearly 100% and approximately 90% of patients, respectively. Five-year retreatment rates are low (6% at five years).
We suggest that Aquablation be offered to men with LUTS interested in preserving ejaculatory function with prostates <150 cc, with or without a middle lobe (conditional recommendation, evidence level C).
# Temporary implantable nitinol device
Temporary implantable nitinol device (iTind) is a temporary (five days and then removed under local anesthetic), mechanical, stent-like device designed to remodel the bladder neck and the prostatic urethra through pressure necrosis.
Three prospective, randomized clinical trials (n=269) have demonstrated IPSS reduction of 45-60%, Qmax increase of 50-110%, no changes in erectile or ejaculatory function, and a retreatment rate of 9% at three years. Long-term durability studies are pending.
We recommend that iTind may be offered to men with LUTS interested in preserving ejaculatory function, with prostates 30-80 cc. Patients should be made aware of the higher retreatment rate at 3 years (conditional recommendation, evidence level C).
# Prostatic artery embolization
Prostatic artery embolization (PAE) is a minimally invasive treatment option exclusively performed by interventional radiologists at specialized centers. PAE results in significant IPSS, Qmax, and PVR improvement compared to baseline at 12 months, 99 however, inferior outcomes compared to TURP or OSP. 103 Although PAE has reportedly fewer complications than TURP, non-targeted embolization may lead to rare ischemic complications like transient ischemic proctitis, bladder ischemia, urethral and ureteral stricture, or seminal vesicles ischemia. 104 Efficacy of PAE may be more advanta-elterman et al geous in prostate volumes >80 mL, 105 and can be considered as a treatment for gross hematuria of prostatic origin. 106 At centers with urological and radiological collaboration and technical expertise, highly selected, well-informed patients may be offered PAE if they wish to consider an alternative treatment option. Patients should be informed of lack of long-term durability (conditional recommendation, evidence level C).
Algorithms summarizing the management of a patient with MLUTS/BPH are summarized in Figures 2, 3.
# Special situations AUR
Data suggest that in patients with AUR, the use of alpha-blockers (specifically tamsulosin, alfuzosin, and silodosin) during the period of catheterization will increase the chances of successful voiding after catheter removal, 107,108 while the addition of a 5-ARI may decrease the risk of future prostate surgery. 30,31,109 We suggest that men with AUR secondary to BPH may be offered alpha-blocker therapy during the period of catheterization (conditional recommendation, evidence level B).
# Detrusor underactivity
There is no effective treatment for detrusor underactivity (DU), defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span. 110 In primary DU, treatment approach should be to facilitate bladder emptying, identify agents that can decrease bladder contractility, or increase urethral resistance. Behavioral modification, including scheduled voiding and or double voiding, clean intermittent self-catheterization (CIC), or indwelling catheters, are optional strategies. 111 The data suggests that DU is not necessarily a contraindication for TURP or enucleation. 112,113 We have no evidence-based specific recommendation for management of DU.
# BPH-related bleeding
A complete assessment, including history and physical examination, urinalysis (routine microscopy, culture and sensitivity, cytology), upper tract radiological assessment, and cystoscopy, is necessary to exclude other sources of bleeding. Finasteride has been reported to reduce the risk of recurrent BPH-related hematuria.
# BPH patients with prostate cancer concern
The BPH patient with an elevated serum PSA and negative prostate biopsy may be counselled on the potential benefits of 5-ARI therapy (finasteride, dutasteride) for prostate cancer detection risk reduction. 115,116 The patient must be aware of the possible low absolute increased risk (0.5-0.7%) in incidence of high-grade (Gleason 8-10) cancer with 5-ARI use. Most experts believe this phenomenon was observed due to an artifact of prostate glandular cytoreduction, induced by the 5-ARI, and it appears there is no demonstrable increase in prostate cancer mortality. 117 Patients on 5-ARI therapy who experience a rising PSA 6-12 months after PSA nadir is reached should be assessed for the possibility of high-grade prostate cancer. 118 We recommend case-to-case, patient-specific informed discussion and close PSA followup, as indicated, in men on 5-ARI therapy treatment for BPH (conditional recommendation, evidence level B).
# Summary
MLUTS secondary to BPH remains one of the most common age-related disorders afflicting men. As the aging of the Canadian population continues, more men will be seeking advice and looking for guidance from their healthcare providers on the management of their symptoms. The information offered in this guideline document, based on consensus evaluation of the best available evidence, will aid Canadian urologists as they strive to provide state-of-the-art care to their patients.
Competing interests: Dr. Elterman has attended advisory boards for, is a speaker for, and has received grant funding from Allergan, Astellas, Boston Scientific, Ferring, Medtronic, and Pfizer; and has participated in clinical trials supported by Astellas, Medtronic, Meditate, and Procept Biorobotics. Dr. Aubé-Peterkin is an investigator for the Optilume trial supported by Urotronic. Dr. Elmansy has | # Introduction
The current document summarizes the state-of-the-art knowledge as it relates to management of male lower urinary tract symptoms (MLUTS) secondary to benign prostatic hyperplasia (BPH) by updating the 2018 Canadian Urological Association (CUA) BPH guideline. 1 The process continues to highlight the essential diagnostic and therapeutic information in a Canadian context. The information included in this document includes that reviewed for the 2010 guideline and further information obtained from an updated MEDLINE search of the Englishlanguage literature (search terms included BPH, alpha-blockers, 5-alpha reductase inhibitor, anti-cholinergic, beta3 agonist, phosphodiesterase type 5 inhibitor [PDE5I], transurethral resection of the prostate [TURP], monopolar, bipolar, open simple prostatectomy, enucleation, GreenLight, photoselective vaporization of the prostate [PVP], Aquablation, Rezum, UroLift, temporarily implanted nitinol device [iTiND]), as well as review of the most recent American Urological Association (AUA) 2 and European Association of Urology (EAU) guidelines. 3 References include those of historical importance, but management recommendations are based on literature published between 2000 and 2021. When information and data is available from multiple sources, the most relevant (usually most recent) article is cited based on committee opinion.
These guidelines are directed toward the typical male patient over 50 years of age presenting with LUTS and benign prostatic enlargement (BPE) and/or benign prostatic obstruction (BPO). It is recognized that men with LUTS associated with causes other than BPO may require more extensive diagnostic workup and different treatment considerations. We acknowledge that not all patients identify as male. These guidelines should also be applicable to non-binary people, transwomen, and any patients who may have anatomical features of a cis-male genitourinary tract, such as a prostate. It is our intent to make these guidelines inclusive to all persons experiencing LUTS or an enlarged prostate.
In this document, we will address both diagnostic and treatment issues. Diagnostic guidelines are described in the following terms as: mandatory, recommended, optional, or not recommended. The recommendations for diagnostic guidelines and principles of treatment were developed on the basis of clinical principle (widely agreed upon by Canadian urologists) and/or expert opinion (consensus of committee and reviewers). The grade of recommendation will not be offered for diagnostic recommendations. Guidelines for treatment are described using the GRADE approach 4 for summarizing the evidence and making recommendations.
# Diagnostic guidelines
The committee recommended minor revisions in regard to diagnostic considerations as outlined in the 2018 CUA BPH guideline. 1
# Mandatory
# Mandatory evaluations include:
-History -Physical examination, including DRE -Urinalysis In the initial evaluation of a man presenting with LUTS, the evaluation of symptom severity and bother is essential. Medical history should include relevant prior and current illnesses, as well as prior surgery and trauma. Current medication, including over-the-counter drugs and phyto-Dean Elterman 1 , Mélanie Aubé-Peterkin 2 , Howard Evans 3 , Hazem Elmansy 4 , Malek Meskawi 5 , Kevin C. Zorn 5
# Recommended
# Symptom inventory (should include bother assessment)
A formal symptom inventory (e.g., International Prostate Symptom Score [IPSS] or AUA Symptom Index [AUA-SI]) is recommended for an objective assessment of symptoms at initial consultation, for followup of symptom evolution for those on watchful waiting, and for evaluation of response to treatment. [8][9][10][11]
# Prostate-specific antigen
Testing of prostate-specific antigen (PSA) should be offered to patients who have at least a 10-year life expectancy and for whom knowledge of the presence of prostate cancer would change management, as well as those for whom PSA measurement may change the management of their voiding symptoms (i.e., estimate for prostate volume that may lead to more precise measurements). Among patients without prostate cancer, serum PSA may also be a useful surrogate marker of prostate size and may also predict risk of BPH progression. 12,13
# Optional
In cases where the physician feels diagnostic uncertainty exists, it is reasonable to proceed with one or more of the following:
-
# Not recommended
The following diagnostic modalities are not recommended in the routine initial evaluation of a typical patient with BPHassociated LUTS. These investigations may be required in patients with another indication, such as hematuria, diagnostic uncertainty, DRE abnormalities, poor response to medical therapy, or for surgical planning:
-
# Further diagnostic considerations for surgery
# Indications for surgery
Indications for MLUTS/BPH surgery 1-3 include 1) recurrent or refractory urinary retention; 2) recurrent urinary tract infections (UTIs); 3) bladder stones; 4) recurrent hematuria; 5) renal dysfunction secondary to BPH; 6) symptom deterioration despite medical therapy; and 7) patient preference. The presence of a bladder diverticulum is not an absolute indication for surgery unless associated with recurrent UTI or progressive bladder dysfunction.
# Preoperative testing
Determination of prostate size and extent of median lobe are related to procedure-specific indications (see section on Surgical Treatment). For patients in whom surgery is being considered, cystoscopy should be performed to evaluate prostate size, as well as presence or absence of significant middle/median lobe and/or bladder calculi. Ultrasound (US) (either by transrectal ultrasound [TRUS] or transabdominal US) is recommended to determine the volume of the prostate and the extent of median lobe presence in order to select appropriate modality of surgical therapy. This information
# Treatment guidelines
# Principles of treatment
Therapeutic decision-making should be guided by the severity of the symptoms, the degree of bother, and patient preference. Information on the risks and benefits of BPH treatment options should be explained to all patients who are bothered enough to consider therapy. Patients should be invited to participate as much as possible using a shared decisionmaking approach to determine the best treatment selection for them. This can be facilitated with the use of the CUA surgical BPH decision aid. 14 The patient's therapeutic goal of management should be discussed and documented.
Patients with mild symptoms (e.g., IPSS <7) should be counselled about a combination of lifestyle modification and watchful waiting. Patients with mild symptoms and severe bother should undergo further assessment.
Treatment options for patients with bothersome moderate (e.g., and severe (e.g., IPSS 19-35) symptoms of BPH include watchful waiting/lifestyle modification, as well as medical, minimally invasive, or surgical therapies.
Physicians should use baseline age, LUTS severity, and prostate volume to advise patients of their individual risk of symptom progression, acute urinary retention (AUR) or future need for BPH-related surgery (these risk factors identify patients at risk for progression).
A variety of lifestyle changes may be suggested for patients with non-bothersome symptoms. These can include:
-Fluid restriction, particularly prior to bedtime -Avoidance of caffeinated beverages, alcohol, and spicy foods -Avoidance/monitoring of some drugs (e.g., diuretics, decongestants, antihistamines, antidepressants) -Timed or organized voiding (bladder retraining) -Avoidance or treatment of constipation -Weight loss and prevention or treatment of conditions associated with metabolic syndrome -Pelvic floor physical therapy (PFPT) in cases of suspected non-relaxing pelvic floor dysfunction (causing LUTS, pelvic and or genital pain, bowel and sexual dysfunction, etc.) or overactive bladder and/or urinary incontinence (Kegel exercises, urge suppression, etc.)
# Post-treatment followup
# Watchful waiting
Patients on watchful waiting should have periodic physicianmonitored visits to monitor for any complications associated with their BPO. Physicians should assess either progression of bother, i.e., validated questionnaire such as IPSS (subjective) or worsening urinary function, i.e., uroflowmetry or PVR (objective).
# Medical therapy
Patients started on medical therapy should have followup visit(s) to assess for efficacy and safety (side effects) of medications. If the patient-directed therapeutic goal is achieved, the patient may be followed by the primary care physician as part of a shared-care approach. The primary care physician should be counselled with clear instructions on followup and re-referral as necessary.
# Surgical therapy
Patients who receive prostate surgery for BPH should be reviewed 4-6 weeks after catheter removal to evaluate treatment response (with symptom assessment [e.g., IPSS], and if indicated, uroflowmetry and PVR volume). Side effects and adverse events should also be screened for. The individual patient's circumstances and type of surgical procedure employed will determine the need for and type of further followup required by the urologist and/or primary care physician.
# Medical therapy
The committee recommended few changes in the recommendations for the primary medical management of BPH and MLUTS with alpha-blockers and/or 5-alpha-reductase inhibitors (5ARIs) since 2018. Since the 2018 guideline publication, new evidence is available in regard to other medical therapy, namely beta-3 agonists, for the treatment of MLUTS.
# Alpha-blockers
Alfuzosin, doxazosin, tamsulosin, terazosin, and silodosin are appropriate treatment options for LUTS secondary to BPH. [12][13][14][15][16][17][18][19][20][21][22][23] Doxazosin and terazosin require dose titration and blood pressure monitoring. Alpha-blockers do not alter the natural progression of BPH (little impact on prostate growth, risk of urinary retention, or the need for BPH-related surgery). The most common adverse effect associated with alpha-blockers is dizziness (2-10%, with the highest rates for terazosin and doxazosin), while ejaculatory disturbances are most often reported with tamsulosin and silodosin. Floppy iris syndrome has been reported in patients on alpha-blockers, particularly tamsulosin, but this does not appear to be an issue in men with no planned cataract surgery and can be managed by the ophthalmologist, who is aware that the patient is on the medication. 24 Although there are differences in the adverse event profiles of these agents, all five agents appear to have equal clinical effectiveness. The choice of agent should depend on the patient's comorbidities, side effect profile, and tolerance.
# elterman et al
We recommend alpha-blockers as an excellent first-line therapeutic option for men with symptomatic bother due to BPH who desire treatment (strong recommendation, evidence level A).
# 5-ARIs
Several studies have demonstrated that 5-ARI therapy, in addition to improving symptoms and causing a modest (25-30%) shrinkage of the prostate, can alter the natural history of BPH through a reduction in the risk of AUR and the need for surgical intervention. 25,26 Efficacy is noted in patients with a prostate volume >30 cc (and/or PSA levels >1.5 ng/ml). 5-ARI treatment is associated with erectile dysfunction, decreased libido, ejaculation disorders, and rarely, gynecomastia and post-finasteride syndrome. 27 We recommend 5-ARIs (dutasteride and finasteride) as appropriate and effective treatment for patients with LUTS associated with demonstrable prostatic enlargement (strong recommendation, evidence level A).
# Combination therapy (alpha-blocker and 5-ARI)
Prognostic factors suggesting the potential for BPH progression risk 28,29 include: serum PSA >1.4 ng/mL, age >50 years, and gland volume >30 cc. Clinical trial results have shown that combination therapy significantly improves symptom score and peak urinary flow compared with either of the monotherapy options. Combination medical therapy is associated with decreased risk of urinary retention and/or prostate surgery, but also the additive side effects of dual therapy (in particular, ejaculatory disturbances). 30,31 We recommend the combination of an alpha-adrenergic receptor blocker and a 5-ARI as an appropriate and effective treatment strategy for patients with symptomatic LUTS associated with prostatic enlargement (>30 cc) (strong recommendation, evidence level B).
It may be appropriate to consider discontinuing the alphablockers in patients successfully managed with combination therapy after 6-9 months of combination therapy. 32,33 We suggest that patients successfully treated with combination therapy may be given the option of discontinuing the alpha-blocker. If symptoms recur, the alpha-blocker should be restarted (conditional recommendation, evidence level B).
# Antimuscarinic and beta-3 agonist medications
Storage symptoms (urgency, frequency, nocturia) are a bothersome component of MLUTS associated with BPH. Antimuscarinics (anticholinergics) and the beta-3 agonists have demonstrated improvements in male storage LUTS (with and without BPH), including reductions in frequency, urgency, and urgency incontinence episodes. 34,35 Studies of contemporary antimuscarinics, such as tolterodine and fesoterodine, and the beta-3 agonist, mirabegron, have shown low rates of urinary retention, although caution should be exercised in elderly men and those with significant bladder outlet obstruction (BOO) (with PVR >250-300 cc since there is little evidence of safety in men with high PVRs).
We suggest that antimuscarinics or beta-3 agonists may be useful in predominately storage symptoms and BPH, and used with caution in those with significant BOO and/or an elevated PVR (conditional recommendation, evidence level C).
# Antimuscarinic or beta-3 agonists in combination with alpha-blockers
Mixed LUTS (storage and voiding symptoms) can be managed safely with alpha-blockers in combination with antimuscarinics or beta-3-agonists. Clinical trials studied the following drug combinations: tamsulosin 0.4 mg plus solifenacin 5 mg, tamsulosin plus tolterodine ER 4 mg, and tamsulosin 0.4 mg plus mirabegron 50 mg. [36][37][38][39][40][41] Evidence showed that combination therapies provide significant improvement in storage symptoms without clinical or statistical evidence of decreased maximum flow rate on uroflowmetry (Qmax) or increased risk of retention. Patients with high PVR >200 ml or previous history of AUR were excluded.
We suggest that an alpha-blocker combined with an antimuscarinic or beta-3 agonist may be useful to treat LUTS/ BPH in men with both voiding and storage symptoms and failure of alpha-blocker monotherapy (conditional recommendation, evidence level B).
# Phosphodiesterase inhibitors
PDE5Is have been shown to not only improve erectile function, but also are an effective treatment for male LUTS. Tadalafil 5 mg daily, due to its longer half-life, is approved for MLUTS. Studies have shown improvements in IPSS, storage and voiding symptoms, and quality of life. 42 Evidence shows that combination therapy with PDE5I and alpha-blockers is superior to alpha-blockers alone in men with voiding symptoms and erectile dysfunction. 43 We recommend long-acting PDE5Is as monotherapy for men with LUTS/BPH, particularly in men with both LUTS and erectile dysfunction (strong recommendation, evidence level B).
# Desmopressin
Nocturnal polyuria (NP) often coexists with MLUTS and BPH but may not respond to typical BPH pharmacotherapies. NP is a major contributing factor of nocturia and is defined by the International Continence Society (ICS) as an abnormally cua guideline: luTs/BPh large volume of urine during sleep. More specifically, 33% of the total daily urine volume occurs at night, while the daily total urine output remains normal. Desmopressin is a synthetic analogue of the antidiuretic hormone, arginine vasopressin (AVP). Desmopressin reduces total nocturnal voids and increases hours of undisturbed sleep by reducing urine production in men with NP. 44 While the risk of hyponatremia is low in men with normal baseline serum sodium, sodium must be checked at baseline in all men, as well as 4-8 days and 30 days after initiation of treatment in men taking desmopressin melts or men ≥65 years taking 50 μg oral disintegrating tablet. In men whose predominant symptom is bothersome nocturia and who do not respond to conservative measures or other monotherapies, desmopressin should be considered.
We recommend desmopressin as a therapeutic option in men with LUTS/BPH with nocturia as result of NP (conditional recommendation, evidence level B).
# Phytotherapies
Plant-based herbal preparations may appeal to some patients. Common formulations include Serenoa repens (saw palmetto), Pygeum africanum (African plum bark), and Urtica dioica (stinging nettle). Phytotherapies lack consistent formulation, predictable pharmacokinetics, and regulatory oversight. Numerous studies and Cochrane meta-analyses report no significant difference between phytotherapies and placebo, as measured by AUA-SI, peak flow rates, prostate volume, residual urine volume, PSA, or quality of life. [45][46][47][48] There are few side effects associated with phytotherapies but there are important potential drug interactions.
We do not recommend phytotherapies as standard treatment for MLUTS/BPH (strong recommendation, evidence level B).
# Surgical therapy
# TURP
# Monopolar TURP
Monopolar TURP (M-TURP) remains the primary, standard-reference surgical treatment option for moderate-tosevere LUTS due to BPH in patients with prostate volume 30-80 cc. 49 Perioperative mortality has decreased over time and is currently approximately 0.1%, while morbidity is related to prostate volume (particularly >60 cc). 50 Contemporary series have reported the following complications: bleeding (2-9%), capsule perforation with significant extravasation (2%), TUR syndrome (0.8%), urinary retention (4.5-13%), infection (3-4%; sepsis 1.5%), incontinence (<1%), bladder neck contracture (3-5%), retrograde ejaculation (65%), erectile dysfunction (6.5%), and need for surgical retreatment (2%/year). 51,52 We recommend M-TURP as a standard first-line surgical therapy for men with moderate-to-severe LUTS/BPH with prostate volume of 30-80 cc (strong recommendation, evidence level A).
# Bipolar TURP (including bipolar plasma kinetic vaporization)
Bipolar TURP (B-TURP) offers a resection alternative to M-TURP in men with moderate to-severe LUTS secondary to BPH with similar efficacy, but lower perioperative morbidity. [52][53][54] The predominant difference between M-TURP and B-TURP is the decreased risk of perioperative bleeding and TUR syndrome. The choice of B-TURP should be based on equipment availability, surgeon experience, and patient preference.
We recommend B-TURP as a standard first-line surgical therapy for men with moderate-to-severe LUTS/BPS with prostate volume of 30-80 cc (strong recommendation, evidence level B).
# Open simple prostatectomy
Open simple prostatectomy (OSP) is an effective treatment alternative for men with moderate-to-severe LUTS with substantially enlarged prostates >80 cc and who are significantly bothered by symptoms. 55 Other indications for OSP include plans for concurrent bladder procedure, such as diverticulectomy or cystolithotomy (for very large bladder calculi) and in men who are unable to be placed in dorsal lithotomy position due to severe hip disease. 56 OSP is the most invasive surgical method requiring longer hospitalization and catheterization. The estimated transfusion rate has been reported as 7-14%. 55,56 Complications include transient urinary incontinence (8-10%), bladder neck contracture, and urethral stricture (5-6%). 55,56 We recommend OSP as a first-line surgical therapy when anatomic endoscopic enucleation of the prostate (AEEP) (see below) is unavailable for men with moderate-to-severe LUTS/BPS and enlarged prostate volume >80 cc (strong recommendation, evidence level A).
# Minimally invasive simple prostatectomy
With the advent of minimally invasive surgery, starting with laparoscopy and proceeding to robotic-assisted laparoscopy, the natural evolution came to the OSP as well. These techniques are still relatively new.
Laparoscopic simple prostatectomy (LSP) and robot-assisted simple prostatectomy (RASP), like OSP, are indicated in patients with significantly enlarged prostates (>80-100cc) and bothersome LUTS. 57,58 They are also beneficial when elterman et al performed due to concomitant pathology, such as large bladder stones or bladder diverticulum. There are no randomized controlled trials comparing LSP and RASP to OSP or to any other enucleation procedure. The largest retrospective series includes both techniques and has shown both to be safe and effective. 59 A recent systematic review found that RASP showed similar improvements in IPSS, PVR, Qmax, and quality of life, while having similar complication rates and estimated blood loss (EBL) to laser vaporization and enucleation of the prostate. 60 In comparison to OSP, the length of stay (LOS) and EBL are significantly lower for RASP. 61 Finally, catheterization time and LOS are longer with RASP compared to laser enucleation of the prostate. 60 We recommend LSP or RASP as alternative surgical therapies for men with moderate-to-severe LUTS/BPS and enlarged prostate volume >80 cc in centers where there are surgeons with high-level expertise in robotics or laparoscopy (conditional recommendation, evidence level B).
# AEEP
AEEP adopts the principle of open prostatectomy (OP) using different energy sources and instruments. The holmium laser (HoLEP) with or without Moses technology, GreenLight laser (GreenLEP), monopolar enucleation (MonolEP), bipolar enucleation (BipolEP), diode laser (DiLEP), thulium laser (ThuLEP), and thulium fiber laser (ThuFLEP) are among the available energy sources. The efficacy and safety of AEEP, regardless of the energy source used, have been widely demonstrated. 62 When compared to TURP and OSP, AEEP was associated with greater improvements in IPSS, Qmax, and PVR. AEEP resulted in greater prostate tissue removal, reduced hemoglobin loss, shorter catheterization time, and shorter LOS. 63 Recent evidence supports the use of AEEP in patients with BPH on anticoagulant (AC) or antiplatelet (AP) therapy. [64][65][66] AEEP has demonstrated durable results, with a low reoperation rate of 0-3.7% (attributed to adenoma regrowth) on long-term followup of up to 18 years. [67][68][69][70][71] The procedure requires a steep learning curve (estimated >20-50 cases). 72 We recommend AEEP as an alternative to TURP or OSP in men with moderate-to-severe LUTS and any size prostate >30 cc if performed by an AEEP-trained surgeon. AEEP can be safely performed in patients on AC/AP therapy (strong recommendation, evidence level A).
# PVP
GreenLight-PVP (180W XPS and 120W HPS systems) provides comparable outcomes to TURP in terms of durable improvements in IPSS and Qmax, with similar overall complication rate. 73 Five-year mid-term durability of XPS reported a 1.1% retreatment rate in prostates with volumes of an average 80 g. 74 In the GOLIATH international, multicenter, randomized controlled trial comparing the 180W XPS PVP to TURP for prostate volumes 30-80cc, there was a statistically significant difference in early adverse events, notably bleeding-related one, within the first 30 days favoring XPS PVP. 68,75 Compared to TURP, PVP has better perioperative safety, shorter catheterization time, and shorter hospitalization. 76 Multiple studies have demonstrated that PVP is safe and effective for elderly men, with significant medical comorbidities, 77 large median lobes, 78 and in patients who continue their AC/AP therapy, with negligible transfusion rates. [79][80][81] Further to GreenLight safety profile, PVP has been shown to be a cost-effective alternative to TURP in the Canadian setting. 82 There exists no size or shape limitation to PVP; only surgeon expertise and clinical judgement dictate size limitations.
# We recommend PVP as an alternative to M-TURP or B-TURP in men with moderate-to-severe LUTS (strong recommendation based on high-quality evidence).
We also suggest GreenLight PVP therapy as an alternate surgical approach in men on anticoagulation or with a high cardiovascular risk (conditional recommendation, evidence level B).
# Transurethral incision of the prostate
Transurethral incision of the prostate (TUIP) is an appropriate therapy for men with a small prostate size <30 cc without a middle lobe. 83 Symptoms and voiding parameters are improved and the risk of retrograde ejaculation and TUR syndrome is reduced (18.2% and 0%, respectively) compared to TURP; however, the risk of surgical retreatment for LUTS related to BPH are significantly higher for TUIP (18.4%) than after TURP (7.2%).
We recommend TUIP to treat moderate-to-severe LUTS in men with prostate volume <30 cc without a middle lobe. Patients should be made aware of the high retreatment rate (strong recommendation, evidence level B).
# Minimally invasive techniques
# Transurethral microwave therapy
Transurethral microwave therapy (TUMT) is an option for elderly patients with significant comorbidities or greater anesthesia risks, as this procedure can be performed under local ansthesia. 84,85 Although short-term success for LUTS improvement has been reported, the long-term durability of TUMT is limited, with five-year cumulative retreatment rates from 42-59%. 86 TUMT should not be performed in patients with a significant median lobe.
We suggest TUMT therapy as a consideration for treatment of carefully selected, well-informed men (conditional recommendation, evidence level C). cua guideline: luTs/BPh
# Prostatic stents
Temporary stents can provide short-term relief from BPO in patients temporarily unfit for surgery. 87 In general, stents are subject to misplacement, migration, and poor tolerability because of exacerbation of LUTS and encrustation. Given these common side effects, prostatic stents have a limited role in the treatment of moderate-to-severe LUTS. A newer generation of stents are currently being evaluated and may provide an alternative surgical option for the management of BPH/LUTS in the future.
We suggest prostatic stents only as an alternative to catheterization in men unfit for surgery with a functional detrusor (conditional recommendation, evidence level C).
# Prostatic urethral lift
The prostatic urethral lift procedure, or UroLift ® , (small, permanent, suture-based nitinol tabbed implants compress encroaching lateral lobes delivered under cystoscopic guidance), provides less effective but adequate and durable improvements in IPSS and QMax compared to TURP while preserving sexual function (no reported retrograde ejaculation observed at 12 months). 88 Most complications are mild and resolve within four weeks but include dysuria (34%), hematuria (26%), pelvic pain (19%), urge incontinence (7%), and UTI (3%). Surgical retreatment was 13.6% over five years. 89 A recent study (MedLift study) reported on the use of prostatic urethral lift in patients with a median lobe. For middle lobe deployment, the intravesical tissue is pulled into the prostatic fossa and affixed to either side of the urethra. Fort-four patients underwent this technique and results are very similar to the pivotal L.I.F.T. trial regarding improved IPSS and IPSS quality of life, while preserving ejaculatory function. It should be noted that followup for this study was only 12 months. 90 We suggest that prostatic urethral lift (UroLift) may be considered as an alternative treatment for men with LUTS interested in preserving ejaculatory function with prostates <80 cc. Prostatic urethral lift can also be be offered to patients with a small-to-moderate median lobe and bothersome LUTS. Patients (with or without a median lobe) should be made aware of the higher retreatment rate at five years (conditional recommendation, evidence level C).
# Convective water vapor energy ablation
Ablations using the Rezum ® system (uses the thermodynamic principle of convective energy transfer) report significant improvement of IPSS and Qmax at three months and sustained until 12 months, 91 with preservation of erectile and ejaculatory function. 92 Recent five-year results have confirmed durability of the positive clinical outcomes, with a 57% reduction in IPSS, 45% increase in quality of life, and 44% increase in Qmax. Surgical retreatment rate is 4.4% at five years. 93 We suggest that the Rezum system of convective water vapor energy ablation may be considered an alternative treatment for men with LUTS interested in preserving ejaculatory function with prostates <80 cc, including those with a median lobe (conditional recommendation, evidence level C).
# Image-guided robotic waterjet ablation
Aquablation (robotic-guided hydrodissection ablates prostatic parenchyma while sparing collagenous structures such as blood vessels and the surgical capsule) 94 has shown comparable improvements in efficacy and safety compared to TURP in men with <80 cc prostates. 95 Additional studies have also demonstrated efficacy and safety in glands 80-150 cc. Aquablation preserves erectile and ejaculatory function in nearly 100% and approximately 90% of patients, respectively. Five-year retreatment rates are low (6% at five years).
We suggest that Aquablation be offered to men with LUTS interested in preserving ejaculatory function with prostates <150 cc, with or without a middle lobe (conditional recommendation, evidence level C).
# Temporary implantable nitinol device
Temporary implantable nitinol device (iTind) is a temporary (five days and then removed under local anesthetic), mechanical, stent-like device designed to remodel the bladder neck and the prostatic urethra through pressure necrosis.
Three prospective, randomized clinical trials (n=269) have demonstrated IPSS reduction of 45-60%, Qmax increase of 50-110%, no changes in erectile or ejaculatory function, and a retreatment rate of 9% at three years. [96][97][98] Long-term durability studies are pending.
We recommend that iTind may be offered to men with LUTS interested in preserving ejaculatory function, with prostates 30-80 cc. Patients should be made aware of the higher retreatment rate at 3 years (conditional recommendation, evidence level C).
# Prostatic artery embolization
Prostatic artery embolization (PAE) is a minimally invasive treatment option exclusively performed by interventional radiologists at specialized centers. PAE results in significant IPSS, Qmax, and PVR improvement compared to baseline at 12 months, 99 however, inferior outcomes compared to TURP [100][101][102] or OSP. 103 Although PAE has reportedly fewer complications than TURP, non-targeted embolization may lead to rare ischemic complications like transient ischemic proctitis, bladder ischemia, urethral and ureteral stricture, or seminal vesicles ischemia. 104 Efficacy of PAE may be more advanta-elterman et al geous in prostate volumes >80 mL, 105 and can be considered as a treatment for gross hematuria of prostatic origin. 106 At centers with urological and radiological collaboration and technical expertise, highly selected, well-informed patients may be offered PAE if they wish to consider an alternative treatment option. Patients should be informed of lack of long-term durability (conditional recommendation, evidence level C).
Algorithms summarizing the management of a patient with MLUTS/BPH are summarized in Figures 2, 3.
# Special situations AUR
Data suggest that in patients with AUR, the use of alpha-blockers (specifically tamsulosin, alfuzosin, and silodosin) during the period of catheterization will increase the chances of successful voiding after catheter removal, 107,108 while the addition of a 5-ARI may decrease the risk of future prostate surgery. 30,31,109 We suggest that men with AUR secondary to BPH may be offered alpha-blocker therapy during the period of catheterization (conditional recommendation, evidence level B).
# Detrusor underactivity
There is no effective treatment for detrusor underactivity (DU), defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span. 110 In primary DU, treatment approach should be to facilitate bladder emptying, identify agents that can decrease bladder contractility, or increase urethral resistance. Behavioral modification, including scheduled voiding and or double voiding, clean intermittent self-catheterization (CIC), or indwelling catheters, are optional strategies. 111 The data suggests that DU is not necessarily a contraindication for TURP or enucleation. 112,113 We have no evidence-based specific recommendation for management of DU.
# BPH-related bleeding
A complete assessment, including history and physical examination, urinalysis (routine microscopy, culture and sensitivity, cytology), upper tract radiological assessment, and cystoscopy, is necessary to exclude other sources of bleeding. Finasteride has been reported to reduce the risk of recurrent BPH-related hematuria.
# BPH patients with prostate cancer concern
The BPH patient with an elevated serum PSA and negative prostate biopsy may be counselled on the potential benefits of 5-ARI therapy (finasteride, dutasteride) for prostate cancer detection risk reduction. 115,116 The patient must be aware of the possible low absolute increased risk (0.5-0.7%) in incidence of high-grade (Gleason 8-10) cancer with 5-ARI use. Most experts believe this phenomenon was observed due to an artifact of prostate glandular cytoreduction, induced by the 5-ARI, and it appears there is no demonstrable increase in prostate cancer mortality. 117 Patients on 5-ARI therapy who experience a rising PSA 6-12 months after PSA nadir is reached should be assessed for the possibility of high-grade prostate cancer. 118 We recommend case-to-case, patient-specific informed discussion and close PSA followup, as indicated, in men on 5-ARI therapy treatment for BPH (conditional recommendation, evidence level B).
# Summary
MLUTS secondary to BPH remains one of the most common age-related disorders afflicting men. As the aging of the Canadian population continues, more men will be seeking advice and looking for guidance from their healthcare providers on the management of their symptoms. The information offered in this guideline document, based on consensus evaluation of the best available evidence, will aid Canadian urologists as they strive to provide state-of-the-art care to their patients.
Competing interests: Dr. Elterman has attended advisory boards for, is a speaker for, and has received grant funding from Allergan, Astellas, Boston Scientific, Ferring, Medtronic, and Pfizer; and has participated in clinical trials supported by Astellas, Medtronic, Meditate, and Procept Biorobotics. Dr. Aubé-Peterkin is an investigator for the Optilume trial supported by Urotronic. Dr. Elmansy has | None | None |
5b4716d1854a99ac65ae24de923457b1885cae09 | cma | None | While every attempt has been made to ensure that the information contained herein is clinically accurate and current, Perinatal Services BC and the BC Prenatal Screening Program acknowledge that many issues remain controversial, and therefore may be subject to practice interpretation.#
Prenatal genetic screening estimates the chance of Down syndrome, trisomy 18, and open neural tube defect. The results will assist in determining the need for further testing. The screening tests offered will vary according to the gestational age at the time of presentation, maternal age at the time of delivery, and whether the pregnancy is a singleton or twin gestation.
BC has adopted a serum-based approach to prenatal genetic screening, with nuchal translucency (NT) ultrasound added for women/individuals at higher chance of having a fetus with Down syndrome or trisomy 18 and women/individuals with twin pregnancies. Non-Invasive Prenatal Screening (NIPS) is now also an option for some higher risk women/individuals. This guideline refers to screening options that are available in the public health care system. In BC, Serum Integrated Prenatal Screen (SIPS) is available and should be offered to all pregnant women/individuals. The following women/individuals are eligible for NT ultrasound as a component of Integrated Prenatal Screen (IPS = SIPS in combination with NT):
a) Women/individuals ≥ 35 years old at expected date of delivery (EDD) 1 ;
b) Women/individuals with twin pregnancies; c) Women/individuals pregnant following in vitro fertilization with intracytoplasmic sperm injection (IVF with ICSI) without PGT-A.
Certified (Fetal Medicine Foundation -UK) nuchal translucency ultrasound sites are established in all BC health authorities.
For women/individuals 40 years or older with a singleton pregnancy, or 35 years or older with a multiple gestation pregnancy, amniocentesis is also an option.
Provincially funded NIPS is available for the following eligible women/individuals: a) Women/individuals with a positive screen result from IPS, SIPS, or Quad; b) Women/individuals who have a documented history of a previous child or fetus with Down syndrome, trisomy 18, or trisomy 13; c) Women/individuals whose chance of Down syndrome is equal to or greater than 1/300 based on the finding of ultrasound marker(s) and results of SIPS / IPS / Quad.
The purpose of prenatal genetic screening is to identify pregnancies at increased chance of chromosome disorders or structural anomalies. Serum integrated prenatal screen (SIPS), integrated prenatal screen (IPS), quad marker screen (Quad), NIPS, and a detailed second trimester ultrasound 2 are some of the options available for prenatal genetic screening. IPS involves measurement of first trimester serum PAPP-A and a nuchal translucency (NT) ultrasound and second trimester serum quad markers (AFP, uE3, hCG and inhibin-A). The blood tests are collected as per the timing for SIPS and the NT measurement is done between 11 -13 +6 weeks (best at 12 -13 +3 weeks). Given that NT must be performed by a certified sonographer or sonologist, this test is available only in a select number of publicly funded centres 4 located around BC and use of the service is prioritized to serve those at higher chance of having a fetus with Down syndrome or trisomy 18 and women/individuals with multiple gestations. IPS test results are available within 10 days after the second blood test. If the NT measurement is high and results in a positive screen, counselling and further testing are offered (such as NIPS, chorionic villi sampling (CVS), or amniocentesis) prior to completing the second blood test.
# Counselling
Women/individuals should understand that it is their choice to undertake genetic screening. Information about prenatal screening for Down syndrome, trisomy 18, and open neural tube defects should be given to pregnant women/individuals at the first contact with a healthcare professional. This should occur in the first trimester, ideally prior to 10 weeks gestational age in order to ensure that the appropriate early tests are performed, if desired. Women/individuals who choose screening should ideally be sent for the blood test #2 (SIPS/IPS) or the Quad as early as possible within the allotted (14 -20 +6 weeks) timeframe.
Although blood test #2 can be collected and analyzed up to 20 +6 weeks, the ideal time is much earlier (best at 15 -16 weeks) to allow for earlier results and follow-up (NIPS or amnio) testing if necessary.
To assist women/individuals and their families with prenatal screening information, patient brochures in multiple languages, decision aids, and a video are available at bcprenatalscreening.ca.
# Specific counselling information should include:
The age-based a priori risk for each woman/individual for having a fetus with a chromosomal abnormality (Appendix 1)
The available tests for each woman/individual (Table 2)
The screening pathway for both screen positive and screen negative results
The decisions that need to be made at each point along the pathway and their consequences
The fact that screening does not provide a definitive diagnosis
The fact that women/individuals with a positive screen will have the option of further screening or testing such as funded NIPS, chorionic villi sampling (CVS), or amniocentesis (further testing options offered will be dependent on the woman's/individual's estimated chance of Down syndrome or trisomy 18 from the positive screen) 1. Introduction, cont'd A.
After a discussion of the pros and cons, all pregnant women/individuals regardless of age should be offered prenatal screening for Down syndrome, trisomy 18, and ONTDs. Ideally this discussion needs to occur prior to 10 weeks gestational age (GA) so that the best possible screen for the patient is available. After receiving the information, it is the woman's/individual's choice to proceed with or decline screening. Discussion of prenatal screening and the result should be documented on the BC antenatal record.
B. The prenatal screen offered will depend upon the woman's/individual's gestational age at their first prenatal visit, their previous pregnancy history, maternal age at the time of delivery, and whether the pregnancy is a singleton or twin gestation. NT ultrasound assessment is available only to women/individuals at higher chance of having a fetus with Down syndrome or trisomy 18 8 and women/individuals with multiple gestations.
C. Women/individuals with an increased chance of having a fetus with a chromosomal abnormality 9 should be referred early in their pregnancy to Medical Genetics in Vancouver or Victoria for genetic counselling regarding their screening and diagnostic options.
# E.
For women/individuals who choose to have (private-pay) NIPS as a first tier screen, IPS / SIPS is not indicated and should not be offered. An NT ultrasound scan should not be done if the woman/ individual is having NIPS, given the limited utility of NT measurement in pregnancies with a negative NIPS result and limited NT resources.
# F.
CVS and amniocentesis for fetal karyotyping will not be offered without prior screening except for women/individuals 40 years or older at expected date of delivery, women/individuals at increased chance of having a fetus with a chromosomal abnormality, 11 and women/individuals with multiple gestations who are ≥ 35 years old at expected date of delivery.
G. For women/individuals of any age found to have an NT measurement of 3.0 mm or greater, a calculation will be made based on NT only (or NT and PAPP-A if available). If the result is 1/300 or greater, a report will be issued without waiting for SIPS part 2 (blood test #2). The woman/individual should then be offered further testing: either funded NIPS or CVS / amnio. If the screen result is less than 1/300 based on NT alone (or NT and PAPP-A), no report will be generated, and the woman/individual will continue with serum screening (blood test #2) and the full IPS risk result will be reported 10 days after the collection of blood test #2.
H. The finding of an NT measurement ≥ 3.5 mm increases the chance of congenital heart defects, genetic syndromes, and chromosomal abnormalities other than the common aneuploidies.
A referral to Medical Genetics in Vancouver or Victoria is recommended.
I.
If a screen result is positive for Down syndrome and the screen was calculated based on last menstrual period (LMP), gestational age should be confirmed by ultrasound as soon as possible (see points J and K).
# J.
Although dating ultrasounds in the first trimester are not required for screening, ultrasound is the preferred method for calculating gestational age, as opposed to using LMP. If a first trimester ultrasound is done, the calculated gestational age from the scan should be provided to the Prenatal Biochemistry Laboratory at C&W (by attaching the scan report if available to the lab serum requisition or by faxing the scan report to 604-875-3008) to ensure most accurate screen results.
If an NT ultrasound is done, the calculated gestational age from this scan will be used.
# K.
For any screen calculated based on LMP, if dating by second trimester ultrasound differs by eight days or more from original dates, fax the ultrasound report to the Prenatal Biochemistry Laboratory at C&W for recalculation of chance (fax 604-875-3008). The only exception would be when a screen result is positive for trisomy 18 and dating by LMP and second trimester ultrasound differ. In these cases, the screen will not be recalculated (because trisomy 18 is frequently associated with intrauterine growth restriction).
# L.
If the SIPS / IPS / Quad prenatal screen result is positive for Down syndrome (assuming gestational dating is confirmed) or trisomy 18, women/individuals should be counselled by their health care provider and offered further testing. All women/individuals with a positive screen for trisomy 18 should be offered funded NIPS or amniocentesis. For women/individuals with a positive screen for Down syndrome and a result between 1:900 and 1:301, only funded NIPS should be offered.
For women/individuals with a positive screen for Down syndrome and a result equal or greater than 1:300, the option of funded NIPS or amniocentesis should be offered.
NIPS is a blood test which analyzes cell free fetal DNA circulating in maternal blood and tests for Down syndrome, trisomy 18, trisomy 13, and sex aneuploidy. The detection rate for Down syndrome is approximately 98% with less than 0.1% false positives; the detection rate for trisomy 18 is around 85% with less than a 0.1% false positive rate. For more information on NIPS, how it compares to amniocentesis, and how to access testing, go to www.bcprenatalscreening.ca/NIPT.
M. Women/individuals with a positive NIPS result should be referred to Medical Genetics in Vancouver or Victoria for counselling and diagnostic testing. The positive predictive value of a positive NIPS result varies depending on the patient's prior chance of a trisomy. Amniocentesis is recommended for diagnostic confirmation of the positive NIPS result prior to any irrevocable obstetrical decision.
Women/individuals with a positive IPS / SIPS / Quad screen result who then go on to have a negative NIPS result would no longer qualify for amniocentesis. The woman/individual should be reassured, as the negative predictive value of NIPS is very high. Refer to www.bcprenatalscreening.ca for more details including an algorithm for obstetrical management.
O. If the prenatal screen result is positive for an open neural tube defect, and dating is confirmed, a detailed ultrasound should be immediately done, even if less than 19 weeks gestation. Management of the pregnancy will be dependent on the results of the detailed ultrasound. See Appendix 4 for follow-up of elevated MSAFP.
# P.
A detailed second trimester ultrasound (18 -20 weeks) to assess fetal anatomy and growth should be offered to all pregnant women/individuals. An 18 -20 week ultrasound without soft markers or anomalies is capable of reducing the estimated chance of Down syndrome by approximately 50% (Smith-Bindman, 2007).
Q. Soft markers or anomalies on the 18 -20 week ultrasound increase the chance of aneuploidy and should be interpreted in conjunction with the prenatal screening (SIPS, IPS, or Quad) result. See Appendix 5 for detailed soft marker information.
R. Women/individuals who are found on cytogenetic analysis of amniocytes or chorionic villi to carry a fetus with a chromosomal abnormality may be referred to the Vancouver or Victoria Medical Genetics departments for counselling.
# BC Prenatal Genetic Screening Program Website
The 12 Performance of screening tests applies to singleton pregnancies. 13 The detection rates listed are based on the small cohort of Down syndrome pregnancies in BC.
SIPS, IPS, and Quad are screening tests so may not have 100% detection rate. 14 Higher false positive rate of IPS reflects that this test is done in women/individuals who are at a higher a priori risk. 15 May be higher if ultrasound abnormalities present.
Prenatal Genetic Diagnostic Testing (CVS and Amniocentesis) Chorionic Villus Sampling (CVS) 16 Amniocentesis 5. All patients with MSAFP that is not explained by a fetal abnormality should be considered at increased chance of adverse obstetrical outcome and followed as per following algorithm:
# Soft Markers Identified on Detailed Ultrasound
Several markers identified on second-trimester ultrasound examination are associated with increased chance of Down syndrome. The markers are not equally suggestive of Down syndrome. Based on the presence or absence of these markers, positive or negative likelihood ratios can be applied to the calculation of chance of Down syndrome from SIPS / IPS / Quad or maternal age allowing modification of a patient's chance 10 . Some markers are also indicative of increased chance of condition(s) other than Down syndrome.
Markers that significantly increase the chance of Down syndrome include: Markers that increase the chance of condition(s) other than Down syndrome include:
Consider starting ASA 81 mg qhs if patient is less than 20 weeks GA;
Supplement with Calcium 1g/day if daily intake is < 600mg/day.
Offer ultrasound at 28 -30 weeks to assess fetal growth and amniotic fluid volume. If abnormality detected, recommend consultation with Obstetrician or Maternal Fetal Medicine specialist.
Consider starting ASA 81 mg qhs if patient is less than 20 weeks GA;
Supplement with Calcium 1g/day if daily intake is < 600mg/day.
Recommend consultation with Obstetrician or Maternal Fetal Medicine specialist to establish a fetal surveillance plan which may include ultrasound monitoring and pre-eclampsia blood work every 2 -4 weeks.
# Appendix 5
If NTh is between 6 -7mm and cardiac views are reported as not well seen, in addition to recalculation of the chance of Down syndrome using the Trisomy21 calculator, a prompt reassessment of the cardiac views is needed. For patients from VCH, NHA, IHA, this can be facilitated through referral to Medical Genetics at BCWH; for patients from FHA, referral to the Jim Pattison Maternal Fetal Medicine Service is recommended; for VIHA patients, referral to Medical Genetics at Victoria General Hospital is recommended.
If NTh is 7mm or greater, referral to Medical Genetics (Vancouver or Victoria) is recommended.
# If ultrasound detects echogenic bowel:
If associated dilated bowel loops, referral to the Fetal Diagnosis Service (FDS) is recommended.
# If isolated echogenic bowel as bright as bone:
Chance of an intrauterine infection is increased. Recommend serology IgM and IgG for CMV, Toxoplasmosis and Parvovirus.
Chance of Down syndrome is increased. If patient had negative NIPS, chance of Down syndrome remains low. If patient had SIPS/IPS/Quad or no screen, the chance of Down syndrome should be recalculated using the Trisomy21 calculator (www.perinatalservicesbc.ca/healthprofessionals/professional-resources/screening/ prenatal-genetic/trisomy-21-risk-calculator). Medical Genetics can be consulted for help with calculation as needed. If revised chance of Down syndrome is greater than 1 in 300, patient qualifies for amniocentesis or funded NIPS. If patient chooses funded NIPS, contact medical genetics for NIPS code.
Chance of cystic fibrosis is increased for Caucasian couples. Offer CF carrier screening on patient and partner (requisition available at www.genebc.ca). For midwifery patients, this can be facilitated through referral to Medical Genetics.
Risk of developing IUGR in third trimester is increased. A follow up ultrasound around 30 -32 weeks gestation is recommended.
- If ultrasound detects isolated pyelectasis, abnormal femur/foot ratio (≤0.9) or echogenic intracardiac focus (EICF), and the Down syndrome screen (SIPS /IPS /Quad or NIPS) showed a negative screen (low chance), no further prenatal testing is recommended. If no screening has been done and patient is less than 21 weeks and 6 days gestation, Quad screening should be offered. For patients with an ultrasound finding of pyelectasis, a postnatal renal ultrasound between 5-30 days of age is recommended.
- If Choroid plexus cyst (CPC) is detected, referral to Medical Genetics is recommended only if CPC is seen in combination with structural abnormalities or growth restriction. No further testing is indicated if CPC is identified in isolation and the patient's SIPS /IPS /Quad or NIPS is screen negative for trisomy 18 (for SIPS/ IPS/Quad, risk only appears on report when screen positive).
If no screening has been done and patient is less than 20 weeks and 6 days gestation, Quad screening should be offered. | While every attempt has been made to ensure that the information contained herein is clinically accurate and current, Perinatal Services BC and the BC Prenatal Screening Program acknowledge that many issues remain controversial, and therefore may be subject to practice interpretation.#
Prenatal genetic screening estimates the chance of Down syndrome, trisomy 18, and open neural tube defect. The results will assist in determining the need for further testing. The screening tests offered will vary according to the gestational age at the time of presentation, maternal age at the time of delivery, and whether the pregnancy is a singleton or twin gestation.
BC has adopted a serum-based approach to prenatal genetic screening, with nuchal translucency (NT) ultrasound added for women/individuals at higher chance of having a fetus with Down syndrome or trisomy 18 and women/individuals with twin pregnancies. Non-Invasive Prenatal Screening (NIPS) is now also an option for some higher risk women/individuals. This guideline refers to screening options that are available in the public health care system. In BC, Serum Integrated Prenatal Screen (SIPS) is available and should be offered to all pregnant women/individuals. The following women/individuals are eligible for NT ultrasound as a component of Integrated Prenatal Screen (IPS = SIPS in combination with NT):
a) Women/individuals ≥ 35 years old at expected date of delivery (EDD) 1 ;
b) Women/individuals with twin pregnancies; c) Women/individuals pregnant following in vitro fertilization with intracytoplasmic sperm injection (IVF with ICSI) without PGT-A.
Certified (Fetal Medicine Foundation -UK) nuchal translucency ultrasound sites are established in all BC health authorities.
For women/individuals 40 years or older with a singleton pregnancy, or 35 years or older with a multiple gestation pregnancy, amniocentesis is also an option.
Provincially funded NIPS is available for the following eligible women/individuals: a) Women/individuals with a positive screen result from IPS, SIPS, or Quad; b) Women/individuals who have a documented history of a previous child or fetus with Down syndrome, trisomy 18, or trisomy 13; c) Women/individuals whose chance of Down syndrome is equal to or greater than 1/300 based on the finding of ultrasound marker(s) and results of SIPS / IPS / Quad.
The purpose of prenatal genetic screening is to identify pregnancies at increased chance of chromosome disorders or structural anomalies. Serum integrated prenatal screen (SIPS), integrated prenatal screen (IPS), quad marker screen (Quad), NIPS, and a detailed second trimester ultrasound 2 are some of the options available for prenatal genetic screening. IPS involves measurement of first trimester serum PAPP-A and a nuchal translucency (NT) ultrasound and second trimester serum quad markers (AFP, uE3, hCG and inhibin-A). The blood tests are collected as per the timing for SIPS and the NT measurement is done between 11 -13 +6 weeks (best at 12 -13 +3 weeks). Given that NT must be performed by a certified sonographer or sonologist, this test is available only in a select number of publicly funded centres 4 located around BC and use of the service is prioritized to serve those at higher chance of having a fetus with Down syndrome or trisomy 18 and women/individuals with multiple gestations. IPS test results are available within 10 days after the second blood test. If the NT measurement is high and results in a positive screen, counselling and further testing are offered (such as NIPS, chorionic villi sampling (CVS), or amniocentesis) prior to completing the second blood test.
# Counselling
Women/individuals should understand that it is their choice to undertake genetic screening. Information about prenatal screening for Down syndrome, trisomy 18, and open neural tube defects should be given to pregnant women/individuals at the first contact with a healthcare professional. This should occur in the first trimester, ideally prior to 10 weeks gestational age in order to ensure that the appropriate early tests are performed, if desired. Women/individuals who choose screening should ideally be sent for the blood test #2 (SIPS/IPS) or the Quad as early as possible within the allotted (14 -20 +6 weeks) timeframe.
Although blood test #2 can be collected and analyzed up to 20 +6 weeks, the ideal time is much earlier (best at 15 -16 weeks) to allow for earlier results and follow-up (NIPS or amnio) testing if necessary.
To assist women/individuals and their families with prenatal screening information, patient brochures in multiple languages, decision aids, and a video are available at bcprenatalscreening.ca.
# Specific counselling information should include:
⦁
The age-based a priori risk for each woman/individual for having a fetus with a chromosomal abnormality (Appendix 1)
# ⦁
The available tests for each woman/individual (Table 2)
⦁
The screening pathway for both screen positive and screen negative results
# ⦁
The decisions that need to be made at each point along the pathway and their consequences
# ⦁
The fact that screening does not provide a definitive diagnosis
⦁
The fact that women/individuals with a positive screen will have the option of further screening or testing such as funded NIPS, chorionic villi sampling (CVS), or amniocentesis (further testing options offered will be dependent on the woman's/individual's estimated chance of Down syndrome or trisomy 18 from the positive screen) 1. Introduction, cont'd A.
After a discussion of the pros and cons, all pregnant women/individuals regardless of age should be offered prenatal screening for Down syndrome, trisomy 18, and ONTDs. Ideally this discussion needs to occur prior to 10 weeks gestational age (GA) so that the best possible screen for the patient is available. After receiving the information, it is the woman's/individual's choice to proceed with or decline screening. Discussion of prenatal screening and the result should be documented on the BC antenatal record.
B. The prenatal screen offered will depend upon the woman's/individual's gestational age at their first prenatal visit, their previous pregnancy history, maternal age at the time of delivery, and whether the pregnancy is a singleton or twin gestation. NT ultrasound assessment is available only to women/individuals at higher chance of having a fetus with Down syndrome or trisomy 18 8 and women/individuals with multiple gestations.
C. Women/individuals with an increased chance of having a fetus with a chromosomal abnormality 9 should be referred early in their pregnancy to Medical Genetics in Vancouver or Victoria for genetic counselling regarding their screening and diagnostic options.
# E.
For women/individuals who choose to have (private-pay) NIPS as a first tier screen, IPS / SIPS is not indicated and should not be offered. An NT ultrasound scan should not be done if the woman/ individual is having NIPS, given the limited utility of NT measurement in pregnancies with a negative NIPS result and limited NT resources.
# F.
CVS and amniocentesis for fetal karyotyping will not be offered without prior screening except for women/individuals 40 years or older at expected date of delivery, women/individuals at increased chance of having a fetus with a chromosomal abnormality, 11 and women/individuals with multiple gestations who are ≥ 35 years old at expected date of delivery.
G. For women/individuals of any age found to have an NT measurement of 3.0 mm or greater, a calculation will be made based on NT only (or NT and PAPP-A if available). If the result is 1/300 or greater, a report will be issued without waiting for SIPS part 2 (blood test #2). The woman/individual should then be offered further testing: either funded NIPS or CVS / amnio. If the screen result is less than 1/300 based on NT alone (or NT and PAPP-A), no report will be generated, and the woman/individual will continue with serum screening (blood test #2) and the full IPS risk result will be reported 10 days after the collection of blood test #2.
H. The finding of an NT measurement ≥ 3.5 mm increases the chance of congenital heart defects, genetic syndromes, and chromosomal abnormalities other than the common aneuploidies.
A referral to Medical Genetics in Vancouver or Victoria is recommended.
I.
If a screen result is positive for Down syndrome and the screen was calculated based on last menstrual period (LMP), gestational age should be confirmed by ultrasound as soon as possible (see points J and K).
# J.
Although dating ultrasounds in the first trimester are not required for screening, ultrasound is the preferred method for calculating gestational age, as opposed to using LMP. If a first trimester ultrasound is done, the calculated gestational age from the scan should be provided to the Prenatal Biochemistry Laboratory at C&W (by attaching the scan report if available to the lab serum requisition or by faxing the scan report to 604-875-3008) to ensure most accurate screen results.
If an NT ultrasound is done, the calculated gestational age from this scan will be used.
# K.
For any screen calculated based on LMP, if dating by second trimester ultrasound differs by eight days or more from original dates, fax the ultrasound report to the Prenatal Biochemistry Laboratory at C&W for recalculation of chance (fax 604-875-3008). The only exception would be when a screen result is positive for trisomy 18 and dating by LMP and second trimester ultrasound differ. In these cases, the screen will not be recalculated (because trisomy 18 is frequently associated with intrauterine growth restriction).
# L.
If the SIPS / IPS / Quad prenatal screen result is positive for Down syndrome (assuming gestational dating is confirmed) or trisomy 18, women/individuals should be counselled by their health care provider and offered further testing. All women/individuals with a positive screen for trisomy 18 should be offered funded NIPS or amniocentesis. For women/individuals with a positive screen for Down syndrome and a result between 1:900 and 1:301, only funded NIPS should be offered.
For women/individuals with a positive screen for Down syndrome and a result equal or greater than 1:300, the option of funded NIPS or amniocentesis should be offered.
NIPS is a blood test which analyzes cell free fetal DNA circulating in maternal blood and tests for Down syndrome, trisomy 18, trisomy 13, and sex aneuploidy. The detection rate for Down syndrome is approximately 98% with less than 0.1% false positives; the detection rate for trisomy 18 is around 85% with less than a 0.1% false positive rate. For more information on NIPS, how it compares to amniocentesis, and how to access testing, go to www.bcprenatalscreening.ca/NIPT.
M. Women/individuals with a positive NIPS result should be referred to Medical Genetics in Vancouver or Victoria for counselling and diagnostic testing. The positive predictive value of a positive NIPS result varies depending on the patient's prior chance of a trisomy. Amniocentesis is recommended for diagnostic confirmation of the positive NIPS result prior to any irrevocable obstetrical decision.
Women/individuals with a positive IPS / SIPS / Quad screen result who then go on to have a negative NIPS result would no longer qualify for amniocentesis. The woman/individual should be reassured, as the negative predictive value of NIPS is very high. Refer to www.bcprenatalscreening.ca for more details including an algorithm for obstetrical management.
O. If the prenatal screen result is positive for an open neural tube defect, and dating is confirmed, a detailed ultrasound should be immediately done, even if less than 19 weeks gestation. Management of the pregnancy will be dependent on the results of the detailed ultrasound. See Appendix 4 for follow-up of elevated MSAFP.
# P.
A detailed second trimester ultrasound (18 -20 weeks) to assess fetal anatomy and growth should be offered to all pregnant women/individuals. An 18 -20 week ultrasound without soft markers or anomalies is capable of reducing the estimated chance of Down syndrome by approximately 50% (Smith-Bindman, 2007).
Q. Soft markers or anomalies on the 18 -20 week ultrasound increase the chance of aneuploidy and should be interpreted in conjunction with the prenatal screening (SIPS, IPS, or Quad) result. See Appendix 5 for detailed soft marker information.
R. Women/individuals who are found on cytogenetic analysis of amniocytes or chorionic villi to carry a fetus with a chromosomal abnormality may be referred to the Vancouver or Victoria Medical Genetics departments for counselling.
# BC Prenatal Genetic Screening Program Website
The 12 Performance of screening tests applies to singleton pregnancies. 13 The detection rates listed are based on the small cohort of Down syndrome pregnancies in BC.
SIPS, IPS, and Quad are screening tests so may not have 100% detection rate. 14 Higher false positive rate of IPS reflects that this test is done in women/individuals who are at a higher a priori risk. 15 May be higher if ultrasound abnormalities present.
Prenatal Genetic Diagnostic Testing (CVS and Amniocentesis) Chorionic Villus Sampling (CVS) 16 Amniocentesis 5. All patients with MSAFP that is not explained by a fetal abnormality should be considered at increased chance of adverse obstetrical outcome and followed as per following algorithm:
# Soft Markers Identified on Detailed Ultrasound
Several markers identified on second-trimester ultrasound examination are associated with increased chance of Down syndrome. The markers are not equally suggestive of Down syndrome. Based on the presence or absence of these markers, positive or negative likelihood ratios can be applied to the calculation of chance of Down syndrome from SIPS / IPS / Quad or maternal age allowing modification of a patient's chance 10 . Some markers are also indicative of increased chance of condition(s) other than Down syndrome.
Markers that significantly increase the chance of Down syndrome include: Markers that increase the chance of condition(s) other than Down syndrome include:
#
Consider starting ASA 81 mg qhs if patient is less than 20 weeks GA;
Supplement with Calcium 1g/day if daily intake is < 600mg/day.
Offer ultrasound at 28 -30 weeks to assess fetal growth and amniotic fluid volume. If abnormality detected, recommend consultation with Obstetrician or Maternal Fetal Medicine specialist.
Consider starting ASA 81 mg qhs if patient is less than 20 weeks GA;
Supplement with Calcium 1g/day if daily intake is < 600mg/day.
Recommend consultation with Obstetrician or Maternal Fetal Medicine specialist to establish a fetal surveillance plan which may include ultrasound monitoring and pre-eclampsia blood work every 2 -4 weeks.
# Appendix 5
If NTh is between 6 -7mm and cardiac views are reported as not well seen, in addition to recalculation of the chance of Down syndrome using the Trisomy21 calculator, a prompt reassessment of the cardiac views is needed. For patients from VCH, NHA, IHA, this can be facilitated through referral to Medical Genetics at BCWH; for patients from FHA, referral to the Jim Pattison Maternal Fetal Medicine Service is recommended; for VIHA patients, referral to Medical Genetics at Victoria General Hospital is recommended.
If NTh is 7mm or greater, referral to Medical Genetics (Vancouver or Victoria) is recommended.
# If ultrasound detects echogenic bowel:
If associated dilated bowel loops, referral to the Fetal Diagnosis Service (FDS) is recommended.
# If isolated echogenic bowel as bright as bone:
Chance of an intrauterine infection is increased. Recommend serology IgM and IgG for CMV, Toxoplasmosis and Parvovirus.
Chance of Down syndrome is increased. If patient had negative NIPS, chance of Down syndrome remains low. If patient had SIPS/IPS/Quad or no screen, the chance of Down syndrome should be recalculated using the Trisomy21 calculator (www.perinatalservicesbc.ca/healthprofessionals/professional-resources/screening/ prenatal-genetic/trisomy-21-risk-calculator). Medical Genetics can be consulted for help with calculation as needed. If revised chance of Down syndrome is greater than 1 in 300, patient qualifies for amniocentesis or funded NIPS. If patient chooses funded NIPS, contact medical genetics for NIPS code.
Chance of cystic fibrosis is increased for Caucasian couples. Offer CF carrier screening on patient and partner (requisition available at www.genebc.ca). For midwifery patients, this can be facilitated through referral to Medical Genetics.
Risk of developing IUGR in third trimester is increased. A follow up ultrasound around 30 -32 weeks gestation is recommended.
5. If ultrasound detects isolated pyelectasis, abnormal femur/foot ratio (≤0.9) or echogenic intracardiac focus (EICF), and the Down syndrome screen (SIPS /IPS /Quad or NIPS) showed a negative screen (low chance), no further prenatal testing is recommended. If no screening has been done and patient is less than 21 weeks and 6 days gestation, Quad screening should be offered. For patients with an ultrasound finding of pyelectasis, a postnatal renal ultrasound between 5-30 days of age is recommended.
6. If Choroid plexus cyst (CPC) is detected, referral to Medical Genetics is recommended only if CPC is seen in combination with structural abnormalities or growth restriction. No further testing is indicated if CPC is identified in isolation and the patient's SIPS /IPS /Quad or NIPS is screen negative for trisomy 18 (for SIPS/ IPS/Quad, risk only appears on report when screen positive).
If no screening has been done and patient is less than 20 weeks and 6 days gestation, Quad screening should be offered. | None | None |
20dc71cfc784d49612c669c302e35b8a5f73030a | cma | None | This guideline provides recommendations for the investigation, evaluation, and management of adults at risk of or with known chronic kidney disease (CKD). These recommendations and treatment targets may not be appropriate in all cases because many patients with CKD are complex due to older age and comorbidities. Communication between primary care providers and specialists is strongly encouraged.- Identify high-risk patient groups for evaluation of CKD: diabetes, hypertension, cardiovascular disease, family history, high risk ethnicity (Indigenous peoples, Pacific Islanders, African, Asian, and South Asian descent), history of acute kidney injury (AKI). - Screen high-risk patients using eGFR and uACR. Confirm abnormal test results with a repeat measurement and obtain urinalysis. - Determine likely cause of kidney disease where possible. The cause of CKD has important implications for the risk of end stage renal disease (ESRD) and other complications. - The three dimensions of Cause, eGFR and Albuminuria (CGA) are all important in developing a management plan. - Prompt advice from local internists, local nephrologists or the RACE Line is available to assist in determining the need for and timing of referral.#
Background CKD is associated with other common chronic diseases such as diabetes, hypertension, and cardiovascular disease (CVD) 1 and an estimated 1:10 British Columbians has some form of significant kidney disease. 2 CKD markedly increases the risk of: cardiovascular disease, adverse drug reactions, acute kidney injury and prolonged hospital admissions. Patients with CKD have a risk of progression to end stage renal disease (ESRD), often requiring dialysis or kidney transplantation. 6,9, Most patients with chronic kidney disease die from other comorbidities before they progress to kidney failure. The outcome of many patients who go on to dialysis remains poor with 10 percent annual mortality; the overall 5 year survival rate is worse than that of most cancers. 3 Evidence clearly indicates that control of hypertension and proteinuria can prevent or postpone kidney function decline. 4 -12 This underscores the importance of early detection, evaluation and management of individuals with kidney disease.
# Definition
CKD is defined as an abnormality of kidney structure or function that is present for greater than 3 months. 13 The two key parameters for classification are estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (uACR). eGFR is the best marker for kidney function and is calculated from creatinine. All labs in British Columbia (BC) automatically report eGFR when creatinine is ordered. Note: the recommended equations for eGFR may change over time and are estimates only. Refer to page 3 for more information.
For diagnostic purposes, other evidence of kidney damage includes: urine abnormalities such as hematuria; structural problems on imaging studies e.g., polycystic kidneys on ultrasound; histological findings on kidney biopsy.
# Etiology
The two most common causes of CKD are hypertension and diabetes and they often co-exist. 13 Even if the cause seems obvious (e.g., diabetes), the possibility of a serious underlying primary renal disorder (e.g., glomerulonephritis) must be considered in patients with:
- Abnormal urinalysis, (e.g., proteinuria, hematuria, cellular casts). Note: hyaline casts are normal.
- Rapid sustained decline in kidney function (change in eGFR > 10-15%/year) despite remedy of reversible precipitants (e.g., volume contraction, febrile illness, medications). - Constitutional symptoms suggesting systemic illness.
- Sudden or severe onset of symptoms (e.g., edema unrelated to heart or liver disease).
# Risk Factors and Screening
The following populations are at increased risk for CKD and should be screened:
- Diabetes - Hypertension - Cardiovascular disease (CVD)
- Prior acute kidney injury (AKI)
- Family history of kidney disease (e.g., parent or sibling)
- Specific high-risk ethnic groups: Indigenous peoples, Pacific Islanders, African Asian, and South Asian descent Note: Older age alone is not a reason for screening.
At-risk populations should be screened every 1-2 years depending upon clinical circumstances (e.g., annually for individuals with diabetes) using:
- eGFR - urinalysis (dipstick)- - urine ACR - review of risk factors *Note: urine microscopy is not needed for screening.
# Diagnosis
CKD cannot be diagnosed with one isolated abnormal measurement of eGFR or urine ACR.
# Estimated GFR (eGFR) Values and Interpretation
- Values of > 60 mL/min per 1.73m 2 without other markers of kidney disease (albuminuria, hematuria, structural abnormalities) do not indicate CKD. - Values of < 60 mL/min per 1.73m 2 which are persistent (present for ≥ 3 months) are diagnostic of CKD.
- A single isolated measurement < 60 mL/min does not satisfy diagnostic criteria for CKD, but could reflect reduced kidney function and requires confirmatory testing. - In patients with a new unexpected finding of reduced eGFR, the test should be repeated to establish stability or rapid deterioration.
# Caveats of eGFR
- eGFR is an estimated value that assumes a steady state of creatinine generation. o eGFR may be unreliable in extremes of muscle mass or with certain diets (e.g., very high or very low protein). Some medications can interfere with the excretion of creatinine (e.g., trimethoprim, fenofibrate). 14,15 o In hospitalized patients or patients with AKI the fluctuations in creatinine make eGFR unreliable. In these circumstances, creatinine values should be used to guide management. o As a general rule, the eGFR can be used as a guide to outpatient drug dosing, even if the references use creatinine clearance (eCrCl). More caution is required for drugs with significant potential toxicity or a narrow therapeutic window (e.g., chemotherapy).
# Urinalysis and ACR Values and Interpretation
- Significant abnormalities include persistent white blood cells or red blood cells in the absence of infection or instrumentation, and the presence of cellular casts. - Urine ACR (uACR) is the preferred method to screen for protein in the urine.
- uACR quantifies albuminuria in a range which is not detected by dipstick urinalysis. o The term microalbumin has historically been used. Recent guidelines and consensus from laboratories have recommended abandoning this term and to quote the uACR value instead. 13 o uACR elevation (>3.0 mg/mmol) on serial testing is abnormal. o In patients without diabetes, no specific treatment is recommended for isolated uACR values between 3 and 30 mg/mmol. These individuals remain at risk of CKD progression and cardiovascular disease, therefore surveillance is warranted. o uACR may be unreliable in some patients due to acute illness, vigorous exercise, poorly controlled hypertension or poorly controlled blood glucose. Repeat testing should be done when in doubt.
- Urine test abnormalities, even with persistent eGFR values ≥ 60 mL /min per 1.73m 2 suggest kidney disease.
- 24-hour urine collections are not necessary in most cases.
- For equivalence of dipstick protein measurements, uACR and protein/creatinine ratios (PCR), see Appendix.
# Renal Imaging
- Renal ultrasound should be undertaken to assess structural abnormalities and aid in diagnosis. Renal ultrasound should be performed in the following cases: o Obstructive urinary symptoms o Unexplained microscopic or macroscopic hematuria o Unclear etiology of CKD, especially in young patients o Patients with suspicion of benign prostatic hypertrophy (BPH) o Family history of structural renal disease (e.g., cystic kidney disease)
Staging of CKD Risk staging of kidney disease is important for care planning and patient management. Risk is determined based on Cause, eGFR, and uACR, or CGA. Refer to Figure 1 (page 1). Further details on risk determination are available on the Kidney Disease Improving Global Outcomes (KDIGO) CKD management guideline at kdigo.org/home/guidelines. 13
# Risk Calculators
The Kidney Failure Risk Equation (KFRE) is an equation designed to estimate probability of requiring dialysis within 2 or 5 years. The equation is derived from 4 variables and can be calculated using QxMD: qxmd.com. Risks of > 10 -20% indicate high risk (analogous to Framingham risk scores). The KFRE is a useful tool for prognostication, however its role has yet to be established in routine clinical practice.
# Referral Recommendations
Indications for referral to specialist/nephrologist 22 † Very high risk kidney disease (urgent communication needed)
- Presence of active urine sediments (red blood cell casts or cellular casts ± protein), especially when associated with reduced eGFR. - AKI in absence of readily reversible cause (e.g., volume depletion, NSAIDs) - Abrupt sustained fall in eGFR in a patient with known CKD.
# - eGFR < 15 - Nephrotic syndrome
# High risk kidney disease (patient to be seen within a timely fashion)
- GFR 30 mg/mmol (regardless of eGFR) e.g., in absence of diabetes or HTN - Progressive CKD, with eGFR decline > 5 ml/min/year † - Diabetes and evidence of CKD with eGFR 30
Low to moderate risk kidney disease (patients that could be seen within a longer time interval, e.g., within 6 mos)
- Persistent abnormalities of serum potassium.
- Hereditary kidney disease.
- CKD, eGFR 30-45 - CKD and difficult to treat hypertension † Time to first consultation will vary based on individual circumstances. Discussion with your local nephrologist as to timing of referral for specific individuals is encouraged if in doubt.
# Recommended history and tests to include in referral package:
- A urology consult is more appropriate than nephrology in the following scenarios:
- Renal mass, enlarged prostate, obstruction, and large symptomatic or obstructing kidney stone
# Management
Refer to Figure 1 (page 1) for recommended follow-up intervals.
# Customization of management plan
- Many patients with CKD have multiple comorbidities. In some situations, universal fixed targets may not be applicable and may even be harmful. Clinical judgment and individualized targets are recommended. - Communication with specialists is encouraged if appropriateness of any of the targets is in question.
# Kidney function measurements
- Refer to Figure 1 for frequency of eGFR and uACR measurements in specific risk categories.
- Repeat eGFR sooner (within 10 days) after any change in medications (e.g., ACEi, ARB, or diuretics, SGLT2i), medical intervention, or hospitalization. - Check creatinine and potassium prior to starting ACEi, ARB, SGLT2i, MRA within 7-14 days of starting, and within 7-14 days after a dose increase. - Creatinine rise >20% after dose increase should be followed by further measurements within 7-14 days.
Blood pressure
# Vaccinations
- Influenza vaccine annually.
- Pneumococcal and Hepatitis B vaccines recommended for adults at medically high risk.
- Refer to immunizebc.ca for other recommended vaccines by age and risk profile
Patients with very advanced CKD are less likely to seroconvert after hepatitis B immunization. Confirmation of immunity is required after vaccination, which may need to be repeated (after consultation with specialist)
# Lifestyle and Self-Management
Support patient self management with the means available in your community. Patients with CKD benefit from multidisciplinary renal teams who can support patients to make beneficial changes in diet, smoking and physical activity, and to understand medications, and the uncertainty and emotional distress that can be seen in those with chronic conditions. Denial, often associated with grief, is common in patients with chronic disease affecting a vital organ.
Encourage patients with CKD to consider advance care planning and their goals for future care, including for the end of life. o Provincial advance care planning resources are available at gov.bc.ca/advancecare o BC Guidelines on palliative care are available at bcguidelines.ca/submenu_palliative.html o BC Renal Agency information about end of life care is available at bcrenalagency.ca/healthcare-professionals/end-liferesources
# Complex Scenarios
The following common complex scenarios benefit from discussion with a specialist:
- Whether to change the approach to a patient when eGFR goes down to 30 - Pathways -PathwaysBC.ca An online resource that allows GPs and nurse practitioners and their office staff to quickly access current and accurate referral information, including wait times and areas of expertise, for specialists and specialty clinics. In addition, Pathways makes available hundreds of patient and provider resources that are categorized and searchable.
- HealthLink BC: healthlinkbc.ca HealthLink BC provides reliable non-emergency health information and advice to patients in BC. Information and advice on managing chronic kidney disease in several languages is available by telephone, website, a mobile app and a collection of print resources. Patients can speak to a health services navigator, registered dietitian, registered nurse, qualified exercise professional, or a pharmacist.
Patients may call 8-1-1 toll-free in B.C., or for the deaf and the hard of hearing, call 7-1-1.
- Health Data Coalition: hdcbc.ca An online, physician-led data sharing platform that can assist you in assessing your own practice in areas such as chronic disease management or medication prescribing. HDC data can graphically represent patients in your practice with chronic kidney disease in a clear and simple fashion, allowing for reflection on practice and tracking improvements over time.
The principles of the Guidelines and Protocols Advisory Committee are to:
- encourage appropriate responses to common medical situations - recommend actions that are sufficient and efficient, neither excessive nor deficient - permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: [email protected] Website: www.BCGuidelines.ca | This guideline provides recommendations for the investigation, evaluation, and management of adults at risk of or with known chronic kidney disease (CKD). These recommendations and treatment targets may not be appropriate in all cases because many patients with CKD are complex due to older age and comorbidities. Communication between primary care providers and specialists is strongly encouraged.• Identify high-risk patient groups for evaluation of CKD: diabetes, hypertension, cardiovascular disease, family history, high risk ethnicity (Indigenous peoples, Pacific Islanders, African, Asian, and South Asian descent), history of acute kidney injury (AKI). • Screen high-risk patients using eGFR and uACR. Confirm abnormal test results with a repeat measurement and obtain urinalysis. • Determine likely cause of kidney disease where possible. The cause of CKD has important implications for the risk of end stage renal disease (ESRD) and other complications. • The three dimensions of Cause, eGFR and Albuminuria (CGA) are all important in developing a management plan. • Prompt advice from local internists, local nephrologists or the RACE Line is available to assist in determining the need for and timing of referral.#
Background CKD is associated with other common chronic diseases such as diabetes, hypertension, and cardiovascular disease (CVD) 1 and an estimated 1:10 British Columbians has some form of significant kidney disease. 2 CKD markedly increases the risk of: cardiovascular disease, adverse drug reactions, acute kidney injury and prolonged hospital admissions. [4][5][6][7][8][9][10][13][14] Patients with CKD have a risk of progression to end stage renal disease (ESRD), often requiring dialysis or kidney transplantation. 6,9,[11][12][13][14] Most patients with chronic kidney disease die from other comorbidities before they progress to kidney failure. The outcome of many patients who go on to dialysis remains poor with 10 percent annual mortality; the overall 5 year survival rate is worse than that of most cancers. 3 Evidence clearly indicates that control of hypertension and proteinuria can prevent or postpone kidney function decline. 4 -12 This underscores the importance of early detection, evaluation and management of individuals with kidney disease.
# Definition
CKD is defined as an abnormality of kidney structure or function that is present for greater than 3 months. 13 The two key parameters for classification are estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (uACR). eGFR is the best marker for kidney function and is calculated from creatinine. All labs in British Columbia (BC) automatically report eGFR when creatinine is ordered. Note: the recommended equations for eGFR may change over time and are estimates only. Refer to page 3 for more information.
For diagnostic purposes, other evidence of kidney damage includes: urine abnormalities such as hematuria; structural problems on imaging studies e.g., polycystic kidneys on ultrasound; histological findings on kidney biopsy.
# Etiology
The two most common causes of CKD are hypertension and diabetes and they often co-exist. 13 Even if the cause seems obvious (e.g., diabetes), the possibility of a serious underlying primary renal disorder (e.g., glomerulonephritis) must be considered in patients with:
• Abnormal urinalysis, (e.g., proteinuria, hematuria, cellular casts). Note: hyaline casts are normal.
• Rapid sustained decline in kidney function (change in eGFR > 10-15%/year) despite remedy of reversible precipitants (e.g., volume contraction, febrile illness, medications). • Constitutional symptoms suggesting systemic illness.
• Sudden or severe onset of symptoms (e.g., edema unrelated to heart or liver disease).
# Risk Factors and Screening
The following populations are at increased risk for CKD and should be screened:
• Diabetes • Hypertension • Cardiovascular disease (CVD)
• Prior acute kidney injury (AKI)
• Family history of kidney disease (e.g., parent or sibling)
• Specific high-risk ethnic groups: Indigenous peoples, Pacific Islanders, African Asian, and South Asian descent Note: Older age alone is not a reason for screening.
At-risk populations should be screened every 1-2 years depending upon clinical circumstances (e.g., annually for individuals with diabetes) using:
• eGFR • urinalysis (dipstick)* • urine ACR • review of risk factors *Note: urine microscopy is not needed for screening.
# Diagnosis
CKD cannot be diagnosed with one isolated abnormal measurement of eGFR or urine ACR.
# Estimated GFR (eGFR) Values and Interpretation
• Values of > 60 mL/min per 1.73m 2 without other markers of kidney disease (albuminuria, hematuria, structural abnormalities) do not indicate CKD. • Values of < 60 mL/min per 1.73m 2 which are persistent (present for ≥ 3 months) are diagnostic of CKD.
• A single isolated measurement < 60 mL/min does not satisfy diagnostic criteria for CKD, but could reflect reduced kidney function and requires confirmatory testing. • In patients with a new unexpected finding of reduced eGFR, the test should be repeated to establish stability or rapid deterioration.
# Caveats of eGFR
o eGFR is an estimated value that assumes a steady state of creatinine generation. o eGFR may be unreliable in extremes of muscle mass or with certain diets (e.g., very high or very low protein). Some medications can interfere with the excretion of creatinine (e.g., trimethoprim, fenofibrate). 14,15 o In hospitalized patients or patients with AKI the fluctuations in creatinine make eGFR unreliable. In these circumstances, creatinine values should be used to guide management. o As a general rule, the eGFR can be used as a guide to outpatient drug dosing, even if the references use creatinine clearance (eCrCl). More caution is required for drugs with significant potential toxicity or a narrow therapeutic window (e.g., chemotherapy).
# Urinalysis and ACR Values and Interpretation
• Significant abnormalities include persistent white blood cells or red blood cells in the absence of infection or instrumentation, and the presence of cellular casts. • Urine ACR (uACR) is the preferred method to screen for protein in the urine.
o uACR quantifies albuminuria in a range which is not detected by dipstick urinalysis. o The term microalbumin has historically been used. Recent guidelines and consensus from laboratories have recommended abandoning this term and to quote the uACR value instead. 13 o uACR elevation (>3.0 mg/mmol) on serial testing is abnormal. o In patients without diabetes, no specific treatment is recommended for isolated uACR values between 3 and 30 mg/mmol. These individuals remain at risk of CKD progression and cardiovascular disease, therefore surveillance is warranted. o uACR may be unreliable in some patients due to acute illness, vigorous exercise, poorly controlled hypertension or poorly controlled blood glucose. Repeat testing should be done when in doubt.
• Urine test abnormalities, even with persistent eGFR values ≥ 60 mL /min per 1.73m 2 suggest kidney disease.
• 24-hour urine collections are not necessary in most cases.
• For equivalence of dipstick protein measurements, uACR and protein/creatinine ratios (PCR), see Appendix.
# Renal Imaging
• Renal ultrasound should be undertaken to assess structural abnormalities and aid in diagnosis. Renal ultrasound should be performed in the following cases: o Obstructive urinary symptoms o Unexplained microscopic or macroscopic hematuria o Unclear etiology of CKD, especially in young patients o Patients with suspicion of benign prostatic hypertrophy (BPH) o Family history of structural renal disease (e.g., cystic kidney disease)
Staging of CKD Risk staging of kidney disease is important for care planning and patient management. Risk is determined based on Cause, eGFR, and uACR, or CGA. Refer to Figure 1 (page 1). Further details on risk determination are available on the Kidney Disease Improving Global Outcomes (KDIGO) CKD management guideline at kdigo.org/home/guidelines. 13
# Risk Calculators
The Kidney Failure Risk Equation (KFRE) is an equation designed to estimate probability of requiring dialysis within 2 or 5 years. The equation is derived from 4 variables and can be calculated using QxMD: qxmd.com. Risks of > 10 -20% indicate high risk (analogous to Framingham risk scores). The KFRE is a useful tool for prognostication, however its role has yet to be established in routine clinical practice.
# Referral Recommendations
Indications for referral to specialist/nephrologist 22 † Very high risk kidney disease (urgent communication needed)
• Presence of active urine sediments (red blood cell casts or cellular casts ± protein), especially when associated with reduced eGFR. • AKI in absence of readily reversible cause (e.g., volume depletion, NSAIDs) • Abrupt sustained fall in eGFR in a patient with known CKD.
# • eGFR < 15 • Nephrotic syndrome
# High risk kidney disease (patient to be seen within a timely fashion)
• GFR < 30 † • Unexplained persistent uACR >30 mg/mmol (regardless of eGFR) e.g., in absence of diabetes or HTN • Progressive CKD, with eGFR decline > 5 ml/min/year † • Diabetes and evidence of CKD with eGFR <45, urine ACR >30
Low to moderate risk kidney disease (patients that could be seen within a longer time interval, e.g., within 6 mos)
• Persistent abnormalities of serum potassium.
• Hereditary kidney disease.
• CKD, eGFR 30-45 • CKD and difficult to treat hypertension † Time to first consultation will vary based on individual circumstances. Discussion with your local nephrologist as to timing of referral for specific individuals is encouraged if in doubt.
# Recommended history and tests to include in referral package:
• A urology consult is more appropriate than nephrology in the following scenarios:
• Renal mass, enlarged prostate, obstruction, and large symptomatic or obstructing kidney stone
# Management
Refer to Figure 1 (page 1) for recommended follow-up intervals.
# Customization of management plan
• Many patients with CKD have multiple comorbidities. In some situations, universal fixed targets may not be applicable and may even be harmful. Clinical judgment and individualized targets are recommended. • Communication with specialists is encouraged if appropriateness of any of the targets is in question.
# Kidney function measurements
• Refer to Figure 1 for frequency of eGFR and uACR measurements in specific risk categories.
• Repeat eGFR sooner (within 10 days) after any change in medications (e.g., ACEi, ARB, or diuretics, SGLT2i), medical intervention, or hospitalization. • Check creatinine and potassium prior to starting ACEi, ARB, SGLT2i, MRA within 7-14 days of starting, and within 7-14 days after a dose increase. • Creatinine rise >20% after dose increase should be followed by further measurements within 7-14 days.
Blood pressure
•
# Vaccinations
• Influenza vaccine annually.
• Pneumococcal and Hepatitis B vaccines recommended for adults at medically high risk.
• Refer to immunizebc.ca for other recommended vaccines by age and risk profile
Patients with very advanced CKD are less likely to seroconvert after hepatitis B immunization. Confirmation of immunity is required after vaccination, which may need to be repeated (after consultation with specialist)
# Lifestyle and Self-Management
Support patient self management with the means available in your community. Patients with CKD benefit from multidisciplinary renal teams who can support patients to make beneficial changes in diet, smoking and physical activity, and to understand medications, and the uncertainty and emotional distress that can be seen in those with chronic conditions. Denial, often associated with grief, is common in patients with chronic disease affecting a vital organ.
Encourage patients with CKD to consider advance care planning and their goals for future care, including for the end of life. o Provincial advance care planning resources are available at gov.bc.ca/advancecare o BC Guidelines on palliative care are available at bcguidelines.ca/submenu_palliative.html o BC Renal Agency information about end of life care is available at bcrenalagency.ca/healthcare-professionals/end-liferesources
# Complex Scenarios
The following common complex scenarios benefit from discussion with a specialist:
• Whether to change the approach to a patient when eGFR goes down to 30 • Pathways -PathwaysBC.ca An online resource that allows GPs and nurse practitioners and their office staff to quickly access current and accurate referral information, including wait times and areas of expertise, for specialists and specialty clinics. In addition, Pathways makes available hundreds of patient and provider resources that are categorized and searchable.
• HealthLink BC: healthlinkbc.ca HealthLink BC provides reliable non-emergency health information and advice to patients in BC. Information and advice on managing chronic kidney disease in several languages is available by telephone, website, a mobile app and a collection of print resources. Patients can speak to a health services navigator, registered dietitian, registered nurse, qualified exercise professional, or a pharmacist.
Patients may call 8-1-1 toll-free in B.C., or for the deaf and the hard of hearing, call 7-1-1.
• Health Data Coalition: hdcbc.ca An online, physician-led data sharing platform that can assist you in assessing your own practice in areas such as chronic disease management or medication prescribing. HDC data can graphically represent patients in your practice with chronic kidney disease in a clear and simple fashion, allowing for reflection on practice and tracking improvements over time.
#
The principles of the Guidelines and Protocols Advisory Committee are to:
• encourage appropriate responses to common medical situations • recommend actions that are sufficient and efficient, neither excessive nor deficient • permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: [email protected] Website: www.BCGuidelines.ca
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This guideline is based on scientific evidence current as of the effective date.
The guideline was developed by the Guidelines and Protocols Advisory Committee in collaboration and adopted by the Medical Services Commission.
For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook. | None | None |
80ad34824baaa5c8d7dbe84941879c2b6d054858 | cma | None | # Introduction
This Canadian Thoracic Society (CTS) document aims to provide guidance and relevant information for respiratory health care professionals on COVID-19 vaccination in Canada. Due to limited data, there are areas of uncertainty which have prompted the CTS, and several other national and international Specialty Societies, to provide advice on vaccination based on available evidence and expertise. We highlight this important information in this paper. A Frequently Asked Questions (FAQ) section of this document seeks to address some of the concerns that may arise in discussion with patients who are immunocompromised, treated with biologic therapy or long-term steroids, pre-or post-transplant, etc. We plan to update this guidance as new information becomes available and recommend periodically checking the Canadian Thoracic Society website (/) for updates.
It is important to note that even after vaccination other recommended public health measures, including frequent hand washing or use of alcohol-based hand sanitizers, wearing face masks, and physical distancing should continue to be observed; this is especially important in those with chronic medical conditions.
In Canada, there is a gap in the knowledge about the rate of vaccination in patients with respiratory diseases. However, it is clear from Canadian studies that address vaccine uptake that the vaccination rates for seasonal influenza and for pneumococcal infection are below the ideal level of 80%. 7 A recommendation or contact (visit) with a health care professional was identified in several studies 2,8,9 as an important predictor influencing an individual's decision to be vaccinated. The study by Bourbeau et al. 2 found that COPD patients in Quebec and Ontario who had regular contact with their physician had vaccination rates of 80% for seasonal influenza, as reported by their primary care doctors. In the Boerner et al. study, 8 participants mentioned a physician recommendation along with trust in their physicians as a significant factor in their vaccination decision.
Therefore, the role of physicians, respiratory health care professionals and educators as advocates for vaccination along with consistent messaging on COVID-19 vaccination will likely be effective in improving vaccination rates in this vulnerable population.
# Drugs and COVID-19 vaccines authorized or in progress by Health Canada as of February 2021
- List of authorized drugs, vaccines and expanded indications for COVID-19 - Pfizer-BioNTech COVID-19 vaccine: What you should know - Moderna COVID-19 vaccine: What you should know
# Summary of efficacy and safety of the Pfizer-BioNTech and Moderna vaccines approved by Health Canada:
The first 2 COVID-19 vaccines to receive Health Canada approval for use (Pfizer-BioNTech and Moderna) have shown over 80% efficacy for preventing symptomatic and severe disease. The duration of follow up has been limited to 2-4 months. It is not known how long the protection will last after 1 or both injections. New variants are already emerging, and it is too early to know if it will affect vaccine efficacy.
From the clinical trials, both vaccines are safe. Severe adverse events are rare and usually self-limited. However local and systemic side effects are in keeping with known side effects associated with vaccines and are usually self-limited. Long-term side effects are highly unlikely. Regarding anaphylaxis, Moderna has reported 2.5 cases per million (as of Jan 10, 2021: MMWR January 29, 2021/670 (4): 125-129) and Pfizer 11 cases per million (as of Dec 23, 2020: MMWR: January 15, 2021/ 70 (2): 46-51). The majority of cases involved patients with documented/known allergies or allergic reaction, and 1/3 to 1/2 had previous history of anaphylaxis.
# Recommendations on the use of COVID-19 vaccines in Canada
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization. NACI has provided independent expert advice regarding priority populations for early vaccinations.
# NACI recommendations for priority for early COVID-19 vaccination to the following populations:
- residents and staff of shared living settings who provide care for seniors - adults 70 years of age and older, with order of priority: 1. beginning with adults 80 years of age and older 2. decreasing the age limit by 5-year increments to age 70 years as supply becomes available - health care workers who have direct contact with patients, including:
- those who work in health care settings 2. personal support workers - adults in Indigenous communities As additional COVID-19 vaccine(s) and supplies become available, the following populations should be offered vaccinations:
- health care workers not included in the initial rollout - residents and staff of all other shared living settings, such as: o homeless shelters o correctional facilities o housing for migrant workers - essential workers who face additional risks to maintain services for the functioning of society
# Prioritization of Canadians with lung disease in the vaccination rollout
The COVID-19 Respiratory Roundtable led by the CTS issued a joint statement in January urging the federal, provincial and territorial governments to prioritize people living with lung disease who are at higher risk for more serious COVID-19 complications in the vaccination rollout. In February, NACI released recommendations on the prioritization of key populations for COVID-19 immunization which includes chronic lung disease as a risk factor for poor outcome. PDF document (People who are at risk of more severe disease or outcomes from COVID-19)
# Provincial and Territorial vaccination rollout plans
While NACI provided guidance on vaccination priorities, vaccination rollout plans are province-and territoryspecific. For the latest detailed vaccination rollout plans, visit this website and go to the vaccine page for your province or territory: #a3 NACI recommendations on the use of COVID-19 vaccines 10 (updated recommendations Jan 12, 2021)
# NACI recommendations are now worded as "should" (strong) or "may" (discretionary).
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach.
A complete vaccine series with a currently authorized COVID-19 vaccine should be offered to:
- Individuals in the authorized age group without contraindications to the vaccine. In the context of limited vaccine supply, initial doses of COVID-19 vaccine(s) should be prioritized for the key populations outlined in NACI's Guidance on the prioritization of key populations for COVID-19 immunization which now lists chronic lung disease as a risk factor for poor outcomes.
A discretionary recommendation may be offered for some population/individuals in some circumstances.
A complete vaccine series with a currently authorized COVID-19 vaccine may be offered to:
- Individuals in the authorized age group without contraindications to the vaccine who have had previously polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. In the context of limited vaccine supply, initial doses may be prioritized for those who have not had previously PCR-confirmed SARS-CoV-2 infection. Testing for previous SARS-CoV-2 infection is not needed prior to COVID-19 vaccination.
For some specific populations who were either excluded from, or were represented by small numbers of participants in clinical trials, NACI recommends that a complete vaccine series with a currently authorized COVID-19 vaccine may be offered, if a risk assessment deems that the benefits of vaccination outweigh the potential risks for the individual (e.g., where the risk of severe outcomes of COVID-19 and/or risk of exposure to SARS-CoV-2 is high) or for the fetus/infant (in the case of pregnancy/breastfeeding), and if informed consent includes discussion about the insufficient evidence in these populations:
- Immunosuppressed due to disease or treatment - Individuals with an autoimmune condition - Pregnant or breastfeeding women These recommendations may change as more evidence on safety and/or effectiveness in these populations becomes available. The complete list of NACI recommendations are available at: #a7
# Contraindications
The Health Canada approved COVID-19 vaccines are contraindicated in individuals with a history of anaphylaxis after previous administration of the vaccine. Vaccine is also contraindicated in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its packaging. Clinical trials of the authorized COVID-19 vaccines excluded individuals with a history of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine. Individuals with a history of severe allergic reaction to a component of the COVID-19 vaccine should not receive the COVID-19 vaccine.
For a comprehensive list of components in the vaccine and packaging, please consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database.
# Advice for specific populations
# Children under 16 years of age
The Pfizer-BioNTech COVID-19 vaccine is currently approved for individuals who are 16 years of age and older, and the Moderna COVID-19 vaccine for 18 years of age and older. The COVID-19 vaccine(s) should not be offered to individuals who are not in the authorized age group. There are ongoing clinical trials on vaccine efficacy and safety in children aged 12 years and older and more data will be available in the coming months.
# Advice for pregnant and breastfeeding women
Please see the advice on the Society of Obstetricians and Gynaecologists of Canada (SOGC) website here: Nearly everyone will be able to safely receive the COVID-19 vaccine, although a very small number of people may need to avoid vaccination due to severe allergies to parts of the vaccine.
- If you are taking treatment for TB disease or latent TB infection, it is safe to receive the COVID-19 vaccine when it is offered to you. - If you are not tolerating your TB treatment, you should wait until your treatment is stable before receiving the COVID-19 vaccine. It is not a safety concern, but it is important to separate the side effects of your TB treatment from a potential side effect of the COVID-19 vaccine.
# Advice for immunosuppressed individuals including individuals receiving immunosuppressant therapy
NACI recommends that a complete COVID-19 vaccine series may be offered to individuals who are immunosuppressed due to disease or treatment in the authorized age group in this population, if a risk assessment deems that the benefits outweigh the potential risks. Informed consent prior to vaccination should include a discussion about the absence of evidence on the use of COVID-19 vaccine in this population.
- Currently, there are no data on COVID-19 vaccination in individuals who are immunosuppressed. Participants in the mRNA COVID-19 vaccine clinical trials only included individuals who were not immunosuppressed, and those not receiving immunosuppressive therapy during the trial.
- In general, non-replicating vaccines may be administered to immunocompromised people because the antigens in the vaccine cannot replicate. However, the magnitude and duration of vaccine-induced immunity are often reduced. It is currently unknown whether immunocompromised individuals will be able to mount an immune response to mRNA vaccines. - The relative degree of immunodeficiency in individuals who are immunocompromised varies depending on the underlying condition, the progression of disease, and use of medications that suppress immune function. Therefore, the balance of benefits and risks must be made on a case-by-case basis. - Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine. - Although inactivated vaccines can be safely administered at any time before, during or after immunosuppression, inactivated vaccines should be administered at least 14 days before initiation of immunosuppressive therapy to optimize immunogenicity. 11 - Active surveillance in these vaccine recipients is strongly encouraged.
- NACI and CTS will monitor the evidence as it evolves, and update these recommendations as needed.
# Advice for individuals treated with a biological therapy for Asthma
The two large randomized controlled trials (RCTs) of the mRNA vaccines published in the NEJM (Pfizer-BioNTech and Moderna) did not include participants on (asthma) biologics. There is no biological rationale as to why anti-IgE, anti-IL5, anti-IL5R or even anti-IL4/13 therapies should place patients at higher risk for adverse events. Of course, many of these patients ALSO have a history of severe allergy & anaphylaxis. The COVID-19 vaccine RCTs generally excluded these patients but, in post-emergency use authorization, the incidence of anaphylaxis has been about 1/100,000 vs. 1/1,000,000 for other vaccines. To our knowledge, none have resulted in fatality, and all have responded well to Epi-Pen and/or brief ER management.
Thus, patients with asthma on a biologic therapy should be advised: 1) risks are as above, but that benefits outweigh these; 2) have the vaccine when offered, but schedule for a site with onsite EMS/physician coverage; 3) those with a history of allergies to advise the vaccination staff, and to have their Epi-Pen -where relevantwith them, current, and visible on the table.
Advice for individuals with an autoimmune condition NACI recommends that a complete vaccine series with a COVID-19 vaccine may be offered to individuals with an autoimmune condition in the authorized age group in these populations if a risk assessment deems that the benefits outweigh the potential risks for the individual, and if informed consent includes discussion about the insufficiency of evidence on the use of COVID-19 vaccine in these populations.
# Responses to Frequently Asked Questions by Patients 1) Can I have a flu vaccination or the pneumococcal vaccination at the same time as a COVID vaccine?
NACI recommends that COVID-19 vaccines should not be given simultaneously with other vaccines (live or inactivated). Currently, no data exist on the simultaneous administration of COVID-19 vaccine with other vaccines. In the absence of evidence, attempts should be made to avoid simultaneous administration to maximize benefits of COVID-19 vaccination while minimizing any risks of harm, including the potential for immune interference or the erroneous attribution of an adverse event following immunization to a particular vaccine. However, if a COVID-19 vaccine is inadvertently administered at the same time as another vaccine, neither dose should be repeated.
In the absence of evidence, it would be prudent to wait for a period of at least 28 days after the administration of the complete two-dose vaccine series of an mRNA COVID-19 vaccine before the administration of another vaccine (except in the case where another vaccine is required for post-exposure prophylaxis) due to the elicitation of an inflammatory cytokine response. 10 It would be prudent to wait for a period of at least 14 days after the administration of another vaccine before administrating a COVID-19 vaccine to prevent erroneous attribution of an adverse event following immunization to a particular vaccine. 10
Refer to Simultaneous administration with other vaccines 10 and Timing of Vaccine Administration in the Canadian Immunization Guide, Part 1 -Key Immunization Information for additional information on simultaneous administration of other vaccines in general.
# 2) Which COVID vaccine should I have?
The vaccines that are currently approved by Health Canada are effective and safe. However, many more vaccines will be approved over time. We will learn more about differences on the efficacy and safety profile of each of these vaccines. Based on updated knowledge from clinical trials, it is possible that public health authorities will consider making recommendations of preferable use of certain vaccines by age groups or for population with specific medical conditions.
# 3) Should I receive the vaccine and is the vaccine going to work considering I am immunocompromised?
Non-replicating vaccines may be administered to immunocompromised people because the antigens in the vaccine cannot replicate. However, the magnitude and duration of vaccine-induced immunity are often reduced.
It is currently unknown whether immunocompromised individuals will be able to mount an immune response to mRNA vaccines.
# 4) Should I stop taking any of my medications (such as immunosuppressive medications) to make sure the vaccine works well?
Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine. The Canadian Immunization Guide recommends inactivated vaccines be administered at least 14 days before initiation of immunosuppressive therapy to optimize immunogenicity.
# 5) I have been suffering from "Long COVID" -does this mean I shouldn't have the vaccine?
A prior SARS-CoV-2 infection may not provide adequate protection for reinfection, therefore, vaccination against COVID-19 is recommended. However, in setting of limited vaccine supply, doses may be prioritized for those who have not had previously PCR-confirmed SARS-CoV-2 infection.
# 6) What is the rationale for changing the interval between first and second doses?
The NACI statement on vaccine administration and timing of vaccine administration can be found here: #b4
# Useful Links
Canadian | # Introduction
This Canadian Thoracic Society (CTS) document aims to provide guidance and relevant information for respiratory health care professionals on COVID-19 vaccination in Canada. Due to limited data, there are areas of uncertainty which have prompted the CTS, and several other national and international Specialty Societies, to provide advice on vaccination based on available evidence and expertise. We highlight this important information in this paper. A Frequently Asked Questions (FAQ) section of this document seeks to address some of the concerns that may arise in discussion with patients who are immunocompromised, treated with biologic therapy or long-term steroids, pre-or post-transplant, etc. We plan to update this guidance as new information becomes available and recommend periodically checking the Canadian Thoracic Society website (https://ctssct.ca/covid-19/) for updates.
It is important to note that even after vaccination other recommended public health measures, including frequent hand washing or use of alcohol-based hand sanitizers, wearing face masks, and physical distancing should continue to be observed; this is especially important in those with chronic medical conditions.
In Canada, there is a gap in the knowledge about the rate of vaccination in patients with respiratory diseases. However, it is clear from Canadian studies [1][2][3][4][5][6] that address vaccine uptake that the vaccination rates for seasonal influenza and for pneumococcal infection are below the ideal level of 80%. 7 A recommendation or contact (visit) with a health care professional was identified in several studies 2,8,9 as an important predictor influencing an individual's decision to be vaccinated. The study by Bourbeau et al. 2 found that COPD patients in Quebec and Ontario who had regular contact with their physician had vaccination rates of 80% for seasonal influenza, as reported by their primary care doctors. In the Boerner et al. study, 8 participants mentioned a physician recommendation along with trust in their physicians as a significant factor in their vaccination decision.
Therefore, the role of physicians, respiratory health care professionals and educators as advocates for vaccination along with consistent messaging on COVID-19 vaccination will likely be effective in improving vaccination rates in this vulnerable population.
# Drugs and COVID-19 vaccines authorized or in progress by Health Canada as of February 2021
• List of authorized drugs, vaccines and expanded indications for COVID-19 • Pfizer-BioNTech COVID-19 vaccine: What you should know • Moderna COVID-19 vaccine: What you should know
# Summary of efficacy and safety of the Pfizer-BioNTech and Moderna vaccines approved by Health Canada:
The first 2 COVID-19 vaccines to receive Health Canada approval for use (Pfizer-BioNTech and Moderna) have shown over 80% efficacy for preventing symptomatic and severe disease. The duration of follow up has been limited to 2-4 months. It is not known how long the protection will last after 1 or both injections. New variants are already emerging, and it is too early to know if it will affect vaccine efficacy.
From the clinical trials, both vaccines are safe. Severe adverse events are rare and usually self-limited. However local and systemic side effects are in keeping with known side effects associated with vaccines and are usually self-limited. Long-term side effects are highly unlikely. Regarding anaphylaxis, Moderna has reported 2.5 cases per million (as of Jan 10, 2021: MMWR January 29, 2021/670 (4): 125-129) and Pfizer 11 cases per million (as of Dec 23, 2020: MMWR: January 15, 2021/ 70 (2): 46-51). The majority of cases involved patients with documented/known allergies or allergic reaction, and 1/3 to 1/2 had previous history of anaphylaxis.
# Recommendations on the use of COVID-19 vaccines in Canada
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization. NACI has provided independent expert advice regarding priority populations for early vaccinations.
# NACI recommendations for priority for early COVID-19 vaccination to the following populations:
• residents and staff of shared living settings who provide care for seniors • adults 70 years of age and older, with order of priority: 1. beginning with adults 80 years of age and older 2. decreasing the age limit by 5-year increments to age 70 years as supply becomes available • health care workers who have direct contact with patients, including:
1. those who work in health care settings 2. personal support workers • adults in Indigenous communities As additional COVID-19 vaccine(s) and supplies become available, the following populations should be offered vaccinations:
• health care workers not included in the initial rollout • residents and staff of all other shared living settings, such as: o homeless shelters o correctional facilities o housing for migrant workers • essential workers who face additional risks to maintain services for the functioning of society
# Prioritization of Canadians with lung disease in the vaccination rollout
The COVID-19 Respiratory Roundtable led by the CTS issued a joint statement in January urging the federal, provincial and territorial governments to prioritize people living with lung disease who are at higher risk for more serious COVID-19 complications in the vaccination rollout. In February, NACI released recommendations on the prioritization of key populations for COVID-19 immunization which includes chronic lung disease as a risk factor for poor outcome. PDF document (People who are at risk of more severe disease or outcomes from COVID-19)
# Provincial and Territorial vaccination rollout plans
While NACI provided guidance on vaccination priorities, vaccination rollout plans are province-and territoryspecific. For the latest detailed vaccination rollout plans, visit this website and go to the vaccine page for your province or territory: https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirusinfection/prevention-risks/covid-19-vaccine-treatment/vaccine-rollout.html#a3 NACI recommendations on the use of COVID-19 vaccines 10 (updated recommendations Jan 12, 2021)
# NACI recommendations are now worded as "should" (strong) or "may" (discretionary).
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach.
A complete vaccine series with a currently authorized COVID-19 vaccine should be offered to:
• Individuals in the authorized age group without contraindications to the vaccine. In the context of limited vaccine supply, initial doses of COVID-19 vaccine(s) should be prioritized for the key populations outlined in NACI's Guidance on the prioritization of key populations for COVID-19 immunization which now lists chronic lung disease as a risk factor for poor outcomes.
A discretionary recommendation may be offered for some population/individuals in some circumstances.
A complete vaccine series with a currently authorized COVID-19 vaccine may be offered to:
• Individuals in the authorized age group without contraindications to the vaccine who have had previously polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. In the context of limited vaccine supply, initial doses may be prioritized for those who have not had previously PCR-confirmed SARS-CoV-2 infection. Testing for previous SARS-CoV-2 infection is not needed prior to COVID-19 vaccination.
For some specific populations who were either excluded from, or were represented by small numbers of participants in clinical trials, NACI recommends that a complete vaccine series with a currently authorized COVID-19 vaccine may be offered, if a risk assessment deems that the benefits of vaccination outweigh the potential risks for the individual (e.g., where the risk of severe outcomes of COVID-19 and/or risk of exposure to SARS-CoV-2 is high) or for the fetus/infant (in the case of pregnancy/breastfeeding), and if informed consent includes discussion about the insufficient evidence in these populations:
• Immunosuppressed due to disease or treatment • Individuals with an autoimmune condition • Pregnant or breastfeeding women These recommendations may change as more evidence on safety and/or effectiveness in these populations becomes available. The complete list of NACI recommendations are available at: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-onimmunization-naci/recommendations-use-covid-19-vaccines.html#a7
# Contraindications
The Health Canada approved COVID-19 vaccines are contraindicated in individuals with a history of anaphylaxis after previous administration of the vaccine. Vaccine is also contraindicated in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its packaging. Clinical trials of the authorized COVID-19 vaccines excluded individuals with a history of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine. Individuals with a history of severe allergic reaction to a component of the COVID-19 vaccine should not receive the COVID-19 vaccine.
For a comprehensive list of components in the vaccine and packaging, please consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database.
# Advice for specific populations
# Children under 16 years of age
The Pfizer-BioNTech COVID-19 vaccine is currently approved for individuals who are 16 years of age and older, and the Moderna COVID-19 vaccine for 18 years of age and older. The COVID-19 vaccine(s) should not be offered to individuals who are not in the authorized age group. There are ongoing clinical trials on vaccine efficacy and safety in children aged 12 years and older and more data will be available in the coming months.
# Advice for pregnant and breastfeeding women
Please see the advice on the Society of Obstetricians and Gynaecologists of Canada (SOGC) website here: Nearly everyone will be able to safely receive the COVID-19 vaccine, although a very small number of people may need to avoid vaccination due to severe allergies to parts of the vaccine.
•
• If you are taking treatment for TB disease or latent TB infection, it is safe to receive the COVID-19 vaccine when it is offered to you. • If you are not tolerating your TB treatment, you should wait until your treatment is stable before receiving the COVID-19 vaccine. It is not a safety concern, but it is important to separate the side effects of your TB treatment from a potential side effect of the COVID-19 vaccine.
# Advice for immunosuppressed individuals including individuals receiving immunosuppressant therapy
NACI recommends that a complete COVID-19 vaccine series may be offered to individuals who are immunosuppressed due to disease or treatment in the authorized age group in this population, if a risk assessment deems that the benefits outweigh the potential risks. Informed consent prior to vaccination should include a discussion about the absence of evidence on the use of COVID-19 vaccine in this population.
• Currently, there are no data on COVID-19 vaccination in individuals who are immunosuppressed. Participants in the mRNA COVID-19 vaccine clinical trials only included individuals who were not immunosuppressed, and those not receiving immunosuppressive therapy during the trial.
• In general, non-replicating vaccines may be administered to immunocompromised people because the antigens in the vaccine cannot replicate. However, the magnitude and duration of vaccine-induced immunity are often reduced. It is currently unknown whether immunocompromised individuals will be able to mount an immune response to mRNA vaccines. • The relative degree of immunodeficiency in individuals who are immunocompromised varies depending on the underlying condition, the progression of disease, and use of medications that suppress immune function. Therefore, the balance of benefits and risks must be made on a case-by-case basis. • Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine. • Although inactivated vaccines can be safely administered at any time before, during or after immunosuppression, inactivated vaccines should be administered at least 14 days before initiation of immunosuppressive therapy to optimize immunogenicity. 11 • Active surveillance in these vaccine recipients is strongly encouraged.
• NACI and CTS will monitor the evidence as it evolves, and update these recommendations as needed.
# Advice for individuals treated with a biological therapy for Asthma
The two large randomized controlled trials (RCTs) of the mRNA vaccines published in the NEJM (Pfizer-BioNTech and Moderna) did not include participants on (asthma) biologics. There is no biological rationale as to why anti-IgE, anti-IL5, anti-IL5R or even anti-IL4/13 therapies should place patients at higher risk for adverse events. Of course, many of these patients ALSO have a history of severe allergy & anaphylaxis. The COVID-19 vaccine RCTs generally excluded these patients but, in post-emergency use authorization, the incidence of anaphylaxis has been about 1/100,000 vs. 1/1,000,000 for other vaccines. To our knowledge, none have resulted in fatality, and all have responded well to Epi-Pen and/or brief ER management.
Thus, patients with asthma on a biologic therapy should be advised: 1) risks are as above, but that benefits outweigh these; 2) have the vaccine when offered, but schedule for a site with onsite EMS/physician coverage; 3) those with a history of allergies to advise the vaccination staff, and to have their Epi-Pen -where relevantwith them, current, and visible on the table.
Advice for individuals with an autoimmune condition NACI recommends that a complete vaccine series with a COVID-19 vaccine may be offered to individuals with an autoimmune condition in the authorized age group in these populations if a risk assessment deems that the benefits outweigh the potential risks for the individual, and if informed consent includes discussion about the insufficiency of evidence on the use of COVID-19 vaccine in these populations.
# Responses to Frequently Asked Questions by Patients 1) Can I have a flu vaccination or the pneumococcal vaccination at the same time as a COVID vaccine?
NACI recommends that COVID-19 vaccines should not be given simultaneously with other vaccines (live or inactivated). Currently, no data exist on the simultaneous administration of COVID-19 vaccine with other vaccines. In the absence of evidence, attempts should be made to avoid simultaneous administration to maximize benefits of COVID-19 vaccination while minimizing any risks of harm, including the potential for immune interference or the erroneous attribution of an adverse event following immunization to a particular vaccine. However, if a COVID-19 vaccine is inadvertently administered at the same time as another vaccine, neither dose should be repeated.
In the absence of evidence, it would be prudent to wait for a period of at least 28 days after the administration of the complete two-dose vaccine series of an mRNA COVID-19 vaccine before the administration of another vaccine (except in the case where another vaccine is required for post-exposure prophylaxis) due to the elicitation of an inflammatory cytokine response. 10 It would be prudent to wait for a period of at least 14 days after the administration of another vaccine before administrating a COVID-19 vaccine to prevent erroneous attribution of an adverse event following immunization to a particular vaccine. 10
Refer to Simultaneous administration with other vaccines 10 and Timing of Vaccine Administration in the Canadian Immunization Guide, Part 1 -Key Immunization Information for additional information on simultaneous administration of other vaccines in general.
# 2) Which COVID vaccine should I have?
The vaccines that are currently approved by Health Canada are effective and safe. However, many more vaccines will be approved over time. We will learn more about differences on the efficacy and safety profile of each of these vaccines. Based on updated knowledge from clinical trials, it is possible that public health authorities will consider making recommendations of preferable use of certain vaccines by age groups or for population with specific medical conditions.
# 3) Should I receive the vaccine and is the vaccine going to work considering I am immunocompromised?
Non-replicating vaccines may be administered to immunocompromised people because the antigens in the vaccine cannot replicate. However, the magnitude and duration of vaccine-induced immunity are often reduced.
It is currently unknown whether immunocompromised individuals will be able to mount an immune response to mRNA vaccines.
# 4) Should I stop taking any of my medications (such as immunosuppressive medications) to make sure the vaccine works well?
Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine. The Canadian Immunization Guide recommends inactivated vaccines be administered at least 14 days before initiation of immunosuppressive therapy to optimize immunogenicity.
# 5) I have been suffering from "Long COVID" -does this mean I shouldn't have the vaccine?
A prior SARS-CoV-2 infection may not provide adequate protection for reinfection, therefore, vaccination against COVID-19 is recommended. However, in setting of limited vaccine supply, doses may be prioritized for those who have not had previously PCR-confirmed SARS-CoV-2 infection.
# 6) What is the rationale for changing the interval between first and second doses?
The NACI statement on vaccine administration and timing of vaccine administration can be found here: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-onimmunization-naci/recommendations-use-covid-19-vaccines.html#b4
# Useful Links
Canadian | None | None |
e96b4d3609bc14e543d3681bd176b1ddf89351af | cma | None | The COVID-19 pandemic has pushed clinicians to make drastic changes in healthcare delivery across all specialties. In obstetrics and gynaecology, we have been challenged to conduct prenatal visits virtually, optimize medical management of gynaecologic conditions in the face of limited operating time, and uphold patient-centred care while restricting support persons on labour and delivery. Forced by the pandemic, these necessary changes have underscored the precarity of our healthcare systems and resources. Borrowing the advice of Sir Winston Churchill to "never let a good crisis go to waste," as we emerge from the pandemic, we should choose wisely what changes we keep, and what former practices we bring back. The aim of this statement is to summarize the impacts of COVID-19 in obstetrics and gynaecology in Canada, and suggest how the rapid innovations we have made can be maintained to support wise resources use in the post-pandemic era to come.Since its emergence in December of 2019, COVID-19 has infected over 100 million people and killed over 2 million worldwide. While our numbers in Canada are reasonably controlled in comparison to other countries, with over 900,000 infected and 20,000 killed as of March 2021, the virus has nonetheless made a significant, lasting impact on our healthcare system (1). Direct challenges of the virus have included providing evidence-based care to COVID-positive patients and managing a myriad of post-infectious sequelae. Indirect challenges have been the adverse effects on care and outcomes for people who do not have COVID but are affected by the existence of the pandemic. For healthcare systems it has included navigating resource shortages, staff burnout, and rapidly shifting protocols to#
contain the virus. Since COVID-19 can infect all demographics, virtually every specialty in medicine is affected.
In obstetrics and gynaecology, we have had to learn how COVID-19 impacts our patients.
Thankfully, we have learned that low risk pregnancy does not inherently increase susceptibility to infection, although the impact of severe illness for those infected has the potential to be much greater (2). Since fever is a common intrapartum problem, we have had to develop a keen eye to differentiate the more likely causes such as chorioamnionitis from COVID-19. Symptoms of the virus have implications for patients, families, and providers, as pending swab results lead to isolation that lasts hours to days. While most swabs return negative, for those that are positive, we have learned that vertical transmission is possible with infection in the third trimester, but uncommon (3). In rare occurrences of severe infection in pregnancy, the usual principles of managing airway, breathing, and circulation apply; delivery in these contexts must be individualized, and unfortunately adverse outcomes may result from severe illness.
# Adjustments to Practice During the Pandemic
# Obstetrics:
Although many providers have not cared for COVID-19 positive patients, practice has been impacted by changes to limit viral spread such as:
- Universal masking, in many cases extending to labouring patients (2) - Limiting in-person visits to those requiring physical examination (2)
- Restricting visitors and support persons in clinic and labour & delivery (2)
- Adopting virtual visits for low-risk pregnancies; the SOGC recommends at least four inperson visits (at 11-13, 20, 28, and 36 weeks) (2)
- Guiding patients to use home blood pressure cuffs to limit in-person assessment when possible and safe to do so (2)
- Emphasis on kick counting as a marker of fetal wellbeing (2)
# Gynaecology:
Providers have placed more emphasis on medical management as operating time has decreased at many centres, with changes such as:
- Restricting surgical options to cases in which medical options have been exhausted or are inappropriate (4)
- Increased focus on optimizing preoperative hemoglobin through iron supplementation and medical management to conserve blood products (4)
- Increased focus on enhanced recovery after surgery, or ERAS, protocols help to reduce length of stay and limit exposure (4)
- Regional anaesthesia has been increasingly chosen to avoid aerosol generation, and when general anaesthetic is necessary, preoperative swabs, N95 masks, and allowance for "settle time" after intubation may increase resource use and operating time (4)
- For non-surgical patients, such as those seeking contraception, focus on options that limit interaction with the healthcare system, such as oral rather than injectable contraception (5)
# Positive Impacts & Consequences of the Pandemic in Ob/Gyn
Reflecting on the numerous adjustments we have made to practice, there have been both positive and negative side effects, which are summarized in Table 1. 4. Judicious use of resources including limiting unnecessary investigations that can lead to further investigations and potentially unnecessary treatment.
# Conclusion
Since we can optimize healthcare delivery during COVID-19, we should certainly be able to do so after the virus is under control. If we can provide medical management of gynaecological conditions, promote ERAS protocols, and provide patient-centred virtual care during a pandemic, why wouldn't we do it all the time? We must seize the opportunity presented by this pandemic to improve the way we provide care, and to reopen wisely. | The COVID-19 pandemic has pushed clinicians to make drastic changes in healthcare delivery across all specialties. In obstetrics and gynaecology, we have been challenged to conduct prenatal visits virtually, optimize medical management of gynaecologic conditions in the face of limited operating time, and uphold patient-centred care while restricting support persons on labour and delivery. Forced by the pandemic, these necessary changes have underscored the precarity of our healthcare systems and resources. Borrowing the advice of Sir Winston Churchill to "never let a good crisis go to waste," as we emerge from the pandemic, we should choose wisely what changes we keep, and what former practices we bring back. The aim of this statement is to summarize the impacts of COVID-19 in obstetrics and gynaecology in Canada, and suggest how the rapid innovations we have made can be maintained to support wise resources use in the post-pandemic era to come.Since its emergence in December of 2019, COVID-19 has infected over 100 million people and killed over 2 million worldwide. While our numbers in Canada are reasonably controlled in comparison to other countries, with over 900,000 infected and 20,000 killed as of March 2021, the virus has nonetheless made a significant, lasting impact on our healthcare system (1). Direct challenges of the virus have included providing evidence-based care to COVID-positive patients and managing a myriad of post-infectious sequelae. Indirect challenges have been the adverse effects on care and outcomes for people who do not have COVID but are affected by the existence of the pandemic. For healthcare systems it has included navigating resource shortages, staff burnout, and rapidly shifting protocols to#
contain the virus. Since COVID-19 can infect all demographics, virtually every specialty in medicine is affected.
In obstetrics and gynaecology, we have had to learn how COVID-19 impacts our patients.
Thankfully, we have learned that low risk pregnancy does not inherently increase susceptibility to infection, although the impact of severe illness for those infected has the potential to be much greater (2). Since fever is a common intrapartum problem, we have had to develop a keen eye to differentiate the more likely causes such as chorioamnionitis from COVID-19. Symptoms of the virus have implications for patients, families, and providers, as pending swab results lead to isolation that lasts hours to days. While most swabs return negative, for those that are positive, we have learned that vertical transmission is possible with infection in the third trimester, but uncommon (3). In rare occurrences of severe infection in pregnancy, the usual principles of managing airway, breathing, and circulation apply; delivery in these contexts must be individualized, and unfortunately adverse outcomes may result from severe illness.
# Adjustments to Practice During the Pandemic
# Obstetrics:
Although many providers have not cared for COVID-19 positive patients, practice has been impacted by changes to limit viral spread such as:
• Universal masking, in many cases extending to labouring patients (2) • Limiting in-person visits to those requiring physical examination (2)
• Restricting visitors and support persons in clinic and labour & delivery (2)
• Adopting virtual visits for low-risk pregnancies; the SOGC recommends at least four inperson visits (at 11-13, 20, 28, and 36 weeks) (2)
• Guiding patients to use home blood pressure cuffs to limit in-person assessment when possible and safe to do so (2)
• Emphasis on kick counting as a marker of fetal wellbeing (2)
# Gynaecology:
Providers have placed more emphasis on medical management as operating time has decreased at many centres, with changes such as:
• Restricting surgical options to cases in which medical options have been exhausted or are inappropriate (4)
• Increased focus on optimizing preoperative hemoglobin through iron supplementation and medical management to conserve blood products (4)
• Increased focus on enhanced recovery after surgery, or ERAS, protocols help to reduce length of stay and limit exposure (4)
• Regional anaesthesia has been increasingly chosen to avoid aerosol generation, and when general anaesthetic is necessary, preoperative swabs, N95 masks, and allowance for "settle time" after intubation may increase resource use and operating time (4)
• For non-surgical patients, such as those seeking contraception, focus on options that limit interaction with the healthcare system, such as oral rather than injectable contraception (5)
# Positive Impacts & Consequences of the Pandemic in Ob/Gyn
Reflecting on the numerous adjustments we have made to practice, there have been both positive and negative side effects, which are summarized in Table 1. 4. Judicious use of resources including limiting unnecessary investigations that can lead to further investigations and potentially unnecessary treatment.
# Conclusion
Since we can optimize healthcare delivery during COVID-19, we should certainly be able to do so after the virus is under control. If we can provide medical management of gynaecological conditions, promote ERAS protocols, and provide patient-centred virtual care during a pandemic, why wouldn't we do it all the time? We must seize the opportunity presented by this pandemic to improve the way we provide care, and to reopen wisely. | None | None |
5e35867ad2e2a91c618d4cd103257c90c2904a3c | cma | None | The COVID-19 pandemic, declared in March, has revealed planning deficiencies on a national/regional level in Canada. We are all aware of the shortages of testing capabilities, personal protective equipment, health human resources and ventilators.#
The issue of ventilator access and resource allocation has been particularly pressing and garnered much media attention.
Receiving far less attention has been the concern for inadequacies in the supply of the necessary medications to permit mechanical ventilation. Media and anecdotal reports from within the Canadian medical community have suggested that these medications are in short supply and may be reaching a critical shortage in the coming weeks. This would have significant clinical impact and therefore requires immediate investigation and action.
Ventilation is a physiologically complex, painful and anxiety inducing process. Patients who do not have control over their breathing, especially those who require paralytics to allow adequate ventilation, can be terrified, and some ICU patients can develop delirium. All these patients require specific medications to provide sedation, pain control and, in some cases, paralysis.
The list of medications used in managing the ventilated patient is short, and includes: Propofol, a short-acting sedative agent, and the short-acting benzodiazepine, Midazolam. The addition of analgesics such as Fentanyl and Morphine is usually necessary for patient comfort and reduces the amount of sedative required. Neuromuscular blockade or paralytic agents, such as Succinylcholine and Rocuronium are generally required for intubation and for short term use in the management of the ventilated patient. COVID patients appear to require the support of a ventilator for longer times than other ICU patients and, as such, require more of these essential drugs.
These medications are increasingly used in the Emergency Department, in addition to their traditional use in the OR and ICU. As such, emergency physicians have some agency with respect to their use and, increasing responsibility for their stewardship.
Their current limited availability is a complex problem involving factors within and beyond our profession.
# Responsibilities of local, provincial and national authorities:
1) In order to understand the scope of the problem and allow optimal time for preparation, there should be local processes to inform physicians of existing stock and alternatives including the use of older or alternative drugs than our traditional first line choices.
2) We call for national review of existing stocks, their distribution across provinces, and management of existing stocks to ensure appropriate sharing.
3) Lastly, we call for national management of procurement and distribution, and efforts to incentivize domestic production.
# Responsibilities within the medical profession:
Emergency physicians must continue to strive to protect our current stockpile by:
1) Using alternate sources of analgesia where appropriate (e.g., hematoma blocks, regional nerve blocks, with ultrasound guidance). 2) Reducing waste of intravenous analgesics and sedatives 3) Careful choice of medications, considering nonpharmacological approaches and opportunities to apply alternate techniques, all in order to effect compassionate care in the emergency department, particularly as it relates to analgesia and procedural comfort.
We must also endeavour to collaborate with our anesthesiology and intensive care colleagues to provide the best possible analgesia and sedation to our emergency patients and safeguard our supply of agents required for the mechanical ventilation of our most critically ill. | The COVID-19 pandemic, declared in March, has revealed planning deficiencies on a national/regional level in Canada. We are all aware of the shortages of testing capabilities, personal protective equipment, health human resources and ventilators.#
The issue of ventilator access and resource allocation has been particularly pressing and garnered much media attention.
Receiving far less attention has been the concern for inadequacies in the supply of the necessary medications to permit mechanical ventilation. Media and anecdotal reports from within the Canadian medical community have suggested that these medications are in short supply and may be reaching a critical shortage in the coming weeks. This would have significant clinical impact and therefore requires immediate investigation and action.
Ventilation is a physiologically complex, painful and anxiety inducing process. Patients who do not have control over their breathing, especially those who require paralytics to allow adequate ventilation, can be terrified, and some ICU patients can develop delirium. All these patients require specific medications to provide sedation, pain control and, in some cases, paralysis.
The list of medications used in managing the ventilated patient is short, and includes: Propofol, a short-acting sedative agent, and the short-acting benzodiazepine, Midazolam. The addition of analgesics such as Fentanyl and Morphine is usually necessary for patient comfort and reduces the amount of sedative required. Neuromuscular blockade or paralytic agents, such as Succinylcholine and Rocuronium are generally required for intubation and for short term use in the management of the ventilated patient. COVID patients appear to require the support of a ventilator for longer times than other ICU patients and, as such, require more of these essential drugs.
These medications are increasingly used in the Emergency Department, in addition to their traditional use in the OR and ICU. As such, emergency physicians have some agency with respect to their use and, increasing responsibility for their stewardship.
Their current limited availability is a complex problem involving factors within and beyond our profession.
# Responsibilities of local, provincial and national authorities:
1) In order to understand the scope of the problem and allow optimal time for preparation, there should be local processes to inform physicians of existing stock and alternatives including the use of older or alternative drugs than our traditional first line choices.
2) We call for national review of existing stocks, their distribution across provinces, and management of existing stocks to ensure appropriate sharing.
3) Lastly, we call for national management of procurement and distribution, and efforts to incentivize domestic production.
# Responsibilities within the medical profession:
Emergency physicians must continue to strive to protect our current stockpile by:
1) Using alternate sources of analgesia where appropriate (e.g., hematoma blocks, regional nerve blocks, with ultrasound guidance). 2) Reducing waste of intravenous analgesics and sedatives 3) Careful choice of medications, considering nonpharmacological approaches and opportunities to apply alternate techniques, all in order to effect compassionate care in the emergency department, particularly as it relates to analgesia and procedural comfort.
We must also endeavour to collaborate with our anesthesiology and intensive care colleagues to provide the best possible analgesia and sedation to our emergency patients and safeguard our supply of agents required for the mechanical ventilation of our most critically ill. | None | None |
42e542a7f45cce66fe39d8e6cb8d4e7e8759d66a | cma | None | BACKGROUND: An important and common cause of pulmonary hypertension (PH) is chronic thromboembolic PH (CTEPH). Many care gaps exist in the evaluation of CTEPH including lack of awareness of the diagnosis, failure of clinicians to routinely consider CTEPH in patients at risk, and misguided diagnostic assessment practices including those which may be incomplete or unnecessary. METHODS: A representative multidisciplinary panel of expert physicians undertook a formal clinical practice guideline development process. A total of 4 key clinical issues were defined according to the Patient/problem, Intervention, Comparison, Outcome (PICO) approach. The panel performed an evidence-based, systematic literature review, assessed and graded the relevant evidence, and made 4 recommendations. RESULTS: Patients should not be routinely screened for the presence of CTEPH (using echo or pulmonary vascular imaging) following an acute pulmonary embolism (PE). Risk factors for CTEPH following acute PE have been established, and patients in these higher risk groups may merit closer attention during clinical follow-up. Routine screening for CTEPH following acute PE has not yet been demonstrated in prospective controlled trials to improve patient outcomes. In patients with PH, clinicians should perform nuclear ventilation/perfusion (V/Q) lung scanning as initial testing to rule out CTEPH. Either planar or single photon emission computed tomography (SPECT) V/Q are acceptable forms of V/Q lung scanning. A normal perfusion scan effectively rules out the possibility of CTEPH. A negative computed tomography pulmonary angiogram (CTPA) does not rule out CTEPH. In patients with suspected CTEPH, CTPA should be performed to confirm the presence and assess the anatomic extent and location of chronic thromboembolic material. A positive CTPA, confirming chronic thromboembolism, should prompt referral to an expert PH centre where a formal diagnosis can be established. A negative, indeterminate or technically poor CTPA does not exclude CTEPH and should also prompt referral to an expert PH centre for further testing. Magnetic resonance pulmonary angiography is not currently recommended for routine assessment in patients with suspected CTEPH. DISCUSSION: The foundation of CTEPH diagnosis remains clinicians' consideration of this possibility in patients at risk. Future research is required to identify the specific diagnostic tests and/or algorithms which will perform best in formal screening protocols for CTEPH. The current diagnosis of CTEPH will until then continue to rely on clinician led case finding, with diagnostic investigations arranged during the course of clinical care. Once case finding investigations have been initiated, an approach which follows the recommendations and sequence of testing outlined in this guideline may improve the rate of diagnosis of CTEPH and potentially the outcomes in these patients. This guideline will be reviewed every three years or sooner, in accordance with the Canadian Thoracic Society Living Guideline Model.# Introduction
# Chronic thromboembolic pulmonary hypertension
Pulmonary hypertension (PH) is a serious condition of the pulmonary blood vessels characterized by increased pulmonary arterial pressure (PAP) and is often associated with progressive right ventricular (RV) failure and a high risk of death. PH is increasingly recognized as an important cause of dyspnea and exercise limitation in many patients. As per the current World Health Organization (WHO) PH classification updated at the Sixth World Symposium on Pulmonary Hypertension held in 2018 in Nice, France (Tables 1 and 2), PH can be associated with underlying disorders of the heart and lungs or be due to intrinsic disease of the small pulmonary arteries, known as pulmonary arterial hypertension (PAH).
A very important and common 1 cause of PH is chronic thromboembolic PH (CTEPH). CTEPH is a result of pulmonary vascular obstruction characterized by recurrent, unresolved pulmonary emboli (PE) and/or progressive pulmonary vascular thrombosis and scarring. In the present document, CTEPH has been defined as follows:
- A mean PAP (mPAP) of 25 mmHg or greater and pulmonary vascular resistance (PVR) of 3 Wood units (240 dynes/cm 5 ) or greater; and 2. Persistent pulmonary arterial thrombotic obstruction despite at least three months of effective, uninterrupted anticoagulation.
It is of note that following completion of the evidence review and recommendations for this guideline document, the WHO hemodynamic definition of PH 2 was revised to include mPAP> 20 mmHg, pulmonary artery wedge pressure (PAWP) of 15 mmHg or less and a PVR 3 Wood units or greater. This revised hemodynamic definition was not used in this document but will be considered in future guideline updates.
The potential differential diagnosis for CTEPH includes a range of pulmonary vascular diseases such as: (i) central pulmonary artery thrombosis in the setting of dilated pulmonary arteries secondary to PAH, emphysema or congenital heart disease (ii) pulmonary artery sarcoma; (iii) extrinsic vascular compression such as from fibrosing mediastinitis;
(iv) pulmonary veno-occlusive disease (PVOD); (v) large vessel pulmonary artery vasculitis; and (vi) congenital pulmonary artery branch stenosis.
Clinical recognition of CTEPH is important for several reasons. First, CTEPH is believed to be one of the more common causes of PH, affecting approximately 3% of patients following PE. 1,3 Second, CTEPH is a serious, progressive and often fatal disease. Patients with untreated CTEPH experience significantly increased mortality. Historical observational studies 4,5 have estimated the median survival rate in severe untreated CTEPH patients to be as low as 10-20% at 2-3 years. Contemporary registry data 6 also illustrate the significant mortality of CTEPH, with 3-year survival rates in some subpopulations as low as 70%, even with access to modern era therapies. Third, CTEPH is potentially curable with pulmonary endarterectomy (PEA) surgery. Finally, CTEPH patients may also benefit from other treatments such as with balloon pulmonary angioplasty (BPA), PAH-targeted medications and/or other interventions.
The objective of the present guideline is to inform and provide evidence-based recommendations in the following areas:
# Differences from prior guideline published in 2010
This Clinical Practice Guideline (CPG) represents an update from an earlier guideline published in 2010 by the Canadian Thoracic Society (CTS). 7 Changes from the prior guideline include the following: This CPG is focused on case finding and the diagnostic evaluation of CTEPH. CTEPH treatments are not within the scope of this document (but will be included in a subsequent CPG publication focused on CTEPH management). A graphical diagnostic algorithm is provided. Guideline applicability and implementability have been considered throughout the CPG development process. Updated reviews of CTEPH epidemiology and incidence are not provided.
# Sections
Clinical Questions Section 1: Screening for CTEPH Should patients be screened for CTEPH (using echo and/or pulmonary vascular imaging with ventilation/perfusion (V/Q) lung scan or computed tomography pulmonary angiography (CTPA)) following an acute pulmonary embolism to increase the rate of diagnosis or improve clinical outcomes of CTEPH? In patients with suspected CTEPH, should magnetic resonance pulmonary angiography (MRPA) be used to establish the diagnosis and assess the anatomic extent and location of chronic thromboembolic material? In Section 1 on screening for CTEPH following acute PE, the specific patient population has been broadened from asymptomatic patients to now include all patients following acute PE, irrespective of symptoms. This change was felt by the panel to lead to a recommendation that would be more actionable by clinicians and made with consideration of the practical challenges which can arise in attempting to define normal versus abnormal symptoms following acute PE.
# Target patient population
The current CPG applies to all adult individuals with prior acute PE, undifferentiated PH, and suspected CTEPH.
# Target users
The present CPG is intended for use by the health care teams that care for individuals with venous thromboembolic disease, PH and CTEPH. Specifically, family practitioners and specialist physicians (respirologists, cardiologists, hematologists, internists, cardiac and thoracic surgeons, and radiologists), and other health care professionals who suspect or currently care for patients with deep vein thrombosis (DVT)/PE, PH and/or CTEPH can use these guidelines to help improve their clinical practice. This document should also be useful to patients and patient advocates. Finally, health care decision makers may also use this guideline in policy processes to inform coverage decisions.
# Guideline panel composition
The CTEPH guideline panel was comprised of clinicians and health care professionals with content expertise. The panel was chaired by one author (DH) and included 10 respirologists (2 international experts), one cardiologist, one radiologist specializing in cardiothoracic imaging and one thoracic surgeon. All author conflicts of interests are posted on the CTS website at /.
# Methodology
This CPG was developed in accordance with CTS guideline development process. 8 The panel utilized the AGREE II checklist to guide the development of this guideline. 9
# Formulation of key clinical questions
The panel determined key clinical questions in the areas of screening and/or case finding, assessment and diagnosis of CTEPH. Questions were crafted with consideration of those disease areas where the panel felt there to be substantial current knowledge-to-care gaps: for example, existing clinical practices contributing to cases of CTEPH being missed. The PICO method was used taking into consideration the Patient group or groups that should be addressed; the Intervention or interventions that should be examined; the Comparison groups that should be part of the studies of the various interventions; and the Outcome or outcomes of interest (Appendix 1). In the second part of the PICO process, panel members were asked to consider issues that influence implementability when choosing PICO questions: these include the magnitude of the knowledge-to-care gap; target audience(s); known barriers and supports to implementation; possible implementation strategies; societal impact; and measurability of any implementation program.
Literature search and screening of abstracts An initial literature search was completed current to December 14, 2015 using MEDLINE (OVID); Embase (OVID); HealthStar; the Cochrane Library: the Canadian Medical Association InfoBase; and the National Guideline Clearinghouse. The second literature search was conducted through to March 10, 2017 and a third search from January 1, 2017 to September 30, 2017 was also conducted to include the most recent literature, across the same databases. Additional articles were found by review of the references in the articles accepted. Details of the search strategy are outlined in Appendix 1. A graphical representation of the flow of citations and articles reviewed are shown in Figure 1. The title and abstracts of each article were scrutinized by two panel members to decide whether the article was relevant.
Where there was a difference of opinion, the panel members endeavored to reach consensus. When a consensus was reached on the list of relevant abstracts, copies of the articles of all relevant and possibly relevant articles were obtained. The chosen inclusion and exclusion criteria were noted at the abstract and full text review stages.
# Study selection criteria
Articles selected for inclusion in the systematic review of the evidence reported data on CTEPH diagnosis. Animal studies, pathology or preclinical studies, clinical images, isolated hemodynamic reports, letters, editorials, duplicate publications without original data, reviews, studies published in a language other than English and French, and studies of uniquely pediatric populations were excluded. Studies were evaluated in detail by pairs of reviewers who did the data extraction to ensure that selection criteria were met and agreed upon.
# Critical appraisal of identified studies
Data from all articles relevant to each PICO question were compiled into tables by each section and are found on the CTS website. During discussion of each question via webinars held in 2017 and 2018, all data were reviewed by all members of the panel, and group consensus was established regarding the quality of the evidence addressing each clinical question, according to the components of the GRADE criteria 11 (Table 3).
# Synthesis of evidence-base and clinical judgment of risk versus benefit
For each clinical question, the panel considered the strength and directness of the published evidence supporting an intervention or treatment approach. The panel discussed the potential health benefit to patient, the overall impact on the population burden of morbidity and mortality of CTEPH, and issues of risk, burden on a patient to adhere, and cost effectiveness of an intervention or treatment (implementability factors categorized under the "Contextualizations and Deliberations" domain of guidelines 12 ). These discussions and the resulting synthesis of evidence and summary clinical judgement are presented for each recommendation. Good practice points are included in association with each clinical question and are intended to offer short pieces of advice to the target user. Some of these good practice points may not have an evidence base but are viewed as good clinical practice by the expert panel. All good practice points were arrived at by consensus, based on the clinical experience of the guideline panel members.
# Formulation of recommendations and classification
Following the open and extensive discussions and review for each PICO question, a draft recommendation was proposed by the entire group. The strength of the recommendation was based on consideration both of the GRADE quality of evidence, and the expert panel's synthesis of clinical judgment. The recommendations were then vetted by the CTS Canadian Respiratory Guidelines Committee (CRGC) Chair to optimize the language of each recommendation to ensure implementability. The recommendation consensus process was completed by electronic survey using a six-point voting scale (Table 4), whereby it was defined a priori that a recommendation would only be accepted if each panel member voted for option 1, 2 or 3 (wholeheartedly agree, agree or can support). For a recommendation to be accepted, it had to be voted on by 75% of the eligible panel members and achieve ratings of 1, 2 or 3 by 80% of the voting panelists.
No panel member was excluded from voting. In the event of a failure to reach 80% of votes with ratings of 1, 2 or 3, another period of discussion ensued, whereby dissenting opinions were heard and considered. The recommendation was revised and followed by a second round of voting by electronic survey using a three-point scale, for which acceptance of a recommendation required a majority (80%) of panelists to choose option 1 or 2 (Table 4). Through this process, all recommendations achieved acceptance, with a second round of voting required for only one recommendation.
# Applicability/implementability
Recommendations were formulated with the aim of being clear and actionable by clinicians within the user group, in accordance with best principles for guideline language and format. 13 For example, precise criteria were utilized in defining patient populations and diagnostic tests results, wherever possible. Lack of access to key modalities (i.e., echocardiogram, pulmonary vascular imaging) could represent a barrier to guideline applicability in some jurisdictions. A graphical algorithm addressing assessment of CTEPH in patients with For a recommendation to be accepted, it had to be voted on by 75% of the eligible panel members and achieve ratings of wholeheartedly agree, agree or can support by 80% of the voting panelists. If this was not achieved, additional discussion ensued and revision of the recommendation was made, after which the second round of voting proceeded using a three-point scale, for which acceptance of a recommendation required a majority (80%) for option 1 or 2. PH is provided as a tool for clinicians to aid in implementing recommendations. The potential resource implications of applying the recommendations from this CPG were considered. This includes the possible need for increased diagnostic tests to be performed in order to improve patient outcomes via effective screening and/or case finding of CTEPH and through more precise diagnostic evaluation.
Our goal is to monitor the impact of these CPG recommendations through their ability to correct knowledge gaps within the target user group (a pre and post guideline survey project is underway) as well as to track characteristics and frequency of CTEPH cases at the expert PH centres (a Canadian PH database project is underway, including enrollment of CTEPH patients).
# Review and approval process
In accordance with the CTS guideline review and approval process, before completion, the CTS independently invited formal review of the guideline by: two external (non-CTS) international content experts and two internal (CTS) reviewers. One of the internal reviewers performed an AGREE assessment of the guideline. The draft guideline was reviewed by the Canadian Society of Thoracic Radiology Executive Committee. The Pulmonary Hypertension Association (PHA) of Canada coordinated a patient review of the draft guideline. The authors were blinded to the identities of the reviewers. The lead author provided responses to the comments and made corresponding changes to the manuscript. These reviews and the AGREE II scoresheet were provided to the CTS CRGC for review. Two members of the CRGC then completed a review of the guideline and these documents and provided further feedback for consideration by authors. Upon acceptance, the CRGC recommended approval of the guideline to the CTS Executive Committee. All reviews and author responses are posted on the CTS website at /.
Living guideline/future updates The Diagnosis of CTEPH guideline PICO questions will be uploaded in the CTS/McMaster Plus database. The authors will use the continuously updated McMaster Plus database to review new articles published in top journals starting from the last date of the literature conducted for this CPG. The studies are indexed according to the PICO questions and made available to the guideline panel on a dedicated software platform for manual assignment to individual reviewers. This evidence service will prompt guideline updates and facilitate reviews. The guideline will be formally reviewed every three years or sooner to determine the need for and nature of any updates, in accordance with the CTS Living Guideline Model (details available at www.cts-sct/guidelines.ca).
# Summary of evidence
# Key evidence
A systematic review of the literature found no randomized controlled trials (RCTs) or controlled studies of the effectiveness of CTEPH screening in improving the diagnosis of CTEPH or clinical outcomes in patients post-acute PE, nor in any specific high-risk subgroups. Many uncontrolled studies have followed patients post-acute PE, "screening" for the presence of PH by echo in all patients or selectively in patients with symptoms suggestive of CTEPH, as reviewed in a metaanalysis 3 of 21 published studies. Several studies found a higher prevalence of CTEPH in patients with residual symptoms following 3-6 months of effective anticoagulation postacute PE (e.g., dyspnea, exercise limitation, chest pain), although the vast majority of these symptomatic patients did not have CTEPH. 7,16,25 Although most studies suggest that echo screening can identify a number of patients with PH post-acute PE, these studies are limited by highly variable criteria that were not consistent with recommendations for echo detection of PH (e.g., right ventricular systolic pressure (RVSP) thresholds from 30 to 50 mmHg). Moreover, there was often limited formal diagnosis of the presence or the cause of PH by right heart catheterization (RHC) and only infrequent definitive CTEPH diagnosis in many of these studies.
In the aforementioned meta-analysis, 3 of the 14 studies which confirmed CTEPH by RHC, 4,7,8,18,19,21,23,26 9 studies had screened all included patients with echo, 8,11,12,18,21,26 whereas echo was only performed in patients reporting dyspnea in 4 other studies. 4,7,13,23 Overall, systematic screening did not increase CTEPH detection rate, as the incidence of CTEPH was the same whether all patients were screened post-PE or only symptomatic patients were investigated.
Thus, the recommendation informing this question is crafted in the absence of any direct evidence, and is based on indirect evidence (case series, cohort studies) showing no clear benefit of screening, as well as the consensus of the expert panel.
# Expert panel synthesis of evidence-base and clinical judgment of risk versus benefit
The panel recognized the lack of any direct evidence to address the specific question of whether screening increases the rate of diagnosis of CTEPH or results in improved CTEPH outcomes. Other relevant factors in screening for CTEPH were considered, including the moderate likelihood of significant direct benefit to the individual patient, the low burden of adherence but moderate potential adverse effects of pursuing screening and subsequent further work-up. In addition, the panel expected low overall impact on morbidity and mortality for the population of patients post-acute PE. There are no cost-effectiveness data available, but the panel strongly felt that routine screening for CTEPH was unlikely to be costeffective. None of the three tests of echocardiogram, V/Q scanning or CTPA fulfilled the WHO /Wilson's 27,28 requirements for good screening tests, when used to screen for CTEPH.
# Patient values and preferences
No studies were found that assessed patient values or preferences with regards to screening for CTEPH. It was the panel's consensus that most patients with acute PE would be willing to undergo clinical and noninvasive assessments if they were effective in diagnosing CTEPH sooner and especially if they were effective in improving clinical outcomes.
# Good practice points
The panel emphasized that the negative recommendation for routine screening of patients post-acute PE may not apply to certain subpopulations. The panel recognized the importance of clinically based follow-up in higher risk groups but emphasized that this clinical follow-up should be tailored to the specific situation and does not always need to include a follow-up echocardiogram and/or pulmonary vascular imaging. Specific subpopulations which warrant closer follow-up post-acute PE include: although conversely, a single study suggested a higher risk of CTEPH in younger patients. 4 Although not yet validated in prospective controlled trials, patients postacute PE with risk factors for CTEPH may merit closer clinical attention during follow-up, which most importantly involves clinical monitoring for symptoms (e.g., dyspnea) and functional limitation, but also the targeted use of echocardiography (e.g., to look for elevated RVSP, secondary signs of PH such as RV enlargement and/or RV systolic dysfunction). The panel emphasized that routine follow-up pulmonary vascular imaging (V/Q lung scan or CTPA) is not indicated for screening of CTEPH, even in these higher risk groups. The recommended techniques and diagnostic sequencing of pulmonary vascular imaging when used for CTEPH case finding is summarized in our algorithm (Figure 2). 3. Patients with acute PE who remain symptomatic despite 3 months of effective anticoagulation. Persistent symptoms or low health related quality of life (HRQoL) scores are common in patients with acute PE despite appropriate anticoagulation. 15,29,30 Unexplained dyspnea and functional limitation which persist following at least 3 months of effective anticoagulation can suggest the presence of CTEPH. Such patients merit appropriate clinical and diagnostic investigation for common conditions which may contribute to these persisting symptoms including the "post PE syndrome" 29 and other types of lung or heart diseases, as well as CTEPH. 4. Other clinical indications for follow-up pulmonary vascular imaging. The panel recognized that there may be other clinical indications to perform follow-up pulmonary vascular imaging (V/Q lung scan or CTPA) in selected patients post-acute PE, such as to decide on duration of anticoagulation, to assess risk of recurrent PE, or to establish a baseline before ongoing surveillance for recurrent PE.
# Areas for future research
Given the clinical importance of CTEPH, and the significant benefits of available treatment approaches, research to better identify asymptomatic patients post-acute PE who have an elevated risk of developing CTEPH would be helpful. There is a need for studies to further identify and assess the magnitude of risk factors for CTEPH within the range of populations reflective of clinical practice, including symptomatic and asymptomatic patients as well as those with comorbid conditions. There may also be benefit to the development of scoring systems which combine multiple risk factors to define a composite or overall CTEPH risk, thereby identifying specific subpopulations of patients post-acute PE who could benefit from structured CTEPH screening. Future research should focus on clinical benefit, costeffectiveness, and patient preferences around screening approaches for CTEPH, ideally within prospective controlled trials.
# Introduction
CTEPH is a common and important cause of PH, with a distinct management strategy. Thus, the possibility of CTEPH should be carefully considered in all patients with PH. History alone is insufficient to confirm or exclude CTEPH, as at least one-quarter of CTEPH patients in registries 1 and likely a greater proportion in clinical practice have not experienced symptomatic or documented acute PE. Moreover, physiologic tests such as cardiopulmonary exercise testing also lack the required high sensitivity to rule out CTEPH. 2,3 A diagnosis of CTEPH requires appropriate pulmonary vascular imaging. The three most commonly proposed imaging modalities for initial testing of CTEPH in PH patients are nuclear V/Q lung scanning, CTPA and lung perfusion magnetic resonance imaging (MRI). There have been technical innovations in all of these imaging modalities since our prior guideline recommendations in 2010.
In this section we address how patients with PH should be assessed for CTEPH.
# Key evidence
Our review found no RCTs or other direct evidence addressing the effect of testing for CTEPH in patients found to have PH. Thus, the recommendation addressing this question is based upon indirect evidence from several cohort studies, as well as the consensus of the expert panel.
# Planar V/Q
Our previous 2010 guideline 4 recommended nuclear V/Q for CTEPH assessment in patients with PH. This recommendation was significantly influenced by one single centre retrospective study 5 in which 227 patients with PH referred to a tertiary centre were assessed for CTEPH. Conventional pulmonary angiography was used as the reference standard technique. Planar V/Q was compared with 4-8 detector CTPA in assessing for CTEPH. Large vessel CTEPH was detected by V/ Q with a sensitivity of 97.4% and a specificity of 90%. CTPA had a sensitivity of only 51% but a specificity of 99%.
A cohort study by He et al. 6 assessed 114 patients with suspected CTEPH who all underwent planar V/Q scan, 16 or 64 detector CTPA and conventional pulmonary angiography. Fifty-one patients were diagnosed with CTEPH, 60 with idiopathic PAH and 3 with an atrial septal defect. Conventional pulmonary angiography was used as the reference standard technique. CTEPH was detected by V/Q with a sensitivity of 100% and a specificity of 93.7%. CTPA had a sensitivity 92.2% and specificity of 95.2%. To explain the higher sensitivity of CTPA in this study in comparison to Tunariu et al. 5 it is proposed that there may have been a lower proportion of subsegmental PE in the cohort evaluated by He et al. 6 and/or CTPA improvements related to the use of more advanced CT scanners.
# SPECT V/Q
SPECT nuclear V/Q scanning represents the state of the art of perfusion scintigraphy and has emerged as being more sensitive than planar scintigraphy for the diagnosis of acute PE. 7,8 Many centres in the world, including those within Canada, have replaced planar V/Q equipment with SPECT V/Q as the standard of care.
No studies were found which specifically evaluate SPECT V/Q as an initial test to rule out CTEPH.
A single centre prospective blinded cohort study 9 compared planar V/Q to SPECT V/Q for a clinical question indirectly related to this PICO question; the assessment of extent and location of chronic thromboembolic material in 17 patients with CTEPH. The reference standard involved an evaluation of the PEA surgical specimen as a "mold" of the obstructed pulmonary vasculature. Obstructed segments were detected by SPECT V/Q with a sensitivity of 63.5% and specificity of 62.6%. Planar V/Q had a sensitivity of 42.7% and specificity of 76. 8%. These differences in sensitivity were statistically significant (P < 0.01). This small study suggests that SPECT V/Q might be more sensitive than planar V/Q in detecting the obstructed pulmonary vessels characteristic of CTEPH. A normal perfusion (Q) scan effectively rules out the possibility of CTEPH.
A negative CTPA does NOT effectively rule out CTEPH.
A subsequent cohort study from the same authors 10 compared SPECT V/Q to 4-and 64-detector CTPA in 9 patients with CTEPH undergoing PEA surgery. The reference standard again involved an evaluation of anatomic distribution of chronic thrombotic material in the removed PEA specimen. SPECT V/Q had a sensitivity of 62% and specificity of 72% for detecting the obstructed pulmonary arteries. CTPA had significantly lower sensitivity of 47.8% (p < 0.03), and similar specificity of 80%. This study suggests that SPECT V/Q may be more sensitive than 4 and 64 detector CTPA in detecting the obstructed pulmonary vessels characteristic of CTEPH.
# DE-CTPA
Dual energy CTPA (DE-CTPA) is a novel CT angiographic technology which maps the iodine content of the lung microcirculation to provide information about pulmonary vessel obstruction and its downstream functional consequences.
A cohort study of 51 patients with established CTEPH 11 evaluated DE-CTPA in comparison to SPECT V/Q as the reference standard. The sensitivity of DE-CTPA was high (96%) with a lower specificity (76%). In some of the DE-CTPA cases, the lung segments containing perfusion defects (8.3%) could not be evaluated due to artifacts.
Another single centre prospective cohort study using DE-CTPA 12 assessed 40 patients referred with PH, of whom 14 were diagnosed with CTEPH. The reference standard for CTEPH diagnosis in this study was also based on planar V/Q (the presence of at least once segmental perfusion defect). This study compared planar V/Q to !64 detector CTPA and DE-CTPA. The sensitivity of DE-CTPA and CTPA were both reported at 100%. The specificities were 92% for DE-CTPA and 96% for CTPA. In the subgroup of CTEPH patients, 7.9% of lung segments were of non-diagnostic quality on DE-CTPA iodine maps due to artifact. There was better agreement between DE-CTPA and V/Q (k ¼ 0.44) than between CTPA and V/Q (k ¼ 0.09-0.31) at the segmental level.
Giordano et al. 13 evaluated DE-CTPA in a pre-selected group of patients without emphysema and with either PAH (n ¼ 13) or "peripheral type" CTEPH (n ¼ 9). There was a high concordance (100%) between V/Q and DE-CTPA in the peripheral type CTEPH group, with all studies showing defects. In the PAH group there were a number of false positive perfusion defects (3/13 ¼ 23%) identified with DE-CTPA.
In summary, the body of evidence pertaining to DE-CTPA fails to establish superiority in comparison to V/Q (which was used as the reference standard technique in all of the studies) and also demonstrates imaging artifacts which may limit interpretation of the DE-CTPA perfusion defects.
Access to DE-CTPA as well as expertise in its diagnostic interpretation remains limited. DE-CTPA has complex image acquisition and post processing needs, which require appropriate expertise.
# DCE lung perfusion MRI
Cardiac MRI is an important tool to assess the right ventricle in patients with PH. Cardiac MRI should be distinguished from dynamic contrast enhanced (DCE) lung perfusion MRI which is a time-resolved form of magnetic resonance (MR) pulmonary angiography designed to assess distal lung perfusion. The PH centre in Papworth UK has extensive experience using 3D DCE lung perfusion MRI in the evaluation of patients referred for assessment of suspected CTEPH. 14 In a cohort of 132 patients referred (78 diagnosed with CTEPH), lung perfusion MRI was reported to have test characteristics (sensitivity 97%, specificity 92%) similar to nuclear Q scanning (sensitivity 96%, specificity 90%). No invasive pulmonary angiography was performed in this cohort. The reference standard for the diagnosis of CTEPH was based on a multidisciplinary meeting involving data from CTPA, MRI and nuclear V/Q scanning.
A single centre blinded retrospective cohort study using lung perfusion MRI 15 enrolled 74 patients undergoing evaluation for CTEPH. Within this cohort, 36 patients were diagnosed with CTEPH, 10 patients with CTED (without PH) and 28 patients had chronic thromboembolic disease excluded. The reference standard for the diagnosis of CTEPH was based on a multidisciplinary meeting using V/Q and CT data. SPECT V/Q was compared to a 3-dimensional DCE lung perfusion MRI. The lung perfusion MRI demonstrated similar sensitivity (100%) and specificity (81%) to SPECT V/Q (sensitivity 97%, specificity 81%) for the diagnosis of chronic thromboembolism.
No studies were found that suggest the superiority of lung perfusion MRI over nuclear V/Q scanning in the assessment of CTEPH.
Access to lung perfusion MRI technology, as well as expertise in its diagnostic interpretation, is currently limited in most centres worldwide. Lung perfusion MRI has complex image acquisition and post processing needs, which require appropriate expertise.
# Other imaging technologies
While Electrocardiogram (ECG)-gated multidetector CT, 16,17 cone beam CT angiography 17 and 320 detector CTPA 18 have been used in the assessment of CTEPH, these particular studies have focused on establishing the diagnosis and assessing the anatomical extent/location of thromboembolic material (reviewed in PICO 3) rather than as initial testing for CTEPH in populations of patients referred with PH.
# Expert panel synthesis of evidence-base and clinical judgement of risk versus benefit
The panel graded the body of evidence as low. The higher sensitivity of V/Q and lower sensitivity of CTPA in screening PH patients for CTEPH was consistent with the clinical experience of panel members. The lack of evidence for superiority of either DE-CTPA or DCE lung perfusion MRI in comparison to V/Q was also considered. The panel emphasized the significant potential for direct health benefit to the patient with accurate initial testing and subsequent diagnosis of CTEPH. The minimal adverse effects and minimal burden on the patient to adhere to the recommendation was considered. The panel considered the possible medium to high impact on morbidity and mortality for the population of PH patients as a whole with the recommended approach. The panel recognized the lack of cost effectiveness data, leading to the inconclusive economic benefits of the recommended approach.
# Patient values and preferences
No studies were found that assessed patient values or preferences with regards to assessment of the possibility of CTEPH in patients with PH. It was the panel's consensus that most patients with PH would be willing to undergo testing with V/Q lung scanning, particularly if this led to a more accurate diagnostic approach with fewer missed cases of CTEPH.
# Discussions/areas for future research
The panel identified the need for future RCTs of CTEPH assessment in patients with PH. Future trial designs need to consider the varying incidence of CTEPH in different populations of patients 23 and should focus upon populations which are most reflective of clinical practice. Future studies should include patients with a broad range of characteristics, including those with and without co-existing parenchymal lung disease. For example, future research to define the prevalence of CTEPH in populations of patients followed in emphysema or left heart failure clinics would be of particular relevance to the clinicians working in these areas.
Further study is required to fully define the test characteristics of V/Q when used to rule out CTEPH in the setting of an abnormal chest X-ray. Future research should be designed to guide the practices of both tertiary and community care centre physicians.
Multistep screening algorithms may increase the precision of CTEPH assessment. A recently published study 24 has demonstrated the utility of an algorithm starting with a structured symptom questionnaire and followed by diagnostic imaging. The panel suggests ongoing research into multimodality screening algorithms for CTEPH.
Further study is required to assess the outcomes when clinicians use testing algorithms and/or clinical probability scores to assess for acute PE in non-anticoagulated patients presenting with undifferentiated PH.
The panel emphasized the need for clinical research to maintain pace with the rapid development of new imaging technology. As new screening tools are developed, prospective controlled trials should be conducted which include robust gold standard definitions of CTEPH as well as meaningful clinical endpoints (Appendix 1). Future trials should consider the long-term impact of screening protocols, not just upon those patients in whom CTEPH is confirmed, but also upon those patients ultimately diagnosed with other causes of PH.
The clinical importance of mild abnormalities on V/Q lung scans (especially in the case of SPECT V/Q) remains uncertain. Future studies are needed in order to define significance of low probability V/Q abnormalities, particularly as it relates to their negative predictive value for a diagnosis of CTEPH.
Future studies using newer generations of CT scanners may help further define the role of CTPA in initial testing for CTEPH.
# Introduction
Confirmation of a diagnosis of CTEPH requires establishment of the presence of chronic thromboembolic lesions typical of this condition by at least one form of pulmonary angiography. 1,2 Angiography is also necessary to characterize the anatomic extent and location of chronic thromboembolic material, to assess for the most appropriate therapy; including accessibility for surgical PEA or BPA.
Several pulmonary angiographic modalities exist. Traditionally, conventional, invasive DSA has been considered the reference standard angiographic technique for CTEPH. Conventional pulmonary angiography is performed using contrast injections through catheters placed directly within the pulmonary arteries to provide detailed images of the pulmonary arterial tree. Conventional pulmonary angiography requires significant centre specific experience in order to obtain the most accurate results.
CTPA can also be used for imaging of the pulmonary arterial tree. CTPA has the advantages of being less invasive (contrast injections are given through peripheral IV) and more widely available than conventional angiography. There are important technical issues to consider in optimizing detection of chronic thromboembolism using CTPA.
Some centres have used MRPA with peripheral gadolinium contrast injection to assess the anatomic extent and location of chronic thromboembolism. 3 It has been unclear if CT or MRI pulmonary angiography can routinely be used to establish a diagnosis of CTEPH, and whether these modalities provide adequate image quality to properly evaluate chronic thromboembolic lesions for consideration of specific interventional therapies (e.g., PEA, BPA).
# Key evidence
Our review found no RCTs or other direct evidence assessing the use of CTPA for confirmation of diagnosis and/or assessment of anatomic extent of CTEPH. Specifically, there are no RCTs comparing CTPA to conventional pulmonary DSA. The recommendation informing this question is therefore based upon indirect evidence from one meta-analysis, several medium and small sized cohort studies, and the consensus of the expert panel. Dong et al. 4 published a meta-analysis based on systematic review of literature published between 1990 and 2015 assessing the diagnostic accuracy of CTPA in patients with CTEPH. Eleven articles met inclusion criteria (including a total of 712 patients). Some but not all reports used DSA as a gold standard, and there were minimal details provided on the DSA technique. Pooled analysis showed CTPA to have a sensitivity and specificity of 95% and 96% for main/lobar pulmonary artery disease, and of 88% and 89% for segmental disease, respectively. Subsegmental disease was not assessed.
A cohort study by Sugiura et al. 5 compared 320-detector CTPA to DSA in 44 patients with CTEPH and reported sensitivity and specificity for main/lobar pulmonary arterial disease of 97% and 97% and for segmental disease 86% and 95%. Subsegmental disease was not assessed.
Another cohort study by Reichelt et al. 6 used 64-slice CTPA in comparison to DSA in the assessment of 27 patients (CTEPH confirmed in 24). Sensitivity and specificity of CTPA for main/lobar disease was 98% and 95% and for segmental disease 94% and 93%.
A study by He et al. 7 assessed 114 patients referred with PH, of whom 51 were diagnosed with CTEPH. Several analyses were performed in this study, including an analysis of 16 and 64-slice CTPA images in comparison to DSA. Sensitivity and specificity of CTPA for the diagnosis of CTEPH were 92% and 95%. No information was presented on the anatomic extent of the disease.
Grgic et al. 8 used rigidly interpreted CTPA (using vascular obstruction index) and SPECT V/Q (using percentage of Box 3. Diagnosis of CTEPH PICO 3a: In patients with suspected CTEPH, should CTPA be used to establish the diagnosis and assess anatomic extent and location of chronic thromboembolic material?
Recommendation:
- We recommend that clinicians perform CTPA to confirm the presence and assess the anatomic extent and location of chronic thromboembolic material in patients with suspected CTEPH. (GRADE 1B)
# Clinical remarks:
A positive CTPA, confirming chronic thromboembolism, should prompt a referral to an expert PH centre for establishment of a formal diagnosis of CTEPH, and assessment of most appropriate treatment.
Findings of chronic thromboembolism on CTPA include intraluminal fibrous bands or webs, stenoses, partial occlusions, total occlusions (pouch defects), and eccentric organized thrombi that form an obtuse angle with the vessel wall.
A negative, indeterminate, or technically poor CTPA does not exclude CTEPH. Patients with these non-positive CTPA results and suspected CTEPH should be referred to an expert PH centre for further diagnostic testing, such as conventional pulmonary angiography.
vascular obstruction index) to predict PEA operability in 49 patients with CTEPH. CTPA performed well in depicting the central thromboembolic material, however, the extent of perfusion abnormalities was better depicted on the functional SPECT V/Q examination. CTPA and SPECT V/Q were therefore thought to provide complementary information in assessment of operability for PEA. Three retrospective cohort studies published by the group in Hannover, Germany have evaluated a novel form of invasive pulmonary angiography utilizing cone beam CT images instead of DSA. Cone beam invasive angiography revealed high resolution images of the pulmonary arteries, including some to the subsegmental level, with potential superior intermodality agreement and delineation of distal CTEPH lesions in comparison to 64-detector CTPA 10 or DSA. 9
# Expert panel synthesis of evidence-base and clinical judgment of risk versus benefit
The panel graded the body of evidence as moderate. The evidence for the high specificity of CTPA in confirming the diagnosis of CTEPH was recognized, and this was consistent with the clinical experience of panel members. There was concern CTPA may not be sensitive enough to exclude CTEPH, particularly in patients with segmental/subsegmental disease as well as situations where the CTPA is performed or interpreted in less experienced centres. The panel emphasized the limited published evidence supporting CTPA when used for defining anatomic extent of CTEPH to plan PEA or BPA. But several panel members described their own clinical experience using CTPA to plan PEA. It was recognized that wider detector scanners (i.e., 320 slice) tend to provide superior image quality for chronic thromboembolic lesions. However, it was also noted that the bulk of the evidence informing this recommendation was obtained from studies which used 64 detector scanners. The panel had some concerns about the extent to which the evidence directly addressed the clinical question. The potential significant health benefit to the individual patient from a confirmed diagnosis of CTEPH was recognized. The panel also considered the minimal risk of harm to patient with CTPA, the minimal burden on the patient to adhere and the potential high impact on morbidity and mortality for the target population as a whole. Due to the lack of cost effectiveness data, the panel felt it was inconclusive as to whether the recommendation would be cost effective.
# Key evidence
Our review found no RCTs or other direct evidence assessing the use of MRPA for confirmation of diagnosis and/or assessment of anatomic extent of CTEPH. Specifically, there are no RCTs comparing MRPA to conventional invasive pulmonary angiography. The recommendation informing this question is therefore based upon the experience of the expert panel and indirect evidence from the following two retrospective cohorts.
The PH centre in Papworth, UK have used 3D DCE MRI for the confirmation of CTEPH and planning of PEA surgery. In a retrospective cohort 12 of 106 patients (53 with CTEPH, including 22 with segmental level disease), MRPA had high sensitivity of 98% and specificity of 94% in diagnosing CTEPH and was superior to 64-detector CTPA in depicting stenoses and post-stenotic dilatations. The addition of an unenhanced proton MR technique improved the detection of proximal disease. A subsequent research letter 13 described the results with this cohort expanded to 132 patients, showing similar results for MRPA for the diagnosis of CTEPH (97% sensitivity, 92% specificity). There were no comparisons with any forms of invasive pulmonary angiography in this cohort, either via DSA or cone beam CT.
Ley et al. 14 published a small retrospective cohort of 24 patients with CTEPH who underwent contrast enhanced MRPA, 40 to 64-detector CTPA and invasive DSA. Unfortunately, there were challenges with the DSA image quality in this study, with only half of the patients having DSA images rated excellent or good. For the diagnosis of main/lobar pulmonary arterial disease sensitivity and specificity were highest with CTPA (100% and 100%, respectively), followed by MRPA (83%, 99%) and DSA (66%, 100%). For the detection of segmental pulmonary arterial disease, the sensitivities and specificities were: CTPA (100% and 99%), MRPA (88%, 98%) and DSA (75%, 100%).
# Expert panel synthesis of evidence-base and clinical judgment of risk versus benefit
The panel graded the body of evidence as low. The body of evidence was thought to only indirectly address the clinical question. MRPA was considered to have potentially minimal health benefit to the individual patient in comparison to the more widely available and more studied techniques of CTPA and invasive pulmonary angiography. The panel also considered the minimal burden of adherence and minimal harm to the patient with MRPA, as well as its anticipated low impact on the morbidity or mortality of the target population. The panel emphasized the lack of cost effectiveness data but felt that MRPA was unlikely to be cost effective. The panel acknowledged the limited access to MRPA technology and emphasized the lack of widespread experience or expertise in MRPA assessment of CTEPH.
# Patient values and preferences (3a and 3b)
No studies were found that assessed patient values or preferences with regards to CTPA, MRPA or invasive pulmonary angiography. It was the panel's consensus that most patients would be willing to undergo CTPA, and then be referred to a local expert PH centre, and if required subsequently to a PEA/BPA centre, for additional investigations and treatments.
Good practice points (3a and 3b)
- CTPA images may be non-diagnostic or suboptimal due to technical issues. Specific recommended technical criteria include a short breath hold acquisition (3-5 sec) as well as thin collimation and thin-slice reconstruction ( 1 mm) in axial, coronal and sagittal planes. 3-dimensional surface-shaded reconstructions may improve depiction of vessel cutoff. 15 Maximum intensity projections and oblique reconstructions along the long axis of the left and right pulmonary arteries may also be helpful.
# Evaluation for CTEPH in patients with contrast allergy
-r renal dysfunction can represent a clinical challenge. These cases should be discussed with a PH expert centre. 3. Misinterpretation of CTPA images can lead to a missed or delayed diagnosis of CTEPH and/or the use of inappropriate therapies. 16 Referring centres should work with PH expert centres at (or prior to) the stage of CTPA image interpretation, when assessing patients with suspected CTEPH (see diagnostic algorithm, Figure 2). 4. Pulmonary angiographic and V/Q imaging data may be complementary when used for the planning of CTEPH treatments. 5. Most types of pulmonary vascular imaging can underestimate the true anatomic extent of CTEPH, when compared to intraoperative evaluation at the time of PEA. 6. Conventional DSA is the traditional reference standard, but like all imaging techniques can be suboptimal due to technical issues. Regular DSA quality control efforts should be undertaken at expert PH centres, to optimize the techniques of image acquisition.
Areas for future research (3a and 3b)
Future studies using newer generations of CT scanners may help further define the role of CTPA in confirming a diagnosis of CTEPH and in more effectively assessing the anatomic extent and location of chronic thromboembolic material. The panel highlighted the need for clinical research to maintain pace with the rapid development of new imaging technology. As new forms of CTPA are developed, prospective trials should be conducted in comparison to the traditional reference standard of a high quality DSA, for example a DSA performed in an experienced and high-volume CTEPH expert centre.
There remains only a small body of evidence to support CTPA or other noninvasive imaging techniques aimed at the evaluation of subsegmental level chronic thromboembolic material. Future studies on subsegmental disease which compare a variety of imaging techniques in comparison to DSA are required. Further study of imaging techniques for segmental and more distal levels of disease may reveal clinically important insights, particularly as it relates to assessment of potential candidates for BPA.
Cone beam CT represents a novel form of imaging during invasive pulmonary angiography, but there are only single-centre reports thus far. Potential future clinical use will require multi-centre validation studies.
Similarly, ongoing research into MRPA techniques may allow MRPA to expand beyond its current use in only a few selected centres worldwide.
The panel emphasized the importance of ongoing research regarding optimizing technical best practices for imaging techniques as well as future knowledge translation of such quality control practices.
# Dissemination and implementation
Our guideline will be disseminated through traditional channels including this publication, through the CTS website and social media channels, and through an accompanying slide deck which will be used to present this content to various groups across the country. Furthermore, an abridged online and electronic "quick reference" guide, including the algorithm addressing assessment of CTEPH in patients with PH (Figure 2), with a reference link to the full document will be produced. These materials will be circulated to all 15 expert adult PH centres in Canada and will be used in educational interventions with non-PH experts.
Our group has also considered the anticipated barriers/ enablers to implementation of our recommendations, which types of initiatives might be considered for implementation of recommendations, which metrics should be measured as indices of success, and how these might be measured.
The first recommendation (PICO 1) within this CPG is a negative recommendation aimed at reducing unnecessary routine testing in patients following acute PE. This could be a cost saving initiative, if implemented successfully. Strategies for (de-)implementation of unnecessary testing could include educational and practice improvement programs targeting those users that routinely evaluate patients following acute PE (e.g., thrombosis clinics), and/or those who routinely provide the tests (cardiologists, radiologists). Other behavior change strategies could include audit and feedback, iterative physician learning and practice improvement cycles. Such efforts might be successful in partnership with the Choosing Wisely Canada initiative and Canadian university departments of continuing medical education (CME). Metrics of successful (de)implementation could include a reduction in the proportion of patients at low risk for CTEPH post-acute PE who undergo routine screening echo, V/Q, and/or CTPA scans. Although administrative databases could be used to assess trends in the frequency of these tests among patients with PE, a rigorous measure of successful de-implementation would not be possible through administrative databases, since the indication for each test would need to be considered. Such an analysis would require individual centre and/or individual physician practice audits.
The second recommendation (PICO 2) is a positive recommendation designed to increase the rate of CTEPH diagnosis by placing the most sensitive test (V/Q) as the initial test within the recommended diagnostic algorithm. This recommendation is expected to improve patient outcomes through an earlier diagnosis of CTEPH and through a reduction in the number of misclassified or missed cases of CTEPH. Implementation of this recommendation will similarly require target audience education, and will also require practice improvement programs, in this instance, for users that evaluate patients with PH (ie. respirologists, cardiologists). One barrier to implementation might be the existence of previously established protocols and practice patterns.
Another barrier may be the lack of access to V/Q and/or radiologist expertise in V/Q interpretation in some centres. Metrics of successful implementation would include increased use of V/Q scanning in appropriate patients, increased rates of CTEPH diagnosis and possibly a shortened time from symptom onset to diagnosis, and/or reduced severity of disease at the time of diagnosis as measured by WHO class and right-sided hemodynamics.
The third recommendation (PICO 3) is aimed at helping clinicians to establish an accurate diagnosis of CTEPH and to direct patients to a PH expert centre at the most appropriate stage of the diagnostic evaluation. This is accompanied by the parallel goal to establish the best modality to assess the anatomic extent and location of disease. This recommendation is expected to improve patient outcomes through an increased rate of CTEPH diagnosis, through earlier diagnosis of CTEPH, and by a reduction in the number of misclassified or missed cases of CTEPH. CTEPH can be missed at this stage in the diagnostic process as a result of a false negative CTPA (due to technical inadequacy of the test, inadequate expertise of the interpreting radiologist, or due to distal CTEPH) leading to the patient not being referred to an expert PH centre. This represents a diagnostic care gap which we feel this recommendation will help to address. A key metric of success would be an increased number of appropriate CTEPH referrals to the PH centres.
Considering the various possible targets of our dissemination and implementation strategy, for messages targeting expert centres, it may be of benefit to define (and audit practices of) PH centres of excellence. Audits could include peer assessments of the technical adequacy and performance of readers for key imaging technologies pertinent to CTEPH including V/Q, CTPA and conventional pulmonary angiography. Such initiatives might be possible in collaboration with PHA Canada, similar to a PH centre accreditation process instituted by PHA in the United States.
For messages targeting non-experts, there is currently significant uncertainty surrounding the types and magnitude of existing knowledge gaps. In order to tailor educational material, some of these knowledge gaps are currently being assessed. Specifically, a pre and post guidelines survey is underway to assess knowledge gaps in urban and rural respirologists as well as urban internists and hematologists. Further research to assess knowledge gaps specifically affecting clinicians in rural and remote settings would be of benefit. An anticipated barrier to implementation of the CPG recommendations in these contexts is the possible lack of access to key diagnostic technologies (i.e., echocardiography and/or V/Q scan) and/or expert interpretation of these tests. Clinicians working in rural or remote areas are therefore likely to have unique implementation needs. Interventions targeting non-experts might also include CTEPH training modules and local quality improvement programs for clinicians, radiologists and health system managers. 1. We recommend against routine screening for the presence of CTEPH following an acute pulmonary embolism.
# 1C
Initial testing for CTEPH How should patients with PH be tested for CTEPH? 2. In patients with PH, we recommend that clinicians perform nuclear V/Q lung scanning as initial testing to rule out CTEPH.
# Clinical remarks:
Either Planar or SPECT nuclear V/Q are acceptable modalities for initial testing to rule out CTEPH.
A normal perfusion (Q) scan effectively rules out the possibility of CTEPH.
A negative CTPA does NOT effectively rule out CTEPH.
# 1C
# Diagnosis of CTEPH
In patients with suspected CTEPH: a) Should CTPA be used to establish the diagnosis and assess anatomic extent and location of chronic thromboembolic material?
3a) We recommend that clinicians perform CTPA to confirm the presence and assess the anatomic extent and location of chronic thromboembolic material in patients with suspected CTEPH.
# Clinical remarks:
A positive CTPA, confirming chronic thromboembolism, should prompt a referral to an expert PH centre for establishment of a formal diagnosis of CTEPH, and assessment of most appropriate treatment.
Findings of chronic thromboembolism on CTPA include intraluminal fibrous bands or webs, stenoses, partial occlusions, total occlusions (pouch defects), and eccentric organized thrombi that form an obtuse angle with the vessel wall.
A negative, indeterminate, or technically poor CTPA does not exclude CTEPH.
Patients with these non-positive CTPA results and suspected CTEPH should be referred to an expert PH centre for further diagnostic testing, such as conventional pulmonary angiography.
# 1B
In patients with suspected CTEPH: b) Should magnetic resonance pulmonary angiography (MRPA) be used to establish the diagnosis and assess the anatomic extent and location of chronic thromboembolic material? 3b) We do not recommend the routine use of MRPA to establish the diagnosis and/or to assess the anatomic extent and location of chronic thromboembolic material in patients with suspected CTEPH.
# Clinical remarks:
There are few centres with MRPA experience in CTEPH.
MRPA should be distinguished from cardiac MRI protocols used for the assessment of pulmonary hemodynamics and right ventricular function in various types of PH, including CTEPH.
# 1C
Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension; V/Q, ventilation/perfusion; CTPA, computed tomography pulmonary angiogram.
# Summary
Q1: Should patients be screened for CTEPH (using echo and/or pulmonary vascular imaging with V/Q lung scan or CTPA) following an acute pulmonary embolism to increase the rate of diagnosis or improve clinical outcomes of CTEPH? | BACKGROUND: An important and common cause of pulmonary hypertension (PH) is chronic thromboembolic PH (CTEPH). Many care gaps exist in the evaluation of CTEPH including lack of awareness of the diagnosis, failure of clinicians to routinely consider CTEPH in patients at risk, and misguided diagnostic assessment practices including those which may be incomplete or unnecessary. METHODS: A representative multidisciplinary panel of expert physicians undertook a formal clinical practice guideline development process. A total of 4 key clinical issues were defined according to the Patient/problem, Intervention, Comparison, Outcome (PICO) approach. The panel performed an evidence-based, systematic literature review, assessed and graded the relevant evidence, and made 4 recommendations. RESULTS: Patients should not be routinely screened for the presence of CTEPH (using echo or pulmonary vascular imaging) following an acute pulmonary embolism (PE). Risk factors for CTEPH following acute PE have been established, and patients in these higher risk groups may merit closer attention during clinical follow-up. Routine screening for CTEPH following acute PE has not yet been demonstrated in prospective controlled trials to improve patient outcomes. In patients with PH, clinicians should perform nuclear ventilation/perfusion (V/Q) lung scanning as initial testing to rule out CTEPH. Either planar or single photon emission computed tomography (SPECT) V/Q are acceptable forms of V/Q lung scanning. A normal perfusion scan effectively rules out the possibility of CTEPH. A negative computed tomography pulmonary angiogram (CTPA) does not rule out CTEPH. In patients with suspected CTEPH, CTPA should be performed to confirm the presence and assess the anatomic extent and location of chronic thromboembolic material. A positive CTPA, confirming chronic thromboembolism, should prompt referral to an expert PH centre where a formal diagnosis can be established. A negative, indeterminate or technically poor CTPA does not exclude CTEPH and should also prompt referral to an expert PH centre for further testing. Magnetic resonance pulmonary angiography is not currently recommended for routine assessment in patients with suspected CTEPH. DISCUSSION: The foundation of CTEPH diagnosis remains clinicians' consideration of this possibility in patients at risk. Future research is required to identify the specific diagnostic tests and/or algorithms which will perform best in formal screening protocols for CTEPH. The current diagnosis of CTEPH will until then continue to rely on clinician led case finding, with diagnostic investigations arranged during the course of clinical care. Once case finding investigations have been initiated, an approach which follows the recommendations and sequence of testing outlined in this guideline may improve the rate of diagnosis of CTEPH and potentially the outcomes in these patients. This guideline will be reviewed every three years or sooner, in accordance with the Canadian Thoracic Society Living Guideline Model.# Introduction
# Chronic thromboembolic pulmonary hypertension
Pulmonary hypertension (PH) is a serious condition of the pulmonary blood vessels characterized by increased pulmonary arterial pressure (PAP) and is often associated with progressive right ventricular (RV) failure and a high risk of death. PH is increasingly recognized as an important cause of dyspnea and exercise limitation in many patients. As per the current World Health Organization (WHO) PH classification updated at the Sixth World Symposium on Pulmonary Hypertension held in 2018 in Nice, France (Tables 1 and 2), PH can be associated with underlying disorders of the heart and lungs or be due to intrinsic disease of the small pulmonary arteries, known as pulmonary arterial hypertension (PAH).
A very important and common 1 cause of PH is chronic thromboembolic PH (CTEPH). CTEPH is a result of pulmonary vascular obstruction characterized by recurrent, unresolved pulmonary emboli (PE) and/or progressive pulmonary vascular thrombosis and scarring. In the present document, CTEPH has been defined as follows:
1. A mean PAP (mPAP) of 25 mmHg or greater and pulmonary vascular resistance (PVR) of 3 Wood units (240 dynes/cm 5 ) or greater; and 2. Persistent pulmonary arterial thrombotic obstruction despite at least three months of effective, uninterrupted anticoagulation.
It is of note that following completion of the evidence review and recommendations for this guideline document, the WHO hemodynamic definition of PH 2 was revised to include mPAP> 20 mmHg, pulmonary artery wedge pressure (PAWP) of 15 mmHg or less and a PVR 3 Wood units or greater. This revised hemodynamic definition was not used in this document but will be considered in future guideline updates.
The potential differential diagnosis for CTEPH includes a range of pulmonary vascular diseases such as: (i) central pulmonary artery thrombosis in the setting of dilated pulmonary arteries secondary to PAH, emphysema or congenital heart disease (ii) pulmonary artery sarcoma; (iii) extrinsic vascular compression such as from fibrosing mediastinitis;
(iv) pulmonary veno-occlusive disease (PVOD); (v) large vessel pulmonary artery vasculitis; and (vi) congenital pulmonary artery branch stenosis.
Clinical recognition of CTEPH is important for several reasons. First, CTEPH is believed to be one of the more common causes of PH, affecting approximately 3% of patients following PE. 1,3 Second, CTEPH is a serious, progressive and often fatal disease. Patients with untreated CTEPH experience significantly increased mortality. Historical observational studies 4,5 have estimated the median survival rate in severe untreated CTEPH patients to be as low as 10-20% at 2-3 years. Contemporary registry data 6 also illustrate the significant mortality of CTEPH, with 3-year survival rates in some subpopulations as low as 70%, even with access to modern era therapies. Third, CTEPH is potentially curable with pulmonary endarterectomy (PEA) surgery. Finally, CTEPH patients may also benefit from other treatments such as with balloon pulmonary angioplasty (BPA), PAH-targeted medications and/or other interventions.
The objective of the present guideline is to inform and provide evidence-based recommendations in the following areas:
# Differences from prior guideline published in 2010
This Clinical Practice Guideline (CPG) represents an update from an earlier guideline published in 2010 by the Canadian Thoracic Society (CTS). 7 Changes from the prior guideline include the following: This CPG is focused on case finding and the diagnostic evaluation of CTEPH. CTEPH treatments are not within the scope of this document (but will be included in a subsequent CPG publication focused on CTEPH management). A graphical diagnostic algorithm is provided. Guideline applicability and implementability have been considered throughout the CPG development process. Updated reviews of CTEPH epidemiology and incidence are not provided.
# Sections
Clinical Questions Section 1: Screening for CTEPH Should patients be screened for CTEPH (using echo and/or pulmonary vascular imaging with ventilation/perfusion (V/Q) lung scan or computed tomography pulmonary angiography (CTPA)) following an acute pulmonary embolism to increase the rate of diagnosis or improve clinical outcomes of CTEPH? In patients with suspected CTEPH, should magnetic resonance pulmonary angiography (MRPA) be used to establish the diagnosis and assess the anatomic extent and location of chronic thromboembolic material? In Section 1 on screening for CTEPH following acute PE, the specific patient population has been broadened from asymptomatic patients to now include all patients following acute PE, irrespective of symptoms. This change was felt by the panel to lead to a recommendation that would be more actionable by clinicians and made with consideration of the practical challenges which can arise in attempting to define normal versus abnormal symptoms following acute PE.
# Target patient population
The current CPG applies to all adult individuals with prior acute PE, undifferentiated PH, and suspected CTEPH.
# Target users
The present CPG is intended for use by the health care teams that care for individuals with venous thromboembolic disease, PH and CTEPH. Specifically, family practitioners and specialist physicians (respirologists, cardiologists, hematologists, internists, cardiac and thoracic surgeons, and radiologists), and other health care professionals who suspect or currently care for patients with deep vein thrombosis (DVT)/PE, PH and/or CTEPH can use these guidelines to help improve their clinical practice. This document should also be useful to patients and patient advocates. Finally, health care decision makers may also use this guideline in policy processes to inform coverage decisions.
# Guideline panel composition
The CTEPH guideline panel was comprised of clinicians and health care professionals with content expertise. The panel was chaired by one author (DH) and included 10 respirologists (2 international experts), one cardiologist, one radiologist specializing in cardiothoracic imaging and one thoracic surgeon. All author conflicts of interests are posted on the CTS website at https://cts-sct.ca/guideline-library/.
# Methodology
This CPG was developed in accordance with CTS guideline development process. 8 The panel utilized the AGREE II checklist to guide the development of this guideline. 9
# Formulation of key clinical questions
The panel determined key clinical questions in the areas of screening and/or case finding, assessment and diagnosis of CTEPH. Questions were crafted with consideration of those disease areas where the panel felt there to be substantial current knowledge-to-care gaps: for example, existing clinical practices contributing to cases of CTEPH being missed. The PICO method was used taking into consideration the Patient group or groups that should be addressed; the Intervention or interventions that should be examined; the Comparison groups that should be part of the studies of the various interventions; and the Outcome or outcomes of interest (Appendix 1). In the second part of the PICO process, panel members were asked to consider issues that influence implementability when choosing PICO questions: these include the magnitude of the knowledge-to-care gap; target audience(s); known barriers and supports to implementation; possible implementation strategies; societal impact; and measurability of any implementation program.
Literature search and screening of abstracts An initial literature search was completed current to December 14, 2015 using MEDLINE (OVID); Embase (OVID); HealthStar; the Cochrane Library: the Canadian Medical Association InfoBase; and the National Guideline Clearinghouse. The second literature search was conducted through to March 10, 2017 and a third search from January 1, 2017 to September 30, 2017 was also conducted to include the most recent literature, across the same databases. Additional articles were found by review of the references in the articles accepted. Details of the search strategy are outlined in Appendix 1. A graphical representation of the flow of citations and articles reviewed are shown in Figure 1. The title and abstracts of each article were scrutinized by two panel members to decide whether the article was relevant.
Where there was a difference of opinion, the panel members endeavored to reach consensus. When a consensus was reached on the list of relevant abstracts, copies of the articles of all relevant and possibly relevant articles were obtained. The chosen inclusion and exclusion criteria were noted at the abstract and full text review stages.
# Study selection criteria
Articles selected for inclusion in the systematic review of the evidence reported data on CTEPH diagnosis. Animal studies, pathology or preclinical studies, clinical images, isolated hemodynamic reports, letters, editorials, duplicate publications without original data, reviews, studies published in a language other than English and French, and studies of uniquely pediatric populations were excluded. Studies were evaluated in detail by pairs of reviewers who did the data extraction to ensure that selection criteria were met and agreed upon.
# Critical appraisal of identified studies
Data from all articles relevant to each PICO question were compiled into tables by each section and are found on the CTS website. During discussion of each question via webinars held in 2017 and 2018, all data were reviewed by all members of the panel, and group consensus was established regarding the quality of the evidence addressing each clinical question, according to the components of the GRADE criteria 11 (Table 3).
# Synthesis of evidence-base and clinical judgment of risk versus benefit
For each clinical question, the panel considered the strength and directness of the published evidence supporting an intervention or treatment approach. The panel discussed the potential health benefit to patient, the overall impact on the population burden of morbidity and mortality of CTEPH, and issues of risk, burden on a patient to adhere, and cost effectiveness of an intervention or treatment (implementability factors categorized under the "Contextualizations and Deliberations" domain of guidelines 12 ). These discussions and the resulting synthesis of evidence and summary clinical judgement are presented for each recommendation. Good practice points are included in association with each clinical question and are intended to offer short pieces of advice to the target user. Some of these good practice points may not have an evidence base but are viewed as good clinical practice by the expert panel. All good practice points were arrived at by consensus, based on the clinical experience of the guideline panel members.
# Formulation of recommendations and classification
Following the open and extensive discussions and review for each PICO question, a draft recommendation was proposed by the entire group. The strength of the recommendation was based on consideration both of the GRADE quality of evidence, and the expert panel's synthesis of clinical judgment. The recommendations were then vetted by the CTS Canadian Respiratory Guidelines Committee (CRGC) Chair to optimize the language of each recommendation to ensure implementability. The recommendation consensus process was completed by electronic survey using a six-point voting scale (Table 4), whereby it was defined a priori that a recommendation would only be accepted if each panel member voted for option 1, 2 or 3 (wholeheartedly agree, agree or can support). For a recommendation to be accepted, it had to be voted on by 75% of the eligible panel members and achieve ratings of 1, 2 or 3 by 80% of the voting panelists.
No panel member was excluded from voting. In the event of a failure to reach 80% of votes with ratings of 1, 2 or 3, another period of discussion ensued, whereby dissenting opinions were heard and considered. The recommendation was revised and followed by a second round of voting by electronic survey using a three-point scale, for which acceptance of a recommendation required a majority (80%) of panelists to choose option 1 or 2 (Table 4). Through this process, all recommendations achieved acceptance, with a second round of voting required for only one recommendation.
# Applicability/implementability
Recommendations were formulated with the aim of being clear and actionable by clinicians within the user group, in accordance with best principles for guideline language and format. 13 For example, precise criteria were utilized in defining patient populations and diagnostic tests results, wherever possible. Lack of access to key modalities (i.e., echocardiogram, pulmonary vascular imaging) could represent a barrier to guideline applicability in some jurisdictions. A graphical algorithm addressing assessment of CTEPH in patients with For a recommendation to be accepted, it had to be voted on by 75% of the eligible panel members and achieve ratings of wholeheartedly agree, agree or can support by 80% of the voting panelists. If this was not achieved, additional discussion ensued and revision of the recommendation was made, after which the second round of voting proceeded using a three-point scale, for which acceptance of a recommendation required a majority (80%) for option 1 or 2. PH is provided as a tool for clinicians to aid in implementing recommendations. The potential resource implications of applying the recommendations from this CPG were considered. This includes the possible need for increased diagnostic tests to be performed in order to improve patient outcomes via effective screening and/or case finding of CTEPH and through more precise diagnostic evaluation.
Our goal is to monitor the impact of these CPG recommendations through their ability to correct knowledge gaps within the target user group (a pre and post guideline survey project is underway) as well as to track characteristics and frequency of CTEPH cases at the expert PH centres (a Canadian PH database project is underway, including enrollment of CTEPH patients).
# Review and approval process
In accordance with the CTS guideline review and approval process, before completion, the CTS independently invited formal review of the guideline by: two external (non-CTS) international content experts and two internal (CTS) reviewers. One of the internal reviewers performed an AGREE assessment of the guideline. The draft guideline was reviewed by the Canadian Society of Thoracic Radiology Executive Committee. The Pulmonary Hypertension Association (PHA) of Canada coordinated a patient review of the draft guideline. The authors were blinded to the identities of the reviewers. The lead author provided responses to the comments and made corresponding changes to the manuscript. These reviews and the AGREE II scoresheet were provided to the CTS CRGC for review. Two members of the CRGC then completed a review of the guideline and these documents and provided further feedback for consideration by authors. Upon acceptance, the CRGC recommended approval of the guideline to the CTS Executive Committee. All reviews and author responses are posted on the CTS website at https://cts-sct.ca/guideline-library/.
Living guideline/future updates The Diagnosis of CTEPH guideline PICO questions will be uploaded in the CTS/McMaster Plus database. The authors will use the continuously updated McMaster Plus database to review new articles published in top journals starting from the last date of the literature conducted for this CPG. The studies are indexed according to the PICO questions and made available to the guideline panel on a dedicated software platform for manual assignment to individual reviewers. This evidence service will prompt guideline updates and facilitate reviews. The guideline will be formally reviewed every three years or sooner to determine the need for and nature of any updates, in accordance with the CTS Living Guideline Model (details available at www.cts-sct/guidelines.ca).
# Summary of evidence
# Key evidence
A systematic review of the literature found no randomized controlled trials (RCTs) or controlled studies of the effectiveness of CTEPH screening in improving the diagnosis of CTEPH or clinical outcomes in patients post-acute PE, nor in any specific high-risk subgroups. Many uncontrolled studies have followed patients post-acute PE, "screening" for the presence of PH by echo in all patients or selectively in patients with symptoms suggestive of CTEPH, as reviewed in a metaanalysis 3 of 21 published studies. Several studies found a higher prevalence of CTEPH in patients with residual symptoms following 3-6 months of effective anticoagulation postacute PE (e.g., dyspnea, exercise limitation, chest pain), although the vast majority of these symptomatic patients did not have CTEPH. 7,[11][12][13]16,25 Although most studies suggest that echo screening can identify a number of patients with PH post-acute PE, these studies are limited by highly variable criteria that were not consistent with recommendations for echo detection of PH (e.g., right ventricular systolic pressure (RVSP) thresholds from 30 to 50 mmHg). Moreover, there was often limited formal diagnosis of the presence or the cause of PH by right heart catheterization (RHC) and only infrequent definitive CTEPH diagnosis in many of these studies.
In the aforementioned meta-analysis, 3 of the 14 studies which confirmed CTEPH by RHC, 4,7,8,[11][12][13][14][15][16]18,19,21,23,26 9 studies had screened all included patients with echo, 8,11,12,[14][15][16]18,21,26 whereas echo was only performed in patients reporting dyspnea in 4 other studies. 4,7,13,23 Overall, systematic screening did not increase CTEPH detection rate, as the incidence of CTEPH was the same whether all patients were screened post-PE or only symptomatic patients were investigated.
Thus, the recommendation informing this question is crafted in the absence of any direct evidence, and is based on indirect evidence (case series, cohort studies) showing no clear benefit of screening, as well as the consensus of the expert panel.
# Expert panel synthesis of evidence-base and clinical judgment of risk versus benefit
The panel recognized the lack of any direct evidence to address the specific question of whether screening increases the rate of diagnosis of CTEPH or results in improved CTEPH outcomes. Other relevant factors in screening for CTEPH were considered, including the moderate likelihood of significant direct benefit to the individual patient, the low burden of adherence but moderate potential adverse effects of pursuing screening and subsequent further work-up. In addition, the panel expected low overall impact on morbidity and mortality for the population of patients post-acute PE. There are no cost-effectiveness data available, but the panel strongly felt that routine screening for CTEPH was unlikely to be costeffective. None of the three tests of echocardiogram, V/Q scanning or CTPA fulfilled the WHO /Wilson's 27,28 requirements for good screening tests, when used to screen for CTEPH.
# Patient values and preferences
No studies were found that assessed patient values or preferences with regards to screening for CTEPH. It was the panel's consensus that most patients with acute PE would be willing to undergo clinical and noninvasive assessments if they were effective in diagnosing CTEPH sooner and especially if they were effective in improving clinical outcomes.
# Good practice points
The panel emphasized that the negative recommendation for routine screening of patients post-acute PE may not apply to certain subpopulations. The panel recognized the importance of clinically based follow-up in higher risk groups but emphasized that this clinical follow-up should be tailored to the specific situation and does not always need to include a follow-up echocardiogram and/or pulmonary vascular imaging. Specific subpopulations which warrant closer follow-up post-acute PE include: although conversely, a single study suggested a higher risk of CTEPH in younger patients. 4 Although not yet validated in prospective controlled trials, patients postacute PE with risk factors for CTEPH may merit closer clinical attention during follow-up, which most importantly involves clinical monitoring for symptoms (e.g., dyspnea) and functional limitation, but also the targeted use of echocardiography (e.g., to look for elevated RVSP, secondary signs of PH such as RV enlargement and/or RV systolic dysfunction). The panel emphasized that routine follow-up pulmonary vascular imaging (V/Q lung scan or CTPA) is not indicated for screening of CTEPH, even in these higher risk groups. The recommended techniques and diagnostic sequencing of pulmonary vascular imaging when used for CTEPH case finding is summarized in our algorithm (Figure 2). 3. Patients with acute PE who remain symptomatic despite 3 months of effective anticoagulation. Persistent symptoms or low health related quality of life (HRQoL) scores are common in patients with acute PE despite appropriate anticoagulation. 15,29,30 Unexplained dyspnea and functional limitation which persist following at least 3 months of effective anticoagulation can suggest the presence of CTEPH. Such patients merit appropriate clinical and diagnostic investigation for common conditions which may contribute to these persisting symptoms including the "post PE syndrome" 29 and other types of lung or heart diseases, as well as CTEPH. 4. Other clinical indications for follow-up pulmonary vascular imaging. The panel recognized that there may be other clinical indications to perform follow-up pulmonary vascular imaging (V/Q lung scan or CTPA) in selected patients post-acute PE, such as to decide on duration of anticoagulation, to assess risk of recurrent PE, or to establish a baseline before ongoing surveillance for recurrent PE.
# Areas for future research
Given the clinical importance of CTEPH, and the significant benefits of available treatment approaches, research to better identify asymptomatic patients post-acute PE who have an elevated risk of developing CTEPH would be helpful. There is a need for studies to further identify and assess the magnitude of risk factors for CTEPH within the range of populations reflective of clinical practice, including symptomatic and asymptomatic patients as well as those with comorbid conditions. There may also be benefit to the development of scoring systems which combine multiple risk factors to define a composite or overall CTEPH risk, thereby identifying specific subpopulations of patients post-acute PE who could benefit from structured CTEPH screening. Future research should focus on clinical benefit, costeffectiveness, and patient preferences around screening approaches for CTEPH, ideally within prospective controlled trials.
# Introduction
CTEPH is a common and important cause of PH, with a distinct management strategy. Thus, the possibility of CTEPH should be carefully considered in all patients with PH. History alone is insufficient to confirm or exclude CTEPH, as at least one-quarter of CTEPH patients in registries 1 and likely a greater proportion in clinical practice have not experienced symptomatic or documented acute PE. Moreover, physiologic tests such as cardiopulmonary exercise testing also lack the required high sensitivity to rule out CTEPH. 2,3 A diagnosis of CTEPH requires appropriate pulmonary vascular imaging. The three most commonly proposed imaging modalities for initial testing of CTEPH in PH patients are nuclear V/Q lung scanning, CTPA and lung perfusion magnetic resonance imaging (MRI). There have been technical innovations in all of these imaging modalities since our prior guideline recommendations in 2010.
In this section we address how patients with PH should be assessed for CTEPH.
# Key evidence
Our review found no RCTs or other direct evidence addressing the effect of testing for CTEPH in patients found to have PH. Thus, the recommendation addressing this question is based upon indirect evidence from several cohort studies, as well as the consensus of the expert panel.
# Planar V/Q
Our previous 2010 guideline 4 recommended nuclear V/Q for CTEPH assessment in patients with PH. This recommendation was significantly influenced by one single centre retrospective study 5 in which 227 patients with PH referred to a tertiary centre were assessed for CTEPH. Conventional pulmonary angiography was used as the reference standard technique. Planar V/Q was compared with 4-8 detector CTPA in assessing for CTEPH. Large vessel CTEPH was detected by V/ Q with a sensitivity of 97.4% and a specificity of 90%. CTPA had a sensitivity of only 51% but a specificity of 99%.
A cohort study by He et al. 6 assessed 114 patients with suspected CTEPH who all underwent planar V/Q scan, 16 or 64 detector CTPA and conventional pulmonary angiography. Fifty-one patients were diagnosed with CTEPH, 60 with idiopathic PAH and 3 with an atrial septal defect. Conventional pulmonary angiography was used as the reference standard technique. CTEPH was detected by V/Q with a sensitivity of 100% and a specificity of 93.7%. CTPA had a sensitivity 92.2% and specificity of 95.2%. To explain the higher sensitivity of CTPA in this study in comparison to Tunariu et al. 5 it is proposed that there may have been a lower proportion of subsegmental PE in the cohort evaluated by He et al. 6 and/or CTPA improvements related to the use of more advanced CT scanners.
# SPECT V/Q
SPECT nuclear V/Q scanning represents the state of the art of perfusion scintigraphy and has emerged as being more sensitive than planar scintigraphy for the diagnosis of acute PE. 7,8 Many centres in the world, including those within Canada, have replaced planar V/Q equipment with SPECT V/Q as the standard of care.
No studies were found which specifically evaluate SPECT V/Q as an initial test to rule out CTEPH.
A single centre prospective blinded cohort study 9 compared planar V/Q to SPECT V/Q for a clinical question indirectly related to this PICO question; the assessment of extent and location of chronic thromboembolic material in 17 patients with CTEPH. The reference standard involved an evaluation of the PEA surgical specimen as a "mold" of the obstructed pulmonary vasculature. Obstructed segments were detected by SPECT V/Q with a sensitivity of 63.5% and specificity of 62.6%. Planar V/Q had a sensitivity of 42.7% and specificity of 76. 8%. These differences in sensitivity were statistically significant (P < 0.01). This small study suggests that SPECT V/Q might be more sensitive than planar V/Q in detecting the obstructed pulmonary vessels characteristic of CTEPH. A normal perfusion (Q) scan effectively rules out the possibility of CTEPH.
A negative CTPA does NOT effectively rule out CTEPH.
A subsequent cohort study from the same authors 10 compared SPECT V/Q to 4-and 64-detector CTPA in 9 patients with CTEPH undergoing PEA surgery. The reference standard again involved an evaluation of anatomic distribution of chronic thrombotic material in the removed PEA specimen. SPECT V/Q had a sensitivity of 62% and specificity of 72% for detecting the obstructed pulmonary arteries. CTPA had significantly lower sensitivity of 47.8% (p < 0.03), and similar specificity of 80%. This study suggests that SPECT V/Q may be more sensitive than 4 and 64 detector CTPA in detecting the obstructed pulmonary vessels characteristic of CTEPH.
# DE-CTPA
Dual energy CTPA (DE-CTPA) is a novel CT angiographic technology which maps the iodine content of the lung microcirculation to provide information about pulmonary vessel obstruction and its downstream functional consequences.
A cohort study of 51 patients with established CTEPH 11 evaluated DE-CTPA in comparison to SPECT V/Q as the reference standard. The sensitivity of DE-CTPA was high (96%) with a lower specificity (76%). In some of the DE-CTPA cases, the lung segments containing perfusion defects (8.3%) could not be evaluated due to artifacts.
Another single centre prospective cohort study using DE-CTPA 12 assessed 40 patients referred with PH, of whom 14 were diagnosed with CTEPH. The reference standard for CTEPH diagnosis in this study was also based on planar V/Q (the presence of at least once segmental perfusion defect). This study compared planar V/Q to !64 detector CTPA and DE-CTPA. The sensitivity of DE-CTPA and CTPA were both reported at 100%. The specificities were 92% for DE-CTPA and 96% for CTPA. In the subgroup of CTEPH patients, 7.9% of lung segments were of non-diagnostic quality on DE-CTPA iodine maps due to artifact. There was better agreement between DE-CTPA and V/Q (k ¼ 0.44) than between CTPA and V/Q (k ¼ 0.09-0.31) at the segmental level.
Giordano et al. 13 evaluated DE-CTPA in a pre-selected group of patients without emphysema and with either PAH (n ¼ 13) or "peripheral type" CTEPH (n ¼ 9). There was a high concordance (100%) between V/Q and DE-CTPA in the peripheral type CTEPH group, with all studies showing defects. In the PAH group there were a number of false positive perfusion defects (3/13 ¼ 23%) identified with DE-CTPA.
In summary, the body of evidence pertaining to DE-CTPA fails to establish superiority in comparison to V/Q (which was used as the reference standard technique in all of the studies) and also demonstrates imaging artifacts which may limit interpretation of the DE-CTPA perfusion defects.
Access to DE-CTPA as well as expertise in its diagnostic interpretation remains limited. DE-CTPA has complex image acquisition and post processing needs, which require appropriate expertise.
# DCE lung perfusion MRI
Cardiac MRI is an important tool to assess the right ventricle in patients with PH. Cardiac MRI should be distinguished from dynamic contrast enhanced (DCE) lung perfusion MRI which is a time-resolved form of magnetic resonance (MR) pulmonary angiography designed to assess distal lung perfusion. The PH centre in Papworth UK has extensive experience using 3D DCE lung perfusion MRI in the evaluation of patients referred for assessment of suspected CTEPH. 14 In a cohort of 132 patients referred (78 diagnosed with CTEPH), lung perfusion MRI was reported to have test characteristics (sensitivity 97%, specificity 92%) similar to nuclear Q scanning (sensitivity 96%, specificity 90%). No invasive pulmonary angiography was performed in this cohort. The reference standard for the diagnosis of CTEPH was based on a multidisciplinary meeting involving data from CTPA, MRI and nuclear V/Q scanning.
A single centre blinded retrospective cohort study using lung perfusion MRI 15 enrolled 74 patients undergoing evaluation for CTEPH. Within this cohort, 36 patients were diagnosed with CTEPH, 10 patients with CTED (without PH) and 28 patients had chronic thromboembolic disease excluded. The reference standard for the diagnosis of CTEPH was based on a multidisciplinary meeting using V/Q and CT data. SPECT V/Q was compared to a 3-dimensional DCE lung perfusion MRI. The lung perfusion MRI demonstrated similar sensitivity (100%) and specificity (81%) to SPECT V/Q (sensitivity 97%, specificity 81%) for the diagnosis of chronic thromboembolism.
No studies were found that suggest the superiority of lung perfusion MRI over nuclear V/Q scanning in the assessment of CTEPH.
Access to lung perfusion MRI technology, as well as expertise in its diagnostic interpretation, is currently limited in most centres worldwide. Lung perfusion MRI has complex image acquisition and post processing needs, which require appropriate expertise.
# Other imaging technologies
While Electrocardiogram (ECG)-gated multidetector CT, 16,17 cone beam CT angiography 17 and 320 detector CTPA 18 have been used in the assessment of CTEPH, these particular studies have focused on establishing the diagnosis and assessing the anatomical extent/location of thromboembolic material (reviewed in PICO 3) rather than as initial testing for CTEPH in populations of patients referred with PH.
# Expert panel synthesis of evidence-base and clinical judgement of risk versus benefit
The panel graded the body of evidence as low. The higher sensitivity of V/Q and lower sensitivity of CTPA in screening PH patients for CTEPH was consistent with the clinical experience of panel members. The lack of evidence for superiority of either DE-CTPA or DCE lung perfusion MRI in comparison to V/Q was also considered. The panel emphasized the significant potential for direct health benefit to the patient with accurate initial testing and subsequent diagnosis of CTEPH. The minimal adverse effects and minimal burden on the patient to adhere to the recommendation was considered. The panel considered the possible medium to high impact on morbidity and mortality for the population of PH patients as a whole with the recommended approach. The panel recognized the lack of cost effectiveness data, leading to the inconclusive economic benefits of the recommended approach.
# Patient values and preferences
No studies were found that assessed patient values or preferences with regards to assessment of the possibility of CTEPH in patients with PH. It was the panel's consensus that most patients with PH would be willing to undergo testing with V/Q lung scanning, particularly if this led to a more accurate diagnostic approach with fewer missed cases of CTEPH.
# Discussions/areas for future research
The panel identified the need for future RCTs of CTEPH assessment in patients with PH. Future trial designs need to consider the varying incidence of CTEPH in different populations of patients 23 and should focus upon populations which are most reflective of clinical practice. Future studies should include patients with a broad range of characteristics, including those with and without co-existing parenchymal lung disease. For example, future research to define the prevalence of CTEPH in populations of patients followed in emphysema or left heart failure clinics would be of particular relevance to the clinicians working in these areas.
Further study is required to fully define the test characteristics of V/Q when used to rule out CTEPH in the setting of an abnormal chest X-ray. Future research should be designed to guide the practices of both tertiary and community care centre physicians.
Multistep screening algorithms may increase the precision of CTEPH assessment. A recently published study 24 has demonstrated the utility of an algorithm starting with a structured symptom questionnaire and followed by diagnostic imaging. The panel suggests ongoing research into multimodality screening algorithms for CTEPH.
Further study is required to assess the outcomes when clinicians use testing algorithms and/or clinical probability scores to assess for acute PE in non-anticoagulated patients presenting with undifferentiated PH.
The panel emphasized the need for clinical research to maintain pace with the rapid development of new imaging technology. As new screening tools are developed, prospective controlled trials should be conducted which include robust gold standard definitions of CTEPH as well as meaningful clinical endpoints (Appendix 1). Future trials should consider the long-term impact of screening protocols, not just upon those patients in whom CTEPH is confirmed, but also upon those patients ultimately diagnosed with other causes of PH.
The clinical importance of mild abnormalities on V/Q lung scans (especially in the case of SPECT V/Q) remains uncertain. Future studies are needed in order to define significance of low probability V/Q abnormalities, particularly as it relates to their negative predictive value for a diagnosis of CTEPH.
Future studies using newer generations of CT scanners may help further define the role of CTPA in initial testing for CTEPH.
# Introduction
Confirmation of a diagnosis of CTEPH requires establishment of the presence of chronic thromboembolic lesions typical of this condition by at least one form of pulmonary angiography. 1,2 Angiography is also necessary to characterize the anatomic extent and location of chronic thromboembolic material, to assess for the most appropriate therapy; including accessibility for surgical PEA or BPA.
Several pulmonary angiographic modalities exist. Traditionally, conventional, invasive DSA has been considered the reference standard angiographic technique for CTEPH. Conventional pulmonary angiography is performed using contrast injections through catheters placed directly within the pulmonary arteries to provide detailed images of the pulmonary arterial tree. Conventional pulmonary angiography requires significant centre specific experience in order to obtain the most accurate results.
CTPA can also be used for imaging of the pulmonary arterial tree. CTPA has the advantages of being less invasive (contrast injections are given through peripheral IV) and more widely available than conventional angiography. There are important technical issues to consider in optimizing detection of chronic thromboembolism using CTPA.
Some centres have used MRPA with peripheral gadolinium contrast injection to assess the anatomic extent and location of chronic thromboembolism. 3 It has been unclear if CT or MRI pulmonary angiography can routinely be used to establish a diagnosis of CTEPH, and whether these modalities provide adequate image quality to properly evaluate chronic thromboembolic lesions for consideration of specific interventional therapies (e.g., PEA, BPA).
# Key evidence
Our review found no RCTs or other direct evidence assessing the use of CTPA for confirmation of diagnosis and/or assessment of anatomic extent of CTEPH. Specifically, there are no RCTs comparing CTPA to conventional pulmonary DSA. The recommendation informing this question is therefore based upon indirect evidence from one meta-analysis, several medium and small sized cohort studies, and the consensus of the expert panel. Dong et al. 4 published a meta-analysis based on systematic review of literature published between 1990 and 2015 assessing the diagnostic accuracy of CTPA in patients with CTEPH. Eleven articles met inclusion criteria (including a total of 712 patients). Some but not all reports used DSA as a gold standard, and there were minimal details provided on the DSA technique. Pooled analysis showed CTPA to have a sensitivity and specificity of 95% and 96% for main/lobar pulmonary artery disease, and of 88% and 89% for segmental disease, respectively. Subsegmental disease was not assessed.
A cohort study by Sugiura et al. 5 compared 320-detector CTPA to DSA in 44 patients with CTEPH and reported sensitivity and specificity for main/lobar pulmonary arterial disease of 97% and 97% and for segmental disease 86% and 95%. Subsegmental disease was not assessed.
Another cohort study by Reichelt et al. 6 used 64-slice CTPA in comparison to DSA in the assessment of 27 patients (CTEPH confirmed in 24). Sensitivity and specificity of CTPA for main/lobar disease was 98% and 95% and for segmental disease 94% and 93%.
A study by He et al. 7 assessed 114 patients referred with PH, of whom 51 were diagnosed with CTEPH. Several analyses were performed in this study, including an analysis of 16 and 64-slice CTPA images in comparison to DSA. Sensitivity and specificity of CTPA for the diagnosis of CTEPH were 92% and 95%. No information was presented on the anatomic extent of the disease.
Grgic et al. 8 used rigidly interpreted CTPA (using vascular obstruction index) and SPECT V/Q (using percentage of Box 3. Diagnosis of CTEPH PICO 3a: In patients with suspected CTEPH, should CTPA be used to establish the diagnosis and assess anatomic extent and location of chronic thromboembolic material?
Recommendation:
1. We recommend that clinicians perform CTPA to confirm the presence and assess the anatomic extent and location of chronic thromboembolic material in patients with suspected CTEPH. (GRADE 1B)
# Clinical remarks:
A positive CTPA, confirming chronic thromboembolism, should prompt a referral to an expert PH centre for establishment of a formal diagnosis of CTEPH, and assessment of most appropriate treatment.
Findings of chronic thromboembolism on CTPA include intraluminal fibrous bands or webs, stenoses, partial occlusions, total occlusions (pouch defects), and eccentric organized thrombi that form an obtuse angle with the vessel wall.
A negative, indeterminate, or technically poor CTPA does not exclude CTEPH. Patients with these non-positive CTPA results and suspected CTEPH should be referred to an expert PH centre for further diagnostic testing, such as conventional pulmonary angiography.
vascular obstruction index) to predict PEA operability in 49 patients with CTEPH. CTPA performed well in depicting the central thromboembolic material, however, the extent of perfusion abnormalities was better depicted on the functional SPECT V/Q examination. CTPA and SPECT V/Q were therefore thought to provide complementary information in assessment of operability for PEA. Three retrospective cohort studies published by the group in Hannover, Germany [9][10][11] have evaluated a novel form of invasive pulmonary angiography utilizing cone beam CT images instead of DSA. Cone beam invasive angiography revealed high resolution images of the pulmonary arteries, including some to the subsegmental level, with potential superior intermodality agreement and delineation of distal CTEPH lesions in comparison to 64-detector CTPA 10 or DSA. 9
# Expert panel synthesis of evidence-base and clinical judgment of risk versus benefit
The panel graded the body of evidence as moderate. The evidence for the high specificity of CTPA in confirming the diagnosis of CTEPH was recognized, and this was consistent with the clinical experience of panel members. There was concern CTPA may not be sensitive enough to exclude CTEPH, particularly in patients with segmental/subsegmental disease as well as situations where the CTPA is performed or interpreted in less experienced centres. The panel emphasized the limited published evidence supporting CTPA when used for defining anatomic extent of CTEPH to plan PEA or BPA. But several panel members described their own clinical experience using CTPA to plan PEA. It was recognized that wider detector scanners (i.e., 320 slice) tend to provide superior image quality for chronic thromboembolic lesions. However, it was also noted that the bulk of the evidence informing this recommendation was obtained from studies which used 64 detector scanners. The panel had some concerns about the extent to which the evidence directly addressed the clinical question. The potential significant health benefit to the individual patient from a confirmed diagnosis of CTEPH was recognized. The panel also considered the minimal risk of harm to patient with CTPA, the minimal burden on the patient to adhere and the potential high impact on morbidity and mortality for the target population as a whole. Due to the lack of cost effectiveness data, the panel felt it was inconclusive as to whether the recommendation would be cost effective.
# Key evidence
Our review found no RCTs or other direct evidence assessing the use of MRPA for confirmation of diagnosis and/or assessment of anatomic extent of CTEPH. Specifically, there are no RCTs comparing MRPA to conventional invasive pulmonary angiography. The recommendation informing this question is therefore based upon the experience of the expert panel and indirect evidence from the following two retrospective cohorts.
The PH centre in Papworth, UK have used 3D DCE MRI for the confirmation of CTEPH and planning of PEA surgery. In a retrospective cohort 12 of 106 patients (53 with CTEPH, including 22 with segmental level disease), MRPA had high sensitivity of 98% and specificity of 94% in diagnosing CTEPH and was superior to 64-detector CTPA in depicting stenoses and post-stenotic dilatations. The addition of an unenhanced proton MR technique improved the detection of proximal disease. A subsequent research letter 13 described the results with this cohort expanded to 132 patients, showing similar results for MRPA for the diagnosis of CTEPH (97% sensitivity, 92% specificity). There were no comparisons with any forms of invasive pulmonary angiography in this cohort, either via DSA or cone beam CT.
Ley et al. 14 published a small retrospective cohort of 24 patients with CTEPH who underwent contrast enhanced MRPA, 40 to 64-detector CTPA and invasive DSA. Unfortunately, there were challenges with the DSA image quality in this study, with only half of the patients having DSA images rated excellent or good. For the diagnosis of main/lobar pulmonary arterial disease sensitivity and specificity were highest with CTPA (100% and 100%, respectively), followed by MRPA (83%, 99%) and DSA (66%, 100%). For the detection of segmental pulmonary arterial disease, the sensitivities and specificities were: CTPA (100% and 99%), MRPA (88%, 98%) and DSA (75%, 100%).
# Expert panel synthesis of evidence-base and clinical judgment of risk versus benefit
The panel graded the body of evidence as low. The body of evidence was thought to only indirectly address the clinical question. MRPA was considered to have potentially minimal health benefit to the individual patient in comparison to the more widely available and more studied techniques of CTPA and invasive pulmonary angiography. The panel also considered the minimal burden of adherence and minimal harm to the patient with MRPA, as well as its anticipated low impact on the morbidity or mortality of the target population. The panel emphasized the lack of cost effectiveness data but felt that MRPA was unlikely to be cost effective. The panel acknowledged the limited access to MRPA technology and emphasized the lack of widespread experience or expertise in MRPA assessment of CTEPH.
# Patient values and preferences (3a and 3b)
No studies were found that assessed patient values or preferences with regards to CTPA, MRPA or invasive pulmonary angiography. It was the panel's consensus that most patients would be willing to undergo CTPA, and then be referred to a local expert PH centre, and if required subsequently to a PEA/BPA centre, for additional investigations and treatments.
Good practice points (3a and 3b)
1. CTPA images may be non-diagnostic or suboptimal due to technical issues. Specific recommended technical criteria include a short breath hold acquisition (3-5 sec) as well as thin collimation and thin-slice reconstruction ( 1 mm) in axial, coronal and sagittal planes. 3-dimensional surface-shaded reconstructions may improve depiction of vessel cutoff. 15 Maximum intensity projections and oblique reconstructions along the long axis of the left and right pulmonary arteries may also be helpful.
# Evaluation for CTEPH in patients with contrast allergy
or renal dysfunction can represent a clinical challenge. These cases should be discussed with a PH expert centre. 3. Misinterpretation of CTPA images can lead to a missed or delayed diagnosis of CTEPH and/or the use of inappropriate therapies. 16 Referring centres should work with PH expert centres at (or prior to) the stage of CTPA image interpretation, when assessing patients with suspected CTEPH (see diagnostic algorithm, Figure 2). 4. Pulmonary angiographic and V/Q imaging data may be complementary when used for the planning of CTEPH treatments. 5. Most types of pulmonary vascular imaging can underestimate the true anatomic extent of CTEPH, when compared to intraoperative evaluation at the time of PEA. 6. Conventional DSA is the traditional reference standard, but like all imaging techniques can be suboptimal due to technical issues. Regular DSA quality control efforts should be undertaken at expert PH centres, to optimize the techniques of image acquisition.
Areas for future research (3a and 3b)
Future studies using newer generations of CT scanners may help further define the role of CTPA in confirming a diagnosis of CTEPH and in more effectively assessing the anatomic extent and location of chronic thromboembolic material. The panel highlighted the need for clinical research to maintain pace with the rapid development of new imaging technology. As new forms of CTPA are developed, prospective trials should be conducted in comparison to the traditional reference standard of a high quality DSA, for example a DSA performed in an experienced and high-volume CTEPH expert centre.
There remains only a small body of evidence to support CTPA or other noninvasive imaging techniques aimed at the evaluation of subsegmental level chronic thromboembolic material. Future studies on subsegmental disease which compare a variety of imaging techniques in comparison to DSA are required. Further study of imaging techniques for segmental and more distal levels of disease may reveal clinically important insights, particularly as it relates to assessment of potential candidates for BPA.
Cone beam CT represents a novel form of imaging during invasive pulmonary angiography, but there are only single-centre reports thus far. Potential future clinical use will require multi-centre validation studies.
Similarly, ongoing research into MRPA techniques may allow MRPA to expand beyond its current use in only a few selected centres worldwide.
The panel emphasized the importance of ongoing research regarding optimizing technical best practices for imaging techniques as well as future knowledge translation of such quality control practices.
# Dissemination and implementation
Our guideline will be disseminated through traditional channels including this publication, through the CTS website and social media channels, and through an accompanying slide deck which will be used to present this content to various groups across the country. Furthermore, an abridged online and electronic "quick reference" guide, including the algorithm addressing assessment of CTEPH in patients with PH (Figure 2), with a reference link to the full document will be produced. These materials will be circulated to all 15 expert adult PH centres in Canada and will be used in educational interventions with non-PH experts.
Our group has also considered the anticipated barriers/ enablers to implementation of our recommendations, which types of initiatives might be considered for implementation of recommendations, which metrics should be measured as indices of success, and how these might be measured.
The first recommendation (PICO 1) within this CPG is a negative recommendation aimed at reducing unnecessary routine testing in patients following acute PE. This could be a cost saving initiative, if implemented successfully. Strategies for (de-)implementation of unnecessary testing could include educational and practice improvement programs targeting those users that routinely evaluate patients following acute PE (e.g., thrombosis clinics), and/or those who routinely provide the tests (cardiologists, radiologists). Other behavior change strategies could include audit and feedback, iterative physician learning and practice improvement cycles. Such efforts might be successful in partnership with the Choosing Wisely Canada initiative and Canadian university departments of continuing medical education (CME). Metrics of successful (de)implementation could include a reduction in the proportion of patients at low risk for CTEPH post-acute PE who undergo routine screening echo, V/Q, and/or CTPA scans. Although administrative databases could be used to assess trends in the frequency of these tests among patients with PE, a rigorous measure of successful de-implementation would not be possible through administrative databases, since the indication for each test would need to be considered. Such an analysis would require individual centre and/or individual physician practice audits.
The second recommendation (PICO 2) is a positive recommendation designed to increase the rate of CTEPH diagnosis by placing the most sensitive test (V/Q) as the initial test within the recommended diagnostic algorithm. This recommendation is expected to improve patient outcomes through an earlier diagnosis of CTEPH and through a reduction in the number of misclassified or missed cases of CTEPH. Implementation of this recommendation will similarly require target audience education, and will also require practice improvement programs, in this instance, for users that evaluate patients with PH (ie. respirologists, cardiologists). One barrier to implementation might be the existence of previously established protocols and practice patterns.
Another barrier may be the lack of access to V/Q and/or radiologist expertise in V/Q interpretation in some centres. Metrics of successful implementation would include increased use of V/Q scanning in appropriate patients, increased rates of CTEPH diagnosis and possibly a shortened time from symptom onset to diagnosis, and/or reduced severity of disease at the time of diagnosis as measured by WHO class and right-sided hemodynamics.
The third recommendation (PICO 3) is aimed at helping clinicians to establish an accurate diagnosis of CTEPH and to direct patients to a PH expert centre at the most appropriate stage of the diagnostic evaluation. This is accompanied by the parallel goal to establish the best modality to assess the anatomic extent and location of disease. This recommendation is expected to improve patient outcomes through an increased rate of CTEPH diagnosis, through earlier diagnosis of CTEPH, and by a reduction in the number of misclassified or missed cases of CTEPH. CTEPH can be missed at this stage in the diagnostic process as a result of a false negative CTPA (due to technical inadequacy of the test, inadequate expertise of the interpreting radiologist, or due to distal CTEPH) leading to the patient not being referred to an expert PH centre. This represents a diagnostic care gap which we feel this recommendation will help to address. A key metric of success would be an increased number of appropriate CTEPH referrals to the PH centres.
Considering the various possible targets of our dissemination and implementation strategy, for messages targeting expert centres, it may be of benefit to define (and audit practices of) PH centres of excellence. Audits could include peer assessments of the technical adequacy and performance of readers for key imaging technologies pertinent to CTEPH including V/Q, CTPA and conventional pulmonary angiography. Such initiatives might be possible in collaboration with PHA Canada, similar to a PH centre accreditation process instituted by PHA in the United States.
For messages targeting non-experts, there is currently significant uncertainty surrounding the types and magnitude of existing knowledge gaps. In order to tailor educational material, some of these knowledge gaps are currently being assessed. Specifically, a pre and post guidelines survey is underway to assess knowledge gaps in urban and rural respirologists as well as urban internists and hematologists. Further research to assess knowledge gaps specifically affecting clinicians in rural and remote settings would be of benefit. An anticipated barrier to implementation of the CPG recommendations in these contexts is the possible lack of access to key diagnostic technologies (i.e., echocardiography and/or V/Q scan) and/or expert interpretation of these tests. Clinicians working in rural or remote areas are therefore likely to have unique implementation needs. Interventions targeting non-experts might also include CTEPH training modules and local quality improvement programs for clinicians, radiologists and health system managers. 1. We recommend against routine screening for the presence of CTEPH following an acute pulmonary embolism.
# 1C
Initial testing for CTEPH How should patients with PH be tested for CTEPH? 2. In patients with PH, we recommend that clinicians perform nuclear V/Q lung scanning as initial testing to rule out CTEPH.
# Clinical remarks:
Either Planar or SPECT nuclear V/Q are acceptable modalities for initial testing to rule out CTEPH.
A normal perfusion (Q) scan effectively rules out the possibility of CTEPH.
A negative CTPA does NOT effectively rule out CTEPH.
# 1C
# Diagnosis of CTEPH
In patients with suspected CTEPH: a) Should CTPA be used to establish the diagnosis and assess anatomic extent and location of chronic thromboembolic material?
3a) We recommend that clinicians perform CTPA to confirm the presence and assess the anatomic extent and location of chronic thromboembolic material in patients with suspected CTEPH.
# Clinical remarks:
A positive CTPA, confirming chronic thromboembolism, should prompt a referral to an expert PH centre for establishment of a formal diagnosis of CTEPH, and assessment of most appropriate treatment.
Findings of chronic thromboembolism on CTPA include intraluminal fibrous bands or webs, stenoses, partial occlusions, total occlusions (pouch defects), and eccentric organized thrombi that form an obtuse angle with the vessel wall.
A negative, indeterminate, or technically poor CTPA does not exclude CTEPH.
Patients with these non-positive CTPA results and suspected CTEPH should be referred to an expert PH centre for further diagnostic testing, such as conventional pulmonary angiography.
# 1B
In patients with suspected CTEPH: b) Should magnetic resonance pulmonary angiography (MRPA) be used to establish the diagnosis and assess the anatomic extent and location of chronic thromboembolic material? 3b) We do not recommend the routine use of MRPA to establish the diagnosis and/or to assess the anatomic extent and location of chronic thromboembolic material in patients with suspected CTEPH.
# Clinical remarks:
There are few centres with MRPA experience in CTEPH.
MRPA should be distinguished from cardiac MRI protocols used for the assessment of pulmonary hemodynamics and right ventricular function in various types of PH, including CTEPH.
# 1C
Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension; V/Q, ventilation/perfusion; CTPA, computed tomography pulmonary angiogram.
# Summary
Q1: Should patients be screened for CTEPH (using echo and/or pulmonary vascular imaging with V/Q lung scan or CTPA) following an acute pulmonary embolism to increase the rate of diagnosis or improve clinical outcomes of CTEPH?
# Acknowledgments
The authors would like to thank Samir Gupta and Christopher Licskai from the CTS Canadian Respiratory Guideline Executive Committee for their input and guidance throughout the process. We would like to acknowledge the Canadian Society of Thoracic Radiology Executive Committee members for their input and endorsement of the manuscript. We would also like to acknowledge with deep appreciation our Expert Peer Reviewers who made valuable contributions to the manuscript:
#
(MRPA) be used to establish the diagnosis and assess the anatomic extent and location of chronic thromboembolic material?
# Editorial independence
The CTS Pulmonary Vascular Disease (PVD) Assembly is accountable to the CTS CRGC and the CTS Board of Directors. The CTS PVD Assembly is functionally and editorially independent from any funding sources of the CTS and does not receive any direct funding from external sources. The CTS receives unrestricted grants which are combined into a central operating account to facilitate the knowledge translation activities of the CTS Clinical Assemblies. No funders played a role in the collection, review, analysis or interpretation of the scientific literature or in any decisions regarding the key messages presented in this document.
# Disclosures
Members of the CTS CTEPH Guideline Panel declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy.
Individual member conflict of interest statements are posted at https://cts-sct.ca/guideline-library/. | None | None |
eac20518fd03c65311f7f0189e90e76e4def3641 | cma | None | Patients requiring respiratory support (high-flow oxygen, noninvasive ventilation, mechanical ventilation) and/or vasopressor/ inotropic support Remdesivir is not recommended in patients with critical COVID-19 outside of approved clinical trials as it has not demonstrated to improve survival or time to recovery. Based on the current scientific evidence and bestpractice guidelines, the College of Physicians and Surgeons of BC, the College of Pharmacists of BC, the BC College of Nurses and Midwives and the CTC do not approve of the use of ivermectin for treatment or prophylaxis of COVID-19 and BC registrants must not prescribe it for this purpose. Ivermectin should not be used outside of approved clinical trials. Monoclonal antibodies (mAbs; Bamlanivimab/etesevimab, REGEN-COV, Sotrovimab, Regdanvimab) are not recommended. An RCT of REGEN-COV in this population was halted due to signals of harm. Regdanvimab and REGEN-COV conditions for use state that it may be associated with worse outcomes in the critically ill. RECOVERY showed no benefit in the subgroup that required organ support. Various guidelines (IDSA, NIH, INESSS) recommend against mAbs in this setting. Colchicine and other biologics (e.g., anakinra) are not recommended outside of approved clinical trials.#
Prophylactic-intensity dosing of low molecular weight heparin (LMWH) is recommended for VTE prophylaxis in patients who do not have suspected or confirmed VTE (or other indications for therapeutic anticoagulation). There is a high probability of harm when therapeutic anticoagulation is initiated in patients who have received organ support for greater than 48 hours (n=1074; NIH mpRCT). Patients receiving therapeutic anticoagulation for COVID-19 prior to organ support should REMAIN on therapeutic anticoagulation and continue for up to 14 days or until hospital discharge.
Antibiotic therapy is not routinely recommended for the treatment of COVID-19 pneumonia. If bacterial co-infection is suspected, follow local practice guidelines for CAP, HAP and VAP.
# ACE inhibitors and ARBs should not be discontinued solely on the basis of COVID-19
NSAIDs should not be discontinued solely on the basis of COVID-19
# Severely Ill Patients
Hospitalized, ward-based, longterm care
# Patients requiring low flow supplemental oxygen therapy
Based on the current scientific evidence and bestpractice guidelines, the College of Physicians and Surgeons of BC, the College of Pharmacists of BC, the BC College of Nurses and Midwives and the CTC do not approve of the use of ivermectin for treatment of COVID-19 and BC registrants must not prescribe it for this purpose. Ivermectin should not be used outside of approved clinical trials.
Tocilizumab is not recommended for patients receiving low-flow oxygen support. The RECOVERY trial found a survival benefit of 4% (28-day mortality for tocilizumab 29% vs. usual care 33%) in patients who had CRP >75 mg/L AND on low-flow oxygen, non-invasive respiratory support, or invasive mechanical ventilation. However, considering the scarcity of IL-6 blockers in Canada, CTC and CTRAWG recommend prioritizing tocilizumab use only for critically ill patients at this time, which is the population shown to benefit most in both the REMAP and RECOVERY trials.
Monoclonal antibody combination REGEN-COV 2.4g (casirivimab 1.2g + imdevimab 1.2g) is NO LONGER recommended due to its lack of neutralization activity against Omicron. Other antibodies are currently being evaluated for this indication. Other mAbs should not be used as a substitute.
Colchicine and biologics (e.g., anakinra) are not recommended outside of approved clinical trials.
# ACE inhibitors and ARBs should not be discontinued solely on the basis of COVID-19
NSAIDs should not be discontinued solely on the basis of COVID-19
# Mildly-Moderately Ill Patients
See the CTC Clinical Practice Guide and Practice Tool #1: Step-by-Step Assessment for treatment recommendation for ambulatory, LTC and in-patients with mild-moderate COVID-19 with nirmatrelvir/ritonavir, remdesivir and sotrovimab. Recommendations regarding tixagevimab/cilgavimab, colchicine, fluvoaxamine and inhaled corticosteroids are also included in within these resources. Bamlanivimab-etesevimab and REGEN-COV are not recommended due to resistance of Omicron to these agents. Due to lack of impact on hospitalization rates or mortality and low generalizability of clinical studies, administration of any mAbs s not recommended for postexposure prophylaxis.
# NOT RECOMMENDED FOR ANY SEVERITY
Tocilizumab AND/OR Baricitinib are recommended for patients requiring life support due to confirmed COVID-19. This includes high-flow oxygen support (e.g., Optiflow) if flow rate > 30 L/min and FiO2 > 0.4 OR invasive or non-invasive ventilation OR vasopressor or inotropic support. While head-to-head comparative data are lacking, the magnitude of benefit of each agent appears equivalent. However, more robust data exist to support the use of tocilizumab. Baricitinib also carries the additional challenges related to gastric access and cytotoxic precautions. The ultimate choice of agent depends on patient characteristics and practical considerations. Patients receiving baricitinib prior to becoming critically ill may stop baricitinib and be switched to a one-time dose of a tociluzumab or continue baricitinib. In patients who continue to deteriorate on immunomodulator monotherapy due to COVID-related inflammation/cytokine storm, the combination of tocilizumab plus baricitinib can be considered as the addition of baricitinib to tocilizumab has been shown to provide an incremental survival benefit of 2.4% (OR 0.79 CI 0.63 to 0.97; RECOVERY) Tocilizumab 400 mg IV (single dose) is recommended (REMAP-CAP, RECOVERY). Dose capping continues to be recommended over 8mg/kg due to a lack of robust drug supply and similar benefits between the two doses seen in observational studies. Tocilizumab should only be initiated when life support is required because of COVID-19 rather than other causes (such as bacterial infection, pulmonary embolism, etc). AND/OR Baricitinib 4 mg po daily (for GFR ≥ 60 mL/min) or 2 mg po daily (for GFR 30-59 mL/min) or 2 mg po every 2nd day (for GFR 15-29 mL/min) up to 14 days, or until discharge from hospital (whichever occurs first) is recommended (COV-BARRIER, RECOVERY). Baricitinib should only be initiated when life support is required because of COVID rather than other causes (such as bacterial infection, pulmonary embolism, etc). Baricitinib should not be administered to patients with neutrophils 5 x ULN, or eGFR 5 x ULN, eGFR <15 mL/mmin/1.73 m2). Patients who received immunosuppressants (high-dose corticosteroids, biologics, or JAK inhibitors) before randomization were excluded from the COV-BARRIER trial; if baricitinib is being considered in these patients, benefits vs risks of overimmunosuppression should be assessed on a case-by-case basis. *Limited data exist on baricitinib in pregnancy. Risks and benefits should be discussed on a case-by-case basis with pregnant patients with severe COVID-19 Early baricitinib discontinuation should be considered in patients who have clinically improved and no longer require supplemental oxygen Tixagevimab/cilgavimab is not recommended, including in severely immunocompromised patients. Currently, there is a lack of high-quality evidence demonstrating a benefit of tixagevimab/ cilgavimab in preventing hospitalization from COVID-19, particularly from variants of concern (e.g., Omicron). Tixagevimab/cilgavimab was evaluated in unvaccinated non-immunocompromised individuals to prevent symptomatic infection with wild-type, Alpha and Delta virus; its role within the present vaccine and therapeutic landscape is unclear. Retrospective observational studies show it to be of minimal additive value. Tixagevimab/cilgavimab has reduced neutralization activity against BA 4/5 and nearly half of all VoCs in BC are completely resistant; according to real world data, this leads to lower serological and clinical activity that cannot be fully overcome by a dose increase. Further, any theoretical benefit may not outweigh by the potential risk of cardiac serious adverse events (SAEs). | Patients requiring respiratory support (high-flow oxygen, noninvasive ventilation, mechanical ventilation) and/or vasopressor/ inotropic support Remdesivir is not recommended in patients with critical COVID-19 outside of approved clinical trials as it has not demonstrated to improve survival or time to recovery. Based on the current scientific evidence and bestpractice guidelines, the College of Physicians and Surgeons of BC, the College of Pharmacists of BC, the BC College of Nurses and Midwives and the CTC do not approve of the use of ivermectin for treatment or prophylaxis of COVID-19 and BC registrants must not prescribe it for this purpose. Ivermectin should not be used outside of approved clinical trials. Monoclonal antibodies (mAbs; Bamlanivimab/etesevimab, REGEN-COV, Sotrovimab, Regdanvimab) are not recommended. An RCT of REGEN-COV in this population was halted due to signals of harm. Regdanvimab and REGEN-COV conditions for use state that it may be associated with worse outcomes in the critically ill. RECOVERY showed no benefit in the subgroup that required organ support. Various guidelines (IDSA, NIH, INESSS) recommend against mAbs in this setting. Colchicine and other biologics (e.g., anakinra) are not recommended outside of approved clinical trials.#
Prophylactic-intensity dosing of low molecular weight heparin (LMWH) is recommended for VTE prophylaxis in patients who do not have suspected or confirmed VTE (or other indications for therapeutic anticoagulation). There is a high probability of harm when therapeutic anticoagulation is initiated in patients who have received organ support for greater than 48 hours (n=1074; NIH mpRCT). Patients receiving therapeutic anticoagulation for COVID-19 prior to organ support should REMAIN on therapeutic anticoagulation and continue for up to 14 days or until hospital discharge.
Antibiotic therapy is not routinely recommended for the treatment of COVID-19 pneumonia. If bacterial co-infection is suspected, follow local practice guidelines for CAP, HAP and VAP.
# ACE inhibitors and ARBs should not be discontinued solely on the basis of COVID-19
NSAIDs should not be discontinued solely on the basis of COVID-19
# Severely Ill Patients
Hospitalized, ward-based, longterm care
# Patients requiring low flow supplemental oxygen therapy
Based on the current scientific evidence and bestpractice guidelines, the College of Physicians and Surgeons of BC, the College of Pharmacists of BC, the BC College of Nurses and Midwives and the CTC do not approve of the use of ivermectin for treatment of COVID-19 and BC registrants must not prescribe it for this purpose. Ivermectin should not be used outside of approved clinical trials.
Tocilizumab is not recommended for patients receiving low-flow oxygen support. The RECOVERY trial found a survival benefit of 4% (28-day mortality for tocilizumab 29% vs. usual care 33%) in patients who had CRP >75 mg/L AND on low-flow oxygen, non-invasive respiratory support, or invasive mechanical ventilation. However, considering the scarcity of IL-6 blockers in Canada, CTC and CTRAWG recommend prioritizing tocilizumab use only for critically ill patients at this time, which is the population shown to benefit most in both the REMAP and RECOVERY trials.
Monoclonal antibody combination REGEN-COV 2.4g (casirivimab 1.2g + imdevimab 1.2g) is NO LONGER recommended due to its lack of neutralization activity against Omicron. Other antibodies are currently being evaluated for this indication. Other mAbs should not be used as a substitute.
Colchicine and biologics (e.g., anakinra) are not recommended outside of approved clinical trials.
# ACE inhibitors and ARBs should not be discontinued solely on the basis of COVID-19
NSAIDs should not be discontinued solely on the basis of COVID-19
# Mildly-Moderately Ill Patients
See the CTC Clinical Practice Guide and Practice Tool #1: Step-by-Step Assessment for treatment recommendation for ambulatory, LTC and in-patients with mild-moderate COVID-19 with nirmatrelvir/ritonavir, remdesivir and sotrovimab. Recommendations regarding tixagevimab/cilgavimab, colchicine, fluvoaxamine and inhaled corticosteroids are also included in within these resources. Bamlanivimab-etesevimab and REGEN-COV are not recommended due to resistance of Omicron to these agents. Due to lack of impact on hospitalization rates or mortality and low generalizability of clinical studies, administration of any mAbs s not recommended for postexposure prophylaxis.
# NOT RECOMMENDED FOR ANY SEVERITY
#
Tocilizumab AND/OR Baricitinib are recommended for patients requiring life support due to confirmed COVID-19. This includes high-flow oxygen support (e.g., Optiflow) if flow rate > 30 L/min and FiO2 > 0.4 OR invasive or non-invasive ventilation OR vasopressor or inotropic support. While head-to-head comparative data are lacking, the magnitude of benefit of each agent appears equivalent. However, more robust data exist to support the use of tocilizumab. Baricitinib also carries the additional challenges related to gastric access and cytotoxic precautions. The ultimate choice of agent depends on patient characteristics and practical considerations. Patients receiving baricitinib prior to becoming critically ill may stop baricitinib and be switched to a one-time dose of a tociluzumab or continue baricitinib. In patients who continue to deteriorate on immunomodulator monotherapy due to COVID-related inflammation/cytokine storm, the combination of tocilizumab plus baricitinib can be considered as the addition of baricitinib to tocilizumab has been shown to provide an incremental survival benefit of 2.4% (OR 0.79 CI 0.63 to 0.97; RECOVERY) Tocilizumab 400 mg IV (single dose) is recommended (REMAP-CAP, RECOVERY). Dose capping continues to be recommended over 8mg/kg due to a lack of robust drug supply and similar benefits between the two doses seen in observational studies. Tocilizumab should only be initiated when life support is required because of COVID-19 rather than other causes (such as bacterial infection, pulmonary embolism, etc). AND/OR Baricitinib 4 mg po daily (for GFR ≥ 60 mL/min) or 2 mg po daily (for GFR 30-59 mL/min) or 2 mg po every 2nd day (for GFR 15-29 mL/min) up to 14 days, or until discharge from hospital (whichever occurs first) is recommended (COV-BARRIER, RECOVERY). Baricitinib should only be initiated when life support is required because of COVID rather than other causes (such as bacterial infection, pulmonary embolism, etc). Baricitinib should not be administered to patients with neutrophils < 1.0 x 109/L, lymphocytes < 0.2 109/L, ALT or AST > 5 x ULN, or eGFR < 15 mL/min (or receiving renal replacement therapy). *Limited data exist on baricitinib in pregnancy. Risks and benefits of baricitinib should be discussed on a case by case basis with pregnant patients with critical COVID-19 Baricitinib 4 mg PO daily (for GFR ≥ 60 mL/min), or 2 mg PO daily (for GFR 30-59 mL/min), or 2 mg PO every 2nd day (for GFR 15-29 mL/ min) up to 14 days**, or until hospital discharge (whichever occurs first) is recommended (COV-BARRIER) for patients hospitalized from COVID-19 requiring supplemental oxygen who show signs of systemic inflammation/cytokine storm (e.g., C-reactive protein ≥ 50 mg/L, ferritin ≥ 1000 µg/L). Baricitinib should only be initiated when oxygen support is required due to COVID-19 pneumonia (not from other causes such as heart failure, pulmonary embolism, etc.). Baricitinib should not be administered to patients with neutrophils <1.0 109/L, lymphocytes <0.2 109/L, ALT or AST >5 x ULN, eGFR <15 mL/mmin/1.73 m2). Patients who received immunosuppressants (high-dose corticosteroids, biologics, or JAK inhibitors) before randomization were excluded from the COV-BARRIER trial; if baricitinib is being considered in these patients, benefits vs risks of overimmunosuppression should be assessed on a case-by-case basis. *Limited data exist on baricitinib in pregnancy. Risks and benefits should be discussed on a case-by-case basis with pregnant patients with severe COVID-19 **Early baricitinib discontinuation should be considered in patients who have clinically improved and no longer require supplemental oxygen http://www.bccdc.ca/health-professionals/clinical-resources/covid-19-care/treatments Tixagevimab/cilgavimab is not recommended, including in severely immunocompromised patients. Currently, there is a lack of high-quality evidence demonstrating a benefit of tixagevimab/ cilgavimab in preventing hospitalization from COVID-19, particularly from variants of concern (e.g., Omicron). Tixagevimab/cilgavimab was evaluated in unvaccinated non-immunocompromised individuals to prevent symptomatic infection with wild-type, Alpha and Delta virus; its role within the present vaccine and therapeutic landscape is unclear. Retrospective observational studies show it to be of minimal additive value. Tixagevimab/cilgavimab has reduced neutralization activity against BA 4/5 and nearly half of all VoCs in BC are completely resistant; according to real world data, this leads to lower serological and clinical activity that cannot be fully overcome by a dose increase. Further, any theoretical benefit may not outweigh by the potential risk of cardiac serious adverse events (SAEs). | None | None |
a588d25bfceaf697e0dd8edb6defef8fdb10f01a | cma | None | Également disponible en français sous le titre : Directives mises à jour sur les doses de rappel du vaccin contre la COVID-19 au Canada To obtain additional information, please contact:# PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# BACKGROUND
On September 1, 2022, NACI published Recommendations on the use of bivalent Omicroncontaining mRNA COVID-19 vaccines. This followed Health Canada's authorization of the Moderna Spikevax BA.1 Bivalent (50 mcg) Omicron-containing vaccine as a booster dose for adults ≥18 years of age. The statement outlined recommendations for the use of this bivalent Omicron-containing mRNA vaccine as a booster dose in specific populations, ahead of the uncertain trajectory of the COVID-19 pandemic in the coming months, and how this new vaccine fit into the current landscape of the Canadian COVID-19 vaccination program. Since that time:
- On October 7, 2022, Health Canada authorized the use of the Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) COVID-19 vaccine as a booster dose in individuals ≥12 years of age. The Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) COVID-19 vaccine is the second bivalent Omicron-containing mRNA COVID-19 vaccine authorized for use in Canada. The epidemiology of COVID-19 continues to change and there is still considerable uncertainty regarding the likelihood, timing, and severity of potential future COVID -19 waves. It is possible that, consistent with other respiratory viruses, the incidence of COVID-19 may increase in late fall and winter and/or that new variants of concern (VOCs) may emerge. Although Omicron and its sublineages have largely been associated with less severe illness compared to previous VOCs, the severity of Omicron sublineages BA.4 and BA.5 in comparison to other Omicron sublineages is currently unclear, and data are still emerging at this time (1)(2)(3) . The Omicron variant has demonstrated partial evasion of immunity conferred by the original COVID-19 vaccines or by a previous infection with a SARS-CoV-2 variant that emerged prior to Omicron. The immune evasion exhibited by Omicron sub lineages BA.4 and BA.5 may be greater than that exhibited by previous Omicron sub lineages, although evidence is still emerging at this time. While the proportion of Canadians vaccinated with a primary series is high, the proportion who have received at least one additional dose has plateaued at a much lower level.
NACI continues to strongly recommend a primary series with an original mRNA vaccine in all individuals 5 years of age and up, and that children 6 months to 4 years of age may receive a primary series with an original mRNA vaccine. NACI has also previously provided recommendations for a booster dose with an authorized COVID-19 vaccine for all adults, adolescents, and children 5-11 years of age. Immunization of those who are eligible for vaccination but have not yet received their recommended doses (primary series or booster) remains a top priority in Canada. As with previous COVID-19 booster programs, a fall booster dose will be most important for older adults (i.e., ≥65 years of age) and other populations at increased risk of severe COVID-19 disease (e.g., individuals with immunocompromising conditions).
NACI continues to monitor the rapidly evolving scientific data while recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed. Further information on NACI's process and procedures is available elsewhere (4,5) .
# OVERVIEW OF EVIDENCE
Evolving epidemiology Canada experienced a resurgence in confirmed SARS-CoV-2 infections during the 2022 summer months, driven primarily by the Omicron BA.4 and BA.5 sublineages. Although the number of confirmed SARS-CoV-2 infections has decreased in recent weeks, test positivity remains elevated compared to historical trends and is considered high compared to other low points during the Omicron period. It is also possible that, consistent with other respiratory viruses, the incidence of COVID-19 will increase again in the late fall and winter, thus posing a risk for individuals/communities and increasing pressure on health systems. For the most up-to-date epidemiology of COVID-19 in Canada, please refer to the Government of Canada's COVID-19 epidemiology update. Indicators of disease severity (i.e., hospitalizations and intensive care un it admissions) also increased during the summer wave. Recent weeks have seen a decrease in hospitalization and ICU rates; however, it is possible that disease severity indicators increase again in the late fall and winter. The incidence of severe out comes remains significantly higher in unvaccinated compared to vaccinated populations and in adults ≥65 years of age compared to younger age groups; current hospitalization rates in adults ≥80 years of age are higher than pandemic averages. Even though Omicron and its sublineages have largely been associated with a smaller proportion of severe disease compared to the previous variants, there is still uncertainty regarding the disease severity of Omicron BA. 4
# Hybrid immunity & seroprevalence
- Available evidence to date shows that hybrid immunity (i.e., protection conferred from both vaccination and infection) is more robust than immunity due to either infection or vaccination alone. However, the duration of protection from hybrid immunity has yet to be fully characterized, and evidence is still emerging regarding hybrid immunity and protection against Omicron sublineages BA.4 and BA.5, the current predominately circulating variants in Canada. In vaccinated individuals, a previous SARS-CoV-2 infection with an Omicron VOC confers significant protection from reinfection with Omicron BA.4 and/or BA.5, although the durability of this protection has yet to be established (2,3,(6)(7)(8) . However, preliminary evidence also suggests that in vaccinated individuals, protection a gainst reinfection is lower against Omicron BA.5, compared to earlier Omicron sublineages (i.e., BA.2), highlighting the potential immune-escape capability of Omicron BA.5 (3,6,9) .
- Emerging Canadian evidence suggests that a large proportion of older adults are protected by vaccination but may not have acquired hybrid immunity. In Canada, older adults have higher vaccination coverage (both with a primary series and with additional doses) compared to younger adults (10) , and according to recent seroprevalence data, are less likely to have been infected during the Omicron wave compared to younger adults and adolescents (11) . It is expected that individuals who have been infected with SARS-CoV-2 may optimize their benefit from future vaccine doses by timing them according to the interval since infection, using similar immunological principles to those informing intervals between vaccine doses. Emerging evidence indicates that a longer interval between SARS-CoV-2 infection and vaccination is associated with improved immune responses to COVID -19 vaccines (12,13) . Individuals should carefully assess their individual risk (i.e., risk of SARS-CoV-2 infection and severe outcomes from COVID-19) if choosing to delay the interval between SARS-CoV-2 infection and vaccination beyond those suggested.
# Vaccine effectiveness of original COVID-19 booster vaccines
- Evidence has shown a reduced vaccine effectiveness (VE) of original COVID-19 vaccines against Omicron compared to VE observed against previous VOCs. VE against Omicron infection after a first booster dose of an original mRNA COVID-19 vaccine is approximately 60% shortly after receipt of the booster dose, and decreases considerably over time in most studies (14)(15)(16)(17)(18)(19)(20)(21) . However, current data suggests that original mRNA COVID-19 vaccines continue to provide significant protection against hospitalization and severe disease. Initial VE against severe disease is approximately 90% following a first booster dose, and while it remains above 75% up to 26 weeks from the first booster in most studies (22)(23)(24)(25)(26) , the duration of protection is not yet fully characterized. The majority of available studies were conducted while Omicron BA.1 and BA.2 were the predominately circulating sublineages, and data on VE waning against Omicron BA.4 and/or BA.5 are limited at this time (27,28) . Evidence on VE of a second COVID-19 booster dose is currently limited. Recent data from the US have shown that during a period of Omicron BA.2 dominance, among adults at least 50 years of age, a second booster dose of an original mRNA COVID-19 vaccine provided additional protection against emergency department and/or urgent care visits due to COVID-19, as well as hospitalization, compared to those who received one booster dose of an original mRNA COVID-19 vaccine (22) . VE studies from Canada and Israel have also demonstrated additional protection compared to a first booster, including against severe disease (29)(30)(31)(32)(33) . However, the duration of protection from a second booster dose is currently unknown. (34) showed that Moderna Spikevax BA.1 Bivalent (50 mcg) administered as a second booster dose to individuals ≥18 years of age had a similar reactogenicity profile to that of Moderna Spikevax original (50 mcg) given as a second booster dose. Also, the frequency of adverse events following Moderna Spikevax BA.1 Bivalent (50 mcg) given as a second booster dose was similar or lower compared to that of a first booster dose of Moderna Spikevax original (50 mcg), and of the second dose of the Moderna Spikevax original primary series (100 mcg). There were no vaccine -related cases of myocarditis, pericarditis or deaths reported during the study period. No new safety signals were identified with Moderna Spikevax BA.1 Bivalent (50 mcg). However, given the number of participants enrolled in the bivalent clinical trial, it is unlikely that rare adverse events would be detected. NACI will monitor post-market safety surveillance data as it emerges and update its recommendations as needed. The levels of antibodies produced by Moderna Spikevax BA.1 Bivalent (50 mcg) as a booster dose against the original strain were superior to those obtained in Phase 3 studies of Moderna Spikevax original, for which clinical efficacy was demonstrated (35) . However, the clinical relevance (i.e., applicability to VE) of the changes in neutralizing antibody levels observed with Moderna Spikevax BA.
# Potential benefits of bivalent Omicron-containing vaccines
- Omicron and its sublineages are antigenically distinct from the original SARS-CoV-2 virus, as well as earlier SARS-CoV-2 VOCs, with BA.1 and BA.4/BA.5 emerging as some of the most antigenically distinct sublineages observed to date (37) . Given the potential for substantial virus evolution and uncertainty about the emergence of future variants, modification of the strain composition of COVID-19 vaccines is expected to broaden immune protection against divergent SARS-CoV-2 spike protein antigens. Available data, including clinical data on immune responses against BA.1 and BA.4/BA.5 with bivalent Omicron-containing mRNA vaccines, suggest that inclusion of an Omicron component in an updated booster vaccine composition may have benefits in the fo rm of increased protection against Omicron sublineages (38) , although no effectiveness data is currently available. Booster doses with bivalent Omicron-containing mRNA vaccines are expected to elicit a greater breadth of immune response, potentially providing additional protection against future variants of concern, although given the unpredictable nature of the ongoing evolution of SARS-CoV-2, this is uncertain at this time (37) . Infection with Omicron elicits a robust and broadly cross-reactive antibody response (39) .
This includes an elevated antibody response against Omicron BA.1 and BA.4/BA.5 (40) . Real-world evidence to date demonstrates that in vaccinated individuals, a previous SARS-CoV-2 infection with the Omicron VOC confers significant protection from reinfection with Omicron BA.4 and/or BA.5 (2,3,(6)(7)(8) . In a clinical trial, individuals who received a second booster dose with Moderna Spikevax BA.1 Bivalent (50 mcg), and who had no evidence of prior SARS-CoV-2 infection, had larger relative increases in neutralizing antibody titres against Omicron BA.1 and BA.4/BA.5 from pre-to post-second booster when compared to those who had evidence of prior SARS-CoV-2 infection. Individuals who received a second booster dose with Moderna Spikevax BA.1 Bivalent (50 mcg) who had evidence of prior SARS-CoV-2 infection, had significantly higher levels of neutralizing antibody titres against Omicron BA.1 and BA.4/BA.5 at both time points (pre-and post-second booster) compared to individuals without evidence of prior infection, however with a smaller relative increase from pre-second booster levels. Similar data were not available for Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) or BA.1 Bivalent (30 mcg). It is possible individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant. Additionally, individuals who were previously infected may experience a greater and more rapidly-induced immune response from a bivalent Omicron-containing mRNA COVID-19 vaccine.
Post-market safety of original mRNA booster doses Available surveillance data to date from Canada and international jurisdictions indicate that the risk of myocarditis and/or pericarditis following a first booster dose of an original mRNA COVID-19 vaccine appears to be lower than the risk following the second dose of the primary series (41)(42)(43)(44)(45)(46)(47)(48) . o This trend is observed for both Pfizer-BioNTech Comirnaty (30 mcg) and Moderna Spikevax (50 mcg) original vaccine products and across all age groups (including individuals under 30 years of age, for whom the risks are highest). However, a limited number of Moderna Spikevax original (50 mcg) booster doses have been administered to individuals under the age of 30, with even more limited use in adolescents 12-17 years of age given that preferential vaccine recommendations for the Pfizer-BioNTech Comirnaty product for those under the age of 30 exist in many countries and the very limited authorization of adolescent booster doses using Moderna Spikevax original (50 mcg) to date.
- Preliminary post-marketing surveillance data from the US (41) and France (43) did not identify a statistically significant difference in the rates of myocarditis following administration of the Moderna Spikevax (50 mcg) original booster doses compared to Pfizer-BioNTech Comirnaty (30 mcg) booster doses. Of note, during the period of surveillance, in the US, Moderna Spikevax original (50 mcg) was authorized as a booster dose for use among individuals aged ≥18 years and, in France, Moderna Spikevax original (50 mcg) was recommended for use as a booster dose among individuals aged ≥30 years. NACI will also continue to monitor post-market safety and surveillance data and update its recommendations as needed.
Ethics, equity, feasibility, and acceptability
# Other considerations
- As an immunological correlate of protection has not been determined for COVID-19 at this time, it is unknown how the increased neutralizing antibody responses observed with bivalent Omicron-containing mRNA COVID-19 vaccines are related to protection against severe outcomes from COVID-19. There are no clinical data currently available for the use of Pfizer -BioNTech Comirnaty BA.4/5 Bivalent (30 mcg). All data available to date are either preclinical, or indirect clinical data using a similar vaccine candidate (i.e., Comirnaty BA.1 Bivalent or Comirnaty BA.1 Monovalent). NACI will continue to monitor and assess clinical data for Comirnaty BA.4/5 Bivalent as it becomes available. The limited evidence available to date indicates that bivalent Omicron-containing mRNA COVID-19 vaccines induce stronger and more robust immune responses to the Omicron VOC and sublineages, compared to original mRNA vaccines. Currently, there are no clinical data comparing the immune response induced by BA.1 bivalent vaccines to that induced by BA.4/BA.5 bivalent vaccines. Real-world evidence from adult populations (≥18 years of age) suggest that after a twodose primary series, Moderna Spikevax original (100 mcg) may result in higher VE compared to Pfizer-BioNTech Comirnaty original (30 mcg) (49) and is also associated with a higher seroconversion rate among adult immunocompromised patients (50) . Booster vaccination with Moderna Spikevax original (50 mcg) was also found to be more effective than Pfizer-BioNTech Comirnaty original (30 mcg) within the first 12 weeks following vaccination, during a period of Delta followed by Omicron variant dominance (51) . However, the relative effectiveness of a booster dose of Moderna Spikevax BA.1 Bivalent (50mcg) compared to Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) is yet to be determined. Although the number of confirmed SARS-CoV-2 infections has decreased in recent weeks, the future trajectory of the COVID-19 pandemic remains unclear and there remains considerable uncertainty regarding the evolutionary trajectory of SARS-CoV-2. Therefore, it remains a possibility that future waves of COVID-19 are driven by novel and distinct VOCs. At this time, is it unknown if an Omicron BA.1 or an Omicron BA.4/BA.5 bivalent vaccine will be more protective against future waves of COVID-19 or future SARS-CoV-2 VOCs. However, since all authorized bivalent vaccines to date contain an Omicronspecific component, any authorized bivalent mRNA COVID-19 vaccine is likely to provide a broad immune response against Omicron sublineages, other VOCs, as well as potential future variants. As the evidence base evolves and the epidemiology of circulating variants changes, if there is an advantage of one bivalent Omicron -containing vaccine over the other, NACI will revisit its recommendations accordingly, including issuing advice on a recommended interval between vaccine doses. No participants in the Moderna Spikevax BA.1 Bivalent or Pfizer -BioNTech Comirnaty BA.1 Bivalent clinical trial were concurrently administered other vaccines. Data with regard to the safety and immunogenicity of other authorized COVID-19 vaccines (including original mRNA COVID-19 vaccines) when given concurrently with other vaccines (e.g., influenza vaccination), are currently limited. However, no specific safety concerns have been identified to date (52)(53)(54)(55)(56)(57)(58) . Studies to assess the safety and immunogenicity of concurrent administration of COVID-19 vaccines with other vaccines are ongoing.
- Currently, there are no clinical data available on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as a primary series, as a first booster dose or as part of a heterologous vaccine series. All participants in the Moderna Spikevax BA.1 Bivalent and Pfizer-BioNTech Comirnaty BA.1 Bivalent clinical trials were administered the vaccine as a second booster dose after a homologous primary series and first booster dose (38) . It is likely that the immunological benefits and safety profile will be similar in individuals receiving a bivalent Omicron-containing mRNA COVID-19 vaccine as a booster dose, regardless of number or type of doses previously received. NACI will continue to monitor new evidence as it becomes available. Although not authorized or recommended for use as part of a primary series, if a bivalent Omicron-containing mRNA COVID-19 vaccine is administered in error as part of a primary series, this dose should be considered valid as part of the primary series. With regard to the product offered; Individuals who have received an mRNA COVID-19 vaccine as part of a fall COVID-19 vaccine booster program do not require an additional dose of a COVID-19 vaccine at this time. This includes individuals who were vaccinated using any authorized original or bivalent mRNA COVID-19 vaccine. Both original and bivalent mRNA COVID-19 vaccines will boost immune responses and are likely to provide significant protection against hospitalization and severe disease. This recommendation will be reassessed throughout the winter season, as new evidence becomes available. NACI continues to recommend that COVID-19 booster doses given as part of the fall program may be offered at an interval of 6 months after a previous COVID-19 vaccine dose or SARS-CoV-2 infection. However, a shorter interval of at least 3 months may be considered particularly in the context of heightened epidemiologic risk, evolving SARS-COV-2 epidemiology, as well as operational considerations for the efficient deployment of the fall vaccine program. Based on what is known at this time about the virus and vaccines, it is not expected that a booster dose will be routinely provided every 3 months. NACI continues to recommend that for all individuals aged 5 years and older, concurrent administration of other vaccines (e.g., seasonal inactivated influenza vaccine) and any dose of a COVID-19 vaccine, regardless of product offered, is acceptable and may increase program efficiency. (50 mcg) was also found to be more effective than Pfizer-BioNTech Comirnaty original (30 mcg) during a period of Delta followed by Omicron variant dominance. However, these studies were conducted prior to the emergence of the Omicron BA.4/BA.5 VOC, and their applicability to all Omicron sublineages is uncertain. Individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant. There are currently no data on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as part of a primary series. NACI continues to recommend a primary series with an original mRNA vaccine in all authorized age groups. NACI will continue to monitor evidence as it emerges, and update recommendations as needed. At this time, there is a high degree of uncertainty with regards to future booster dose recommendations. To date, SARS-CoV-2 does not have a seasonally established pattern of spread, and the beneficial effects of cumulative population immunity are not yet fully realized. As such, these recommendations apply specifically to NACI's guidance for fall 2022 booster dose programs. There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions, with a focus on protecting those at highest risk for serious outcomes from COVID-19.
# RECOMMENDATIONS
# NACI RESEARCH PRIORITIES
- Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of both the original, and bivalent mRNA COVID-19 vaccines, through clinical trials and studies in real-world settings, including relative VE between COVID-19 vaccine products, degree and duration of protection conferred by each booster dose against circulating variants. Research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as Multisystem Inflammatory Syndrome in Children (MIS-C), post-COVID-19 condition (long COVID), or infection-induced myocarditis and/or pericarditis in older and younger adult, adolescent, and pediatric populations. 2. Continuous monitoring of vaccine coverage and acceptance in the Canadian population, specifically following the authorization of new bivalent Omicron-containing mRNA COVID-19 vaccines. 3. Further evaluations of the optimal interval between booster dose and primary series, and between any subsequent booster doses as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and booster dose administration. 4. Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and/or pericarditis, to accurately inform potential risks associated with booster doses, for all COVID-19 vaccines, including bivalent Omicron-containing mRNA vaccines. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of multiple booster doses of COVID -19 vaccines. 5. Evaluations of whether bivalent Omicron-containing mRNA COVID-19 vaccines can be used as part of a primary series. 6. Continuous monitoring of COVID-19 epidemiology and VE in special populations (e.g., those with high-risk medical conditions, or social risk factors placing them at high-risk for severe outcomes) and the long-term consequences of COVID-19 in these populations. | Également disponible en français sous le titre : Directives mises à jour sur les doses de rappel du vaccin contre la COVID-19 au Canada To obtain additional information, please contact:# PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# BACKGROUND
On September 1, 2022, NACI published Recommendations on the use of bivalent Omicroncontaining mRNA COVID-19 vaccines. This followed Health Canada's authorization of the Moderna Spikevax BA.1 Bivalent (50 mcg) Omicron-containing vaccine as a booster dose for adults ≥18 years of age. The statement outlined recommendations for the use of this bivalent Omicron-containing mRNA vaccine as a booster dose in specific populations, ahead of the uncertain trajectory of the COVID-19 pandemic in the coming months, and how this new vaccine fit into the current landscape of the Canadian COVID-19 vaccination program. Since that time:
On October 7, 2022, Health Canada authorized the use of the Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) COVID-19 vaccine as a booster dose in individuals ≥12 years of age. The Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) COVID-19 vaccine is the second bivalent Omicron-containing mRNA COVID-19 vaccine authorized for use in Canada. The epidemiology of COVID-19 continues to change and there is still considerable uncertainty regarding the likelihood, timing, and severity of potential future COVID -19 waves. It is possible that, consistent with other respiratory viruses, the incidence of COVID-19 may increase in late fall and winter and/or that new variants of concern (VOCs) may emerge. Although Omicron and its sublineages have largely been associated with less severe illness compared to previous VOCs, the severity of Omicron sublineages BA.4 and BA.5 in comparison to other Omicron sublineages is currently unclear, and data are still emerging at this time (1)(2)(3) . The Omicron variant has demonstrated partial evasion of immunity conferred by the original COVID-19 vaccines or by a previous infection with a SARS-CoV-2 variant that emerged prior to Omicron. The immune evasion exhibited by Omicron sub lineages BA.4 and BA.5 may be greater than that exhibited by previous Omicron sub lineages, although evidence is still emerging at this time. While the proportion of Canadians vaccinated with a primary series is high, the proportion who have received at least one additional dose has plateaued at a much lower level.
NACI continues to strongly recommend a primary series with an original mRNA vaccine in all individuals 5 years of age and up, and that children 6 months to 4 years of age may receive a primary series with an original mRNA vaccine. NACI has also previously provided recommendations for a booster dose with an authorized COVID-19 vaccine for all adults, adolescents, and children 5-11 years of age. Immunization of those who are eligible for vaccination but have not yet received their recommended doses (primary series or booster) remains a top priority in Canada. As with previous COVID-19 booster programs, a fall booster dose will be most important for older adults (i.e., ≥65 years of age) and other populations at increased risk of severe COVID-19 disease (e.g., individuals with immunocompromising conditions).
NACI continues to monitor the rapidly evolving scientific data while recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed. Further information on NACI's process and procedures is available elsewhere (4,5) .
# OVERVIEW OF EVIDENCE
Evolving epidemiology Canada experienced a resurgence in confirmed SARS-CoV-2 infections during the 2022 summer months, driven primarily by the Omicron BA.4 and BA.5 sublineages. Although the number of confirmed SARS-CoV-2 infections has decreased in recent weeks, test positivity remains elevated compared to historical trends and is considered high compared to other low points during the Omicron period. It is also possible that, consistent with other respiratory viruses, the incidence of COVID-19 will increase again in the late fall and winter, thus posing a risk for individuals/communities and increasing pressure on health systems. For the most up-to-date epidemiology of COVID-19 in Canada, please refer to the Government of Canada's COVID-19 epidemiology update. Indicators of disease severity (i.e., hospitalizations and intensive care un it [ICU] admissions) also increased during the summer wave. Recent weeks have seen a decrease in hospitalization and ICU rates; however, it is possible that disease severity indicators increase again in the late fall and winter. The incidence of severe out comes remains significantly higher in unvaccinated compared to vaccinated populations and in adults ≥65 years of age compared to younger age groups; current hospitalization rates in adults ≥80 years of age are higher than pandemic averages. Even though Omicron and its sublineages have largely been associated with a smaller proportion of severe disease compared to the previous variants, there is still uncertainty regarding the disease severity of Omicron BA. 4
# Hybrid immunity & seroprevalence
Available evidence to date shows that hybrid immunity (i.e., protection conferred from both vaccination and infection) is more robust than immunity due to either infection or vaccination alone. However, the duration of protection from hybrid immunity has yet to be fully characterized, and evidence is still emerging regarding hybrid immunity and protection against Omicron sublineages BA.4 and BA.5, the current predominately circulating variants in Canada. In vaccinated individuals, a previous SARS-CoV-2 infection with an Omicron VOC confers significant protection from reinfection with Omicron BA.4 and/or BA.5, although the durability of this protection has yet to be established (2,3,(6)(7)(8) . However, preliminary evidence also suggests that in vaccinated individuals, protection a gainst reinfection is lower against Omicron BA.5, compared to earlier Omicron sublineages (i.e., BA.2), highlighting the potential immune-escape capability of Omicron BA.5 (3,6,9) .
Emerging Canadian evidence suggests that a large proportion of older adults are protected by vaccination but may not have acquired hybrid immunity. In Canada, older adults have higher vaccination coverage (both with a primary series and with additional doses) compared to younger adults (10) , and according to recent seroprevalence data, are less likely to have been infected during the Omicron wave compared to younger adults and adolescents (11) . It is expected that individuals who have been infected with SARS-CoV-2 may optimize their benefit from future vaccine doses by timing them according to the interval since infection, using similar immunological principles to those informing intervals between vaccine doses. Emerging evidence indicates that a longer interval between SARS-CoV-2 infection and vaccination is associated with improved immune responses to COVID -19 vaccines (12,13) . Individuals should carefully assess their individual risk (i.e., risk of SARS-CoV-2 infection and severe outcomes from COVID-19) if choosing to delay the interval between SARS-CoV-2 infection and vaccination beyond those suggested.
# Vaccine effectiveness of original COVID-19 booster vaccines
Evidence has shown a reduced vaccine effectiveness (VE) of original COVID-19 vaccines against Omicron compared to VE observed against previous VOCs. VE against Omicron infection after a first booster dose of an original mRNA COVID-19 vaccine is approximately 60% shortly after receipt of the booster dose, and decreases considerably over time in most studies (14)(15)(16)(17)(18)(19)(20)(21) . However, current data suggests that original mRNA COVID-19 vaccines continue to provide significant protection against hospitalization and severe disease. Initial VE against severe disease is approximately 90% following a first booster dose, and while it remains above 75% up to 26 weeks from the first booster in most studies (22)(23)(24)(25)(26) , the duration of protection is not yet fully characterized. The majority of available studies were conducted while Omicron BA.1 and BA.2 were the predominately circulating sublineages, and data on VE waning against Omicron BA.4 and/or BA.5 are limited at this time (27,28) . Evidence on VE of a second COVID-19 booster dose is currently limited. Recent data from the US have shown that during a period of Omicron BA.2 dominance, among adults at least 50 years of age, a second booster dose of an original mRNA COVID-19 vaccine provided additional protection against emergency department and/or urgent care visits due to COVID-19, as well as hospitalization, compared to those who received one booster dose of an original mRNA COVID-19 vaccine (22) . VE studies from Canada and Israel have also demonstrated additional protection compared to a first booster, including against severe disease (29)(30)(31)(32)(33) . However, the duration of protection from a second booster dose is currently unknown. (34) showed that Moderna Spikevax BA.1 Bivalent (50 mcg) administered as a second booster dose to individuals ≥18 years of age had a similar reactogenicity profile to that of Moderna Spikevax original (50 mcg) given as a second booster dose. Also, the frequency of adverse events following Moderna Spikevax BA.1 Bivalent (50 mcg) given as a second booster dose was similar or lower compared to that of a first booster dose of Moderna Spikevax original (50 mcg), and of the second dose of the Moderna Spikevax original primary series (100 mcg). There were no vaccine -related cases of myocarditis, pericarditis or deaths reported during the study period. No new safety signals were identified with Moderna Spikevax BA.1 Bivalent (50 mcg). However, given the number of participants enrolled in the bivalent clinical trial, it is unlikely that rare adverse events would be detected. NACI will monitor post-market safety surveillance data as it emerges and update its recommendations as needed. The levels of antibodies produced by Moderna Spikevax BA.1 Bivalent (50 mcg) as a booster dose against the original strain were superior to those obtained in Phase 3 studies of Moderna Spikevax original, for which clinical efficacy was demonstrated (35) . However, the clinical relevance (i.e., applicability to VE) of the changes in neutralizing antibody levels observed with Moderna Spikevax BA.
# Potential benefits of bivalent Omicron-containing vaccines
Omicron and its sublineages are antigenically distinct from the original SARS-CoV-2 virus, as well as earlier SARS-CoV-2 VOCs, with BA.1 and BA.4/BA.5 emerging as some of the most antigenically distinct sublineages observed to date (37) . Given the potential for substantial virus evolution and uncertainty about the emergence of future variants, modification of the strain composition of COVID-19 vaccines is expected to broaden immune protection against divergent SARS-CoV-2 spike protein antigens. Available data, including clinical data on immune responses against BA.1 and BA.4/BA.5 with bivalent Omicron-containing mRNA vaccines, suggest that inclusion of an Omicron component in an updated booster vaccine composition may have benefits in the fo rm of increased protection against Omicron sublineages (38) , although no effectiveness data is currently available. Booster doses with bivalent Omicron-containing mRNA vaccines are expected to elicit a greater breadth of immune response, potentially providing additional protection against future variants of concern, although given the unpredictable nature of the ongoing evolution of SARS-CoV-2, this is uncertain at this time (37) . Infection with Omicron elicits a robust and broadly cross-reactive antibody response (39) .
This includes an elevated antibody response against Omicron BA.1 and BA.4/BA.5 (40) . Real-world evidence to date demonstrates that in vaccinated individuals, a previous SARS-CoV-2 infection with the Omicron VOC confers significant protection from reinfection with Omicron BA.4 and/or BA.5 (2,3,(6)(7)(8) . In a clinical trial, individuals who received a second booster dose with Moderna Spikevax BA.1 Bivalent (50 mcg), and who had no evidence of prior SARS-CoV-2 infection, had larger relative increases in neutralizing antibody titres against Omicron BA.1 and BA.4/BA.5 from pre-to post-second booster when compared to those who had evidence of prior SARS-CoV-2 infection. Individuals who received a second booster dose with Moderna Spikevax BA.1 Bivalent (50 mcg) who had evidence of prior SARS-CoV-2 infection, had significantly higher levels of neutralizing antibody titres against Omicron BA.1 and BA.4/BA.5 at both time points (pre-and post-second booster) compared to individuals without evidence of prior infection, however with a smaller relative increase from pre-second booster levels. Similar data were not available for Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) or BA.1 Bivalent (30 mcg). It is possible individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant. Additionally, individuals who were previously infected may experience a greater and more rapidly-induced immune response from a bivalent Omicron-containing mRNA COVID-19 vaccine.
Post-market safety of original mRNA booster doses Available surveillance data to date from Canada and international jurisdictions indicate that the risk of myocarditis and/or pericarditis following a first booster dose of an original mRNA COVID-19 vaccine appears to be lower than the risk following the second dose of the primary series (41)(42)(43)(44)(45)(46)(47)(48) . o This trend is observed for both Pfizer-BioNTech Comirnaty (30 mcg) and Moderna Spikevax (50 mcg) original vaccine products and across all age groups (including individuals under 30 years of age, for whom the risks are highest). However, a limited number of Moderna Spikevax original (50 mcg) booster doses have been administered to individuals under the age of 30, with even more limited use in adolescents 12-17 years of age given that preferential vaccine recommendations for the Pfizer-BioNTech Comirnaty product for those under the age of 30 exist in many countries and the very limited authorization of adolescent booster doses using Moderna Spikevax original (50 mcg) to date.
o Preliminary post-marketing surveillance data from the US (41) and France (43) did not identify a statistically significant difference in the rates of myocarditis following administration of the Moderna Spikevax (50 mcg) original booster doses compared to Pfizer-BioNTech Comirnaty (30 mcg) booster doses. Of note, during the period of surveillance, in the US, Moderna Spikevax original (50 mcg) was authorized as a booster dose for use among individuals aged ≥18 years and, in France, Moderna Spikevax original (50 mcg) was recommended for use as a booster dose among individuals aged ≥30 years. NACI will also continue to monitor post-market safety and surveillance data and update its recommendations as needed.
Ethics, equity, feasibility, and acceptability
# Other considerations
As an immunological correlate of protection has not been determined for COVID-19 at this time, it is unknown how the increased neutralizing antibody responses observed with bivalent Omicron-containing mRNA COVID-19 vaccines are related to protection against severe outcomes from COVID-19. There are no clinical data currently available for the use of Pfizer -BioNTech Comirnaty BA.4/5 Bivalent (30 mcg). All data available to date are either preclinical, or indirect clinical data using a similar vaccine candidate (i.e., Comirnaty BA.1 Bivalent or Comirnaty BA.1 Monovalent). NACI will continue to monitor and assess clinical data for Comirnaty BA.4/5 Bivalent as it becomes available. The limited evidence available to date indicates that bivalent Omicron-containing mRNA COVID-19 vaccines induce stronger and more robust immune responses to the Omicron VOC and sublineages, compared to original mRNA vaccines. Currently, there are no clinical data comparing the immune response induced by BA.1 bivalent vaccines to that induced by BA.4/BA.5 bivalent vaccines. Real-world evidence from adult populations (≥18 years of age) suggest that after a twodose primary series, Moderna Spikevax original (100 mcg) may result in higher VE compared to Pfizer-BioNTech Comirnaty original (30 mcg) (49) and is also associated with a higher seroconversion rate among adult immunocompromised patients (50) . Booster vaccination with Moderna Spikevax original (50 mcg) was also found to be more effective than Pfizer-BioNTech Comirnaty original (30 mcg) within the first 12 weeks following vaccination, during a period of Delta followed by Omicron variant dominance (51) . However, the relative effectiveness of a booster dose of Moderna Spikevax BA.1 Bivalent (50mcg) compared to Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (30 mcg) is yet to be determined. Although the number of confirmed SARS-CoV-2 infections has decreased in recent weeks, the future trajectory of the COVID-19 pandemic remains unclear and there remains considerable uncertainty regarding the evolutionary trajectory of SARS-CoV-2. Therefore, it remains a possibility that future waves of COVID-19 are driven by novel and distinct VOCs. At this time, is it unknown if an Omicron BA.1 or an Omicron BA.4/BA.5 bivalent vaccine will be more protective against future waves of COVID-19 or future SARS-CoV-2 VOCs. However, since all authorized bivalent vaccines to date contain an Omicronspecific component, any authorized bivalent mRNA COVID-19 vaccine is likely to provide a broad immune response against Omicron sublineages, other VOCs, as well as potential future variants. As the evidence base evolves and the epidemiology of circulating variants changes, if there is an advantage of one bivalent Omicron -containing vaccine over the other, NACI will revisit its recommendations accordingly, including issuing advice on a recommended interval between vaccine doses. No participants in the Moderna Spikevax BA.1 Bivalent or Pfizer -BioNTech Comirnaty BA.1 Bivalent clinical trial were concurrently administered other vaccines. Data with regard to the safety and immunogenicity of other authorized COVID-19 vaccines (including original mRNA COVID-19 vaccines) when given concurrently with other vaccines (e.g., influenza vaccination), are currently limited. However, no specific safety concerns have been identified to date (52)(53)(54)(55)(56)(57)(58) . Studies to assess the safety and immunogenicity of concurrent administration of COVID-19 vaccines with other vaccines are ongoing.
Currently, there are no clinical data available on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as a primary series, as a first booster dose or as part of a heterologous vaccine series. All participants in the Moderna Spikevax BA.1 Bivalent and Pfizer-BioNTech Comirnaty BA.1 Bivalent clinical trials were administered the vaccine as a second booster dose after a homologous primary series and first booster dose (38) . It is likely that the immunological benefits and safety profile will be similar in individuals receiving a bivalent Omicron-containing mRNA COVID-19 vaccine as a booster dose, regardless of number or type of doses previously received. NACI will continue to monitor new evidence as it becomes available. Although not authorized or recommended for use as part of a primary series, if a bivalent Omicron-containing mRNA COVID-19 vaccine is administered in error as part of a primary series, this dose should be considered valid as part of the primary series. With regard to the product offered; Individuals who have received an mRNA COVID-19 vaccine as part of a fall COVID-19 vaccine booster program do not require an additional dose of a COVID-19 vaccine at this time. This includes individuals who were vaccinated using any authorized original or bivalent mRNA COVID-19 vaccine. Both original and bivalent mRNA COVID-19 vaccines will boost immune responses and are likely to provide significant protection against hospitalization and severe disease. This recommendation will be reassessed throughout the winter season, as new evidence becomes available. NACI continues to recommend that COVID-19 booster doses given as part of the fall program may be offered at an interval of 6 months after a previous COVID-19 vaccine dose or SARS-CoV-2 infection. However, a shorter interval of at least 3 months may be considered particularly in the context of heightened epidemiologic risk, evolving SARS-COV-2 epidemiology, as well as operational considerations for the efficient deployment of the fall vaccine program. Based on what is known at this time about the virus and vaccines, it is not expected that a booster dose will be routinely provided every 3 months. NACI continues to recommend that for all individuals aged 5 years and older, concurrent administration of other vaccines (e.g., seasonal inactivated influenza vaccine) and any dose of a COVID-19 vaccine, regardless of product offered, is acceptable and may increase program efficiency. (50 mcg) was also found to be more effective than Pfizer-BioNTech Comirnaty original (30 mcg) during a period of Delta followed by Omicron variant dominance. However, these studies were conducted prior to the emergence of the Omicron BA.4/BA.5 VOC, and their applicability to all Omicron sublineages is uncertain. Individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant. There are currently no data on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as part of a primary series. NACI continues to recommend a primary series with an original mRNA vaccine in all authorized age groups. NACI will continue to monitor evidence as it emerges, and update recommendations as needed. At this time, there is a high degree of uncertainty with regards to future booster dose recommendations. To date, SARS-CoV-2 does not have a seasonally established pattern of spread, and the beneficial effects of cumulative population immunity are not yet fully realized. As such, these recommendations apply specifically to NACI's guidance for fall 2022 booster dose programs. There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions, with a focus on protecting those at highest risk for serious outcomes from COVID-19.
# RECOMMENDATIONS
# NACI RESEARCH PRIORITIES
1. Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of both the original, and bivalent mRNA COVID-19 vaccines, through clinical trials and studies in real-world settings, including relative VE between COVID-19 vaccine products, degree and duration of protection conferred by each booster dose against circulating variants. Research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as Multisystem Inflammatory Syndrome in Children (MIS-C), post-COVID-19 condition (long COVID), or infection-induced myocarditis and/or pericarditis in older and younger adult, adolescent, and pediatric populations. 2. Continuous monitoring of vaccine coverage and acceptance in the Canadian population, specifically following the authorization of new bivalent Omicron-containing mRNA COVID-19 vaccines. 3. Further evaluations of the optimal interval between booster dose and primary series, and between any subsequent booster doses as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and booster dose administration. 4. Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and/or pericarditis, to accurately inform potential risks associated with booster doses, for all COVID-19 vaccines, including bivalent Omicron-containing mRNA vaccines. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of multiple booster doses of COVID -19 vaccines. 5. Evaluations of whether bivalent Omicron-containing mRNA COVID-19 vaccines can be used as part of a primary series. 6. Continuous monitoring of COVID-19 epidemiology and VE in special populations (e.g., those with high-risk medical conditions, or social risk factors placing them at high-risk for severe outcomes) and the long-term consequences of COVID-19 in these populations.
# ACKNOWLEDGMENTS
This statement was prepared by: J Montroy, E Wong, R Krishnan, R Pless, J Zafack, O Baclic, N, Islam, N Forbes, M Salvadori, MC Tunis, R Harrison, S Wilson and S Deeks, on behalf of NACI.
NACI gratefully acknowledges the contribution of: K Ramotar, SH Lim, E Tarratacca, and the NACI Secretariat. Appendix A: Pfizer-BioNTech Comirnaty BA.4/5 Bivalent Data For complete prescribing information for Pfizer-BioNTech Comirnaty BA.4/5 Bivalent, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the Drug Product Database.
# Vaccine Characteristics
# Trial design
The Pfizer-BioNTech Comirnaty BA.1 Bivalent COVID-19 vaccine candidate was evaluated in an ongoing Phase 3, observer-blinded, randomized clinical trial in participants >55 years of age (Study C4591031, Substudy E). The study evaluated the safety, reactogenicity and immunogenicity of Pfizer-BioNTech Comirnaty BA.1 Bivalent (30 mcg) administered as a fourth dose to adults >55 years of age in the US, who had previously received 3 doses of Pfizer-BioNTech Comirnaty original (30 mcg). Individuals with a previous confirmed SARS-CoV-2 infection were not eligible for inclusion (59,60) . In an interim analysis of 610 individuals, GMRs and seroresponse rates were evaluated at 1 month after booster dose administ ration, up to a data cut-off date of May 16 2022, which represents a median of at least 1.7 months post -booster followup. The Pfizer-BioNTech Comirnaty BA.1 Bivalent (30 mcg) booster dose was administered 4.7 to 11.5 months (median 6.3 months) after the third dose.
# Study Population
Overall, demographic and baseline characteristics were similar between the Pfizer-BioNTech Comirnaty BA.1 Bivalent (30 mcg) and Pfizer-BioNTech Comirnaty original (30 mcg) groups.
# Efficacy
Currently, there are no estimates of vaccine efficacy available for Pfizer-BioNTech Comirnaty BA.1 Bivalent (30 mcg).
# Immunogenicity
The primary objective of the interim analysis was to assess the superiority of Pfizer-BioNTech Comirnaty BA.1 Bivalent (30 mcg) with respect to level of neutralizing antibody titres against Omicron BA.1 and to assess the non-inferiority of Pfizer-BioNTech Comirnaty BA.1 Bivalent (30 mcg) with respect to SRR against Omicron BA.1, compared to Pfizer-BioNTech Comirnaty original (30 mcg) given as a fourth dose in individuals >55 years of age. Superiority was considered met when the lower bound of the 95% CI of GMR is >1 and non-inferiority was considered met when the lower bound of the 95% CI for the percentage difference in SRR is greater than -5. Seroresponse was defined as achieving ≥4-fold increase in GMTs from baseline (i.e., prebooster). A descriptive analysis of GMTs against the original SARS-CoV-2 strain and Omicron BA.4/BA.5 was also performed for both groups.
Superiority of Pfizer-BioNTech Comirnaty BA.1 Bivalent based on GMR against Omicron BA.1 In the interim analysis, the observed GMTs against Omicron BA.1 at 1 month post-booster were 711.0 (95% CI: 588.3-859.2) and 455.8 (95% CI: 365.9-567.6) in the Pfizer-BioNTech Comirnaty BA.1 Bivalent and Pfizer-BioNTech Comirnaty original groups respectively. The superiority criteria was met, with a GMR of 1.56 (95% CI: 1.17-2.08) (59,61) .
Non-inferiority of Pfizer-BioNTech Comirnaty BA.1 Bivalent based on SRR against Omicron BA.1 In the interim analysis, the Omicron BA.1 SRRs were 71.6% (95% CI: 64.2-78.3) and 57.0% (95% CI: 48.7-65.1), at one month post-booster in the Pfizer-BioNTech Comirnaty BA.1 Bivalent and Pfizer-BioNTech Comirnaty original groups, respectively. The SRR difference was 14.6% (95% CI: 4.0-24.9), meeting the non-inferiority criterion (lower bound of CI >-5%) (59) .
Descriptive analysis of antibody response against the original SARS-CoV-2 strain In a descriptive analysis, the observed GMTs against original SARS-CoV-2 at 1 month post-booster were 5933.2 (95% CI: 5188.2-6785.2) and 5988.1 (95% CI: 5223.6-6887.4) in the Pfizer-BioNTech Comirnaty BA.1 Bivalent and Pfizer-BioNTech Comirnaty original groups, respectively. This corresponded to a GMR of 0.99 (95% CI: 0.82-1.20) (61) .
Descriptive analysis of antibody response against Omicron BA.4/BA.5
In a descriptive analysis, the observed GMTs against Omicron BA.4/BA.5 at 1 month postbooster were 226.3 (95% CI: not provided) and 110.9 (95% CI: not provided) in the Pfizer-BioNTech Comirnaty BA.1 Bivalent and Pfizer-BioNTech Comirnaty original groups, respectively (61) .
# Safety
When either vaccine was administered as a fourth dose to individuals >55 years of age who had previously received 3 doses of Pfizer-BioNTech Comirnaty original (30 mcg), both Pfizer-BioNTech Comirnaty BA.1 Bivalent (30 mcg) and Pfizer-BioNTech Comirnaty original (30 mcg) had similar local and systemic reactogenicity (61) . The most frequent adverse reactions reported by Pfizer-BioNTech Comirnaty BA.1 Bivalent (30 mcg) recipients were injection site pain (58%), fatigue (49%), headache (34%), myalgia (22%), chills (13%) and arthralgia (11%), which were reported at similar frequencies by Pfizer-BioNTech original (30 mcg) recipients (61) . There were no serious adverse events in the study deemed to be related to the vaccine, and no life -threatening (Grade 4) adverse events, in either group. No cases of myocarditis, pericarditis or deaths were reported during the study period (61) . However, as the trial was limited to 305 individuals receiving the Pfizer-BioNTech Comirnaty BA.1 Bivalent (30 mcg) COVID-19 vaccine, it is unlikely that any rare adverse event would be detected (36) . | None | None |
0b7572ad88b00dc80fad460640726fe5fb64a61b | cma | None | To provide an overview of point-of-care (POC) international normalized ratio (INR) monitoring.A POC device is a small portable instrument that measures clotting time from a fingerstick blood sample. Most POC devices report the result as an INR. POC INR devices vary in their ease of use due to differences in required blood sample volume, the technique of application of the blood sample to the meter, the type of external quality control testing required (e.g. testing an external quality assessment material, comparison against an instrument that satisfactorily participates in an external quality assessment program, or testing of the POC INR against a separately collected venous sample for laboratory INR testing at defined intervals), the need for test strip refrigeration, and meter portability.# HOW ARE POC DEVICES USED?
For both adults and children, use of a POC INR device provides a simple and convenient way to manage warfarin anticoagulation in both the office/clinic setting and at home. The POC INR device uses a sample of blood acquired by fingerstick in order to produce an INR result within one minute. This enables timely warfarin dose adjustments and allows prompt attention to INR values that fall substantially outside the target range. INR measurements can be performed at a patient's convenience and the need for laboratory visits can be substantially reduced or eliminated. This convenience may facilitate more frequent INR testing. Furthermore, in randomized trials comparing POC testing with patient self-management to standard physician-managed laboratory-based INR monitoring, POC-based monitoring with a weekly INR improved the quality of anticoagulation control (i.e. time in the therapeutic range ). Higher TTR is associated with fewer thromboembolic and bleeding events.
There are three approaches to POC-based INR testing and warfarin management: 1) POC INR testing within a clinic setting, pharmacy or a physician's office where patients receive immediate INR results and instructions on drug dosage by the health professional; 2) Patient self-management in which the patient self-tests using the POC device and also self-adjusts the dose of the warfarin using predetermined dosing instructions, combined with their own accumulated experience; 3) Patient self-testing in which the patient self-tests using the POC device and then calls a clinician for advice on how to adjust the dose of the warfarin.
# WHAT IS THE ACCURACY AND PRECISION OF POC INR DEVICES?
When comparisons are made between laboratory-based and POC-based INR measurements, the differences between values are generally within 15%. Such differences are similar to the variability in INR results obtained in different laboratories using anticoagulant-spiked plasmas. In addition, such differences have been shown to not result in different dosing instructions when assessed by experienced anticoagulation clinicians.
# SPECIAL CONSIDERATIONS:
- The POC devices are less accurate when the INR is above the therapeutic range (i.e. INR > 3.5).
- INR readings in the setting of severe anemia or polycythemia (hematocrit below approximately 25% or above about 55%, respectively), co-administration of other anticoagulants in addition warfarin (e.g. low molecular-weight heparin), or antiphospholipid antibody positivity may be inaccurate on a POC device; these patients should be referred to an anticoagulation clinic or thrombosis specialist. - Children requiring long-term anticoagulation with warfarin may particularly benefit from POC INR testing because of the convenience of home monitoring and the elimination of venipunctures. Parental education, supervision and commitment are essential.
# HOW DOES ONE DEFINE CLINICALLY-IMPORTANT DIFFERENCES IN INR BETWEEN POC AND LABORATORY-BASED MEASUREMENTS?
Although there may be numeric differences in INR results between POC-and laboratory-based INR measurements, the INR values should be within 0.5 of each other.
# CHECKLIST FOR DETERMINING IF PATIENT IS SUITABLE TO USE A POC INR DEVICE:
Generally, patients who would like to use the portable INR device at home must satisfy all of the following 8 criteria:
- Patient is aware of the commitment required to do this safely.
- Patient has demonstrated acceptable adherence to INR test visits and daily warfarin administration. 3. Patient has no physical challenges that preclude use of the device. 4. Patient has been trained and is able to do the testing reliably (the training is generally done by certified community pharmacy distributors of the devices). 5. Patient is willing and able to do their own dosage adjustments by following appropriate predetermined instructions for out-of-range INR values and agrees to keep a record of all INR values and warfarin doses. 6. There is back-up by a committed family physician or anticoagulant clinic for the patient with respect to instructions for treating significant out-of-range INR values and to answer questions.
- Patients should generally be reviewed every 6-12 months in an anticoagulant clinic to do a quality check on their POC device, to review their longitudinal INR/warfarin dose records and to answer questions. 8. Patient can afford the initial cost of the POC device as well as the ongoing costs of the test strips if insurance re-imbursement is not possible.
# ADVANTAGES OF PATIENT SELF-MANAGEMENT:
Self-management empowers the patient to participate in and manage their therapy in a manner similar to glucose self-monitoring in the management of diabetes. Self-managed care assumes that patients can be taught to accurately self-test using a POC INR device and will be able to successfully manage their warfarin therapy. In clinical trials of adults who required long-term warfarin therapy, self-management using a POC INR device was associated with cost-savings to the health care system, as well as to the patient. Self-management of anticoagulation also confers moderate improvement in the time within the therapeutic range and improvements in patients' quality of life.
# ADVANTAGES OF PATIENT SELF-TESTING:
Patients who are able to self-test, but unable to self-manage their dose of warfarin may still benefit from using a POC device, particularly when lab INR testing is difficult.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Warfarin - Warfarin: Management of Out-of-Range INR
Wool GD. Benefits and pitfalls of point-of-care coagulation testing for anticoagulation monitoring -An ACLPS critical review. Am J Clin Pathol 2019;151:1-17.
# Date of Version: 07August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide an overview of point-of-care (POC) international normalized ratio (INR) monitoring.A POC device is a small portable instrument that measures clotting time from a fingerstick blood sample. Most POC devices report the result as an INR. POC INR devices vary in their ease of use due to differences in required blood sample volume, the technique of application of the blood sample to the meter, the type of external quality control testing required (e.g. testing an external quality assessment material, comparison against an instrument that satisfactorily participates in an external quality assessment program, or testing of the POC INR against a separately collected venous sample for laboratory INR testing at defined intervals), the need for test strip refrigeration, and meter portability.# HOW ARE POC DEVICES USED?
For both adults and children, use of a POC INR device provides a simple and convenient way to manage warfarin anticoagulation in both the office/clinic setting and at home. The POC INR device uses a sample of blood acquired by fingerstick in order to produce an INR result within one minute. This enables timely warfarin dose adjustments and allows prompt attention to INR values that fall substantially outside the target range. INR measurements can be performed at a patient's convenience and the need for laboratory visits can be substantially reduced or eliminated. This convenience may facilitate more frequent INR testing. Furthermore, in randomized trials comparing POC testing with patient self-management to standard physician-managed laboratory-based INR monitoring, POC-based monitoring with a weekly INR improved the quality of anticoagulation control (i.e. time in the therapeutic range [TTR]). Higher TTR is associated with fewer thromboembolic and bleeding events.
There are three approaches to POC-based INR testing and warfarin management: 1) POC INR testing within a clinic setting, pharmacy or a physician's office where patients receive immediate INR results and instructions on drug dosage by the health professional; 2) Patient self-management in which the patient self-tests using the POC device and also self-adjusts the dose of the warfarin using predetermined dosing instructions, combined with their own accumulated experience; 3) Patient self-testing in which the patient self-tests using the POC device and then calls a clinician for advice on how to adjust the dose of the warfarin.
# WHAT IS THE ACCURACY AND PRECISION OF POC INR DEVICES?
When comparisons are made between laboratory-based and POC-based INR measurements, the differences between values are generally within 15%. Such differences are similar to the variability in INR results obtained in different laboratories using anticoagulant-spiked plasmas. In addition, such differences have been shown to not result in different dosing instructions when assessed by experienced anticoagulation clinicians.
# SPECIAL CONSIDERATIONS:
• The POC devices are less accurate when the INR is above the therapeutic range (i.e. INR > 3.5).
• INR readings in the setting of severe anemia or polycythemia (hematocrit below approximately 25% or above about 55%, respectively), co-administration of other anticoagulants in addition warfarin (e.g. low molecular-weight heparin), or antiphospholipid antibody positivity may be inaccurate on a POC device; these patients should be referred to an anticoagulation clinic or thrombosis specialist. • Children requiring long-term anticoagulation with warfarin may particularly benefit from POC INR testing because of the convenience of home monitoring and the elimination of venipunctures. Parental education, supervision and commitment are essential.
# HOW DOES ONE DEFINE CLINICALLY-IMPORTANT DIFFERENCES IN INR BETWEEN POC AND LABORATORY-BASED MEASUREMENTS?
Although there may be numeric differences in INR results between POC-and laboratory-based INR measurements, the INR values should be within 0.5 of each other.
# CHECKLIST FOR DETERMINING IF PATIENT IS SUITABLE TO USE A POC INR DEVICE:
Generally, patients who would like to use the portable INR device at home must satisfy all of the following 8 criteria:
1. Patient is aware of the commitment required to do this safely.
2. Patient has demonstrated acceptable adherence to INR test visits and daily warfarin administration. 3. Patient has no physical challenges that preclude use of the device. 4. Patient has been trained and is able to do the testing reliably (the training is generally done by certified community pharmacy distributors of the devices). 5. Patient is willing and able to do their own dosage adjustments by following appropriate predetermined instructions for out-of-range INR values and agrees to keep a record of all INR values and warfarin doses. 6. There is back-up by a committed family physician or anticoagulant clinic for the patient with respect to instructions for treating significant out-of-range INR values and to answer questions.
7. Patients should generally be reviewed every 6-12 months in an anticoagulant clinic to do a quality check on their POC device, to review their longitudinal INR/warfarin dose records and to answer questions. 8. Patient can afford the initial cost of the POC device as well as the ongoing costs of the test strips if insurance re-imbursement is not possible.
# ADVANTAGES OF PATIENT SELF-MANAGEMENT:
Self-management empowers the patient to participate in and manage their therapy in a manner similar to glucose self-monitoring in the management of diabetes. Self-managed care assumes that patients can be taught to accurately self-test using a POC INR device and will be able to successfully manage their warfarin therapy. In clinical trials of adults who required long-term warfarin therapy, self-management using a POC INR device was associated with cost-savings to the health care system, as well as to the patient. Self-management of anticoagulation also confers moderate improvement in the time within the therapeutic range and improvements in patients' quality of life.
# ADVANTAGES OF PATIENT SELF-TESTING:
Patients who are able to self-test, but unable to self-manage their dose of warfarin may still benefit from using a POC device, particularly when lab INR testing is difficult.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Warfarin • Warfarin: Management of Out-of-Range INR
#
Wool GD. Benefits and pitfalls of point-of-care coagulation testing for anticoagulation monitoring -An ACLPS critical review. Am J Clin Pathol 2019;151:1-17.
# Date of Version: 07August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
3411b039dbce009e52c0a2067db26afbeca09857 | cma | None | # A. Introduction
This document provides a practical guide for primary care practitioners, community-based physicians, nurse practitioners, nurses and midwives as well as related staff in clinics and urgent and primary care centres to support appropriate office-based infection prevention and control (IPC) practices to mitigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. This guidance outlines the IPC measures to provide care safely in these settings, including patients with confirmed COVID-19 and suspected COVID-19 cases (e.g., having symptoms of COVID-19 or required to self-isolate following close contact with a confirmed case or travel outside of Canada).
This guidance is based on the latest best practice and scientific evidence. The guidance may change as new information becomes available. Please see appendix A for a COVID-19 community clinic care preparedness checklist to assist with implementing this guidance.
All practitioners and related staff in clinics must follow all orders from the provincial health officer (PHO) and their local medical health officer (MHO).
# COVID-19 Immunization
Approved COVID-19 vaccines in Canada are safe and effective against COVID-19. We are continuing to learn about the impact that immunization has on SARS-CoV-2 transmission, and the effectiveness of vaccines against certain variants of concern. As the evidence evolves, public health and IPC guidance for individuals who have received their COVID-19 immunizations will be updated as needed.
For COVID-19 variants of concern, recommendations for IPC measures remain the same and should be strictly followed and reinforced. See guidance on SARS-CoV-2 variants of concern for more information. Some of the side effects from COVID-19 vaccines are similar to the common symptoms of COVID-19. Individuals experiencing any symptoms of COVID-19 after receiving their immunizations are to continue to use the BC COVID-19 self-assessment tool to determine if testing for COVID-19 is required.
In health-care facilities, regardless of whether an individual (e.g., patient, health-care worker, visitor) has received a COVID-19 vaccine and when they received it, they must continue to follow local processes for COVID-19 screening and managing COVID-19 like symptoms. When providing care to symptomatic patients, health-care workers (HCWs) must continue to conduct point-of-care risk assessments (PCRAs) and implement additional precautions as needed to prevent the transmission of SARS-CoV-2.
# B. Infection Prevention and Control Measures
Implementation of IPC measures help create a safe environment for health-care providers, staff and patients. A hierarchy of infection prevention and exposure control measures for communicable disease describes the measures that can be taken to reduce the transmission of COVID-19. Control measures at the top are more effective and protective than those at the bottom. By implementing a combination of measures at each level, the risk of COVID-19 is substantially reduced.
Public health measures are society-wide actions to limit the spread of the SARS-CoV-2 virus and reduce the impact of COVID-19. The provincial health officer has implemented public health orders, including capacity limits for indoor and outdoor events, effective testing, case finding and contact tracing, and emphasizing the need for people to stay home when they are sick. Please see the Office of the Provincial Health Officer's website for more information related to COVID-19 orders and notices.
Environmental measures are physical changes in a setting that reduce the risk of exposure by isolation or ventilation. Examples include being in outdoor spaces, having suitable ventilation and air exchange, and frequent cleaning and disinfection of work and living spaces.
Administrative measures are the implementation of policies, procedures, training and education. Examples of these include implementing facility or organizational infection prevention and control policies and procedures (e.g., screening for symptoms and risk factors, use of appropriate signage), as well as HCW training.
Personal measures are actions individuals can take to both protect themselves, as well as to prevent the spread to others. Examples include respecting personal space, washing hands frequently, coughing into an elbow, staying home from work when sick and ensuring immunizations are up-to-date.
# Personal protective equipment (PPE)
is the last and least effective of the infection prevention and exposure control measures. It is not effective as a stand-alone preventive measure and should only be considered after implementing all other measures. PPE must be suited to the task and must be worn and disposed of properly.
Clinics can implement a combination of measures from the different levels described above to protect against COVID-19 as detailed below.
# C. Public Health Measures 2. Case Finding, Contact Tracing and Outbreak Management
When a COVID-19 positive person is identified by public health staff, significant efforts are undertaken to determine if that person is part of a cluster of cases or a local outbreak. Specific public health measures are implemented in facilities where an outbreak occurs to prevent further transmission of COVID-19 and keep others safe in the workplace.
Operators should maintain an updated list of staff and patients' first and last names, their phone numbers or emails, and the dates of clinic attendance, to support public health staff in potential contact tracing efforts.
# Self-Isolation
HCWs and staff with common cold, influenza or symptoms of COVID-19 should stay home, get assessed by their health-care provider and get tested for COVID-19 if their symptoms warrant, in accordance with provincial COVID-19 testing criteria.
When someone has symptoms of COVID-19, they should self-isolate and follow directions provided by their health-care provider. Self-isolation may be advised for those who are considered a close-contact of a confirmed case. Follow public health direction on contact management.
# D. Environmental Measures 4. Cleaning and Disinfection
Regular cleaning and disinfection are essential for preventing the transmission of COVID-19 from contaminated objects and surfaces. Clinic spaces should be cleaned and disinfected in accordance with BCCDC's environmental cleaning and disinfectants for clinic settings document.
# This includes the following:
Minimize equipment brought into the exam room. Clean and disinfect shared reusable equipment between patients.
- This includes stethoscopes, blood pressure cuffs, otoscopes, baby scales, tables and examination beds. Clean and disinfect frequently touched surfaces at least twice a day.
- These include medical equipment, doorknobs, light switches, telephones, keyboards, mice, toys and all hard surfaces in bathrooms (e.g., sinks, faucets, handles). Establish clear roles and responsibilities for those responsible for cleaning and disinfecting each piece of medical or non-medical equipment, and environmental surfaces. Clean and disinfect the procedure and examination rooms at least once a day. Clean and disinfect all surfaces that are visibly dirty. Use a hospital grade disinfectant with a drug identification number, in accordance with manufacturer's instructions, and contact (wet) time requirements to ensure pathogens have been killed. Limit items that are not easily cleaned (e.g., fabric or soft items). Follow routine procedures for waste disposal and laundry management. Empty garbage containers daily. Wear disposable gloves when cleaning blood or body fluids (e.g., runny nose, vomit, stool, urine). Perform hand hygiene before wearing and after removing gloves.
The risk of transmission of COVID-19 via paper or other paper-based products is low. 1,2 As such, there is no need to limit the distribution of paper resources, such as leaflets, to patients because of COVID-19.
# Physical Changes to the Clinic
Facilities may not be able to adopt all of the following measures; however, consideration should be given to incorporating as many measures as possible:
- Consider having a process and designated space for triage, waiting areas and examination rooms, for the management of patients presenting with communicable respiratory illnesses, including suspected or confirmed COVID-19.
- For clinics seeing patients on a walk-in basis, consider setting up communicable respiratory illness and COVID-19 screening stations for all individuals entering the facility at each designated entry point. - Maintain existing physical barrier(s) installed during COVID-19 pandemic if they do not impede normal operations. - Physical distancing or maintaining a distance of two metres between two or more people is no longer required. - Capacity limits for higher occupancy waiting rooms/areas are no longer required.
- Exam rooms:
- The exam room(s) closest to the entrance should be designated for patients with respiratory symptoms in order to allow rapid isolation pending formal assessment. o Exam rooms should be emptied of all but the bare minimum equipment (e.g., exam
# Patient and Visitor Screening
Before each appointment, every patient must be screened for symptoms and risk factors associated with COVID-19 and communicable respiratory illness using the COVID-19 patient screening tool for direct care interactions.
For clinics seeing patients on a walk-in basis, screen patients for COVID-19 and communicable respiratory illness symptoms and risk factors upon entry to the clinic using the COVID-19 entrance screening tool for health-care facilities.
All visitors/support-persons accompanying patients must be actively screened for symptoms and risk factors associated with COVID-19 and communicable respiratory illness on every visit. See COVID-19 entrance screening tool for health-care facilities for more information.
# Patient Management
Plan for patient scheduling, patient flow and triage. Consideration should be given to the management of patients presenting with communicable respiratory illnesses including suspected or confirmed COVID-19 cases in the clinic. Options include having dedicated areas for COVID-19 and communicable respiratory illness patients and/or scheduling appointments for these patients later in the day; as well as seeing high-risk patients (e.g., elderly and those with chronic illnesses) as the first appointments of the day.
# Pre-Visit Messaging
Office telephone message/voice mail and the health-care practice website(s) should clearly instruct patients where to seek up-to-date instructions on assessment for COVID-19. For assessment, patients can be directed to the BC COVID-19 self-assessment tool and BCCDC's website for information on lab testing.
# Pre-Appointment Triage
A comprehensive triage process starts prior to a patient arriving at the clinic. When booking a patient's appointment:
Ask the COVID-19 screening questions (see BCCDC's website for a sample COVID-19 patient screening tool for direct care interactions), including whether the patient has symptoms of COVID-19 or has been confirmed to have COVID-19. Advise patients to self-monitor for COVID-19 symptoms and notify staff of any change in their health prior to coming into the clinic.
Ensure the patient is informed of the recommended precautions and requirements such as wearing a medical mask, practicing hand hygiene and respiratory etiquette.
# F. Personal Measures 9. Staff Safety
HCWs and staff are encouraged to become fully immunized against COVID-19 to protect themselves, patients, and others.
All HCWs and staff must stay home and self-isolate:
- if experiencing symptoms of COVID-19 OR - if required by public health following close contact exposure.
To determine the need for testing and whether to self-isolate, direct staff to the BC COVID-19 selfassessment tool.
If concerned, staff can be advised to contact 8-1-1, their health-care provider or the local public health unit to seek further advice.
See the BCCDC's exposures and return to work for health-care workers guidance on HCWs exposed to COVID-19 while at work, what to do if a staff member becomes ill, how long to self-isolate and criteria for return to work for those with symptoms. Please see the sample COVID-19 health-care worker selfcheck and safety checklist for more information.
# Routine Practices
Routine practices should be in place at all times in all health-care settings. This includes performing diligent hand hygiene, adhering to respiratory hygiene, conducting a point of care risk assessment (PCRA) before every patient care interaction and appropriate use of PPE.
# Hand Hygiene
Rigorous hand hygiene with plain soap and water or ABHR is the most effective way to reduce the spread of illness.
- Wash hands with plain soap and water for at least 20 seconds. Antibacterial soap is not needed for COVID-19. If sinks are not available, use ABHR containing at least 70% alcohol. - If hands are visibly soiled, ABHR may not be effective at eliminating respiratory viruses. Soap and water are preferred when hands are visibly dirty.
- To learn about how to perform hand hygiene, please refer to BCCDC's website for a hand hygiene poster.
Strategies to support and promote diligent hand hygiene:
- Hand hygiene stations should be set up at the clinic entrance, so everyone can perform hand hygiene when they enter; - Hand hygiene sinks, plain soap dispensers, paper towel holders, hand sanitizer dispensers, and related supplies, should be readily available throughout the facility; - Post signs or posters to promote regular hand hygiene; and - Paper towels should be disposed of in non-touch waste baskets lined with a garbage bag.
For patients, visitors, HCWs and staff, hand hygiene must be performed:
- On entering the clinic;
- On entering the examination room;
- On leaving the examination room;
- After using the washroom;
- After using a tissue for their face; and - After coughing or sneezing.
For HCWs and staff, hand hygiene must also be performed:
- Before and after contact with patient or the patient care environment;
- Before and after breaks;
- Before clean or sterile procedures;
- After risk of body fluid exposure;
- Before putting on/donning PPE; and - In between each step when taking off/doffing PPE.
# Respiratory Etiquette
Respiratory etiquette is also known as respiratory and cough hygiene.
Patients, HCWs and staff must cough or sneeze into their elbow sleeve or a tissue; throw away used tissues and immediately perform hand hygiene; refrain from touching their eyes, nose or mouth with unwashed hands. They must not share any food, drinks, unwashed utensils, cigarettes or vaping devices.
# Point-of-Care Risk Assessment
Prior to any patient interaction, all HCWs must assess the infectious risks posed to themselves, other HCWs, patients and visitors, the situation or the procedure.
The PCRA is based on professional judgment about the clinical situation, as well as up-to-date information on how the specific health-care facility has designed and implemented appropriate physical (engineering) and administrative controls, and the use and availability of PPE.
To conduct a PCRA, evaluate the likelihood of exposure to COVID-19:
- From a specific interaction (e.g., performing or assisting with aerosol generating medical procedures (AGMPs), non-clinical interactions, direct face-to-face interactions with patients); - With a specific patient (e.g., infants or young children, patients not able to practice hand hygiene or respiratory etiquette, frequent coughing or sneezing); - In a specific environment (e.g., patient is in a shared room).
See the BCCDC's website for a sample COVID-19 PCRA tool.
# G. Guidance for Personal Protective Equipment
# Key PPE Recommendations
HCWs and non-clinical staff must follow provincial guidance for Mask Use in Health-Care Facilities During the COVID-19 Pandemic in all health-care settings.
Use appropriate eye protection based on a PCRA and per additional precautions, where indicated.
For direct care of patients with suspected COVID-19 illness (e.g., patients with risk factors and/or symptoms of COVID-19) or a diagnosis of COVID-19, follow droplet and contact precautions. This includes wearing a medical mask, eye protection, gloves and gown.
Extend the use of PPE wherever possible. This includes:
- In the same patient cohort,0 F a keep PPE on between patient encounters unless damaged or visibly soiled. The exception is gloves, which must be changed between each patient. - Change PPE if moving from patients with confirmed COVID-19 to patients with suspected COVID-19. - Change PPE if moving between patients on additional precautions for non-COVID-19 reasons (e.g., airborne, droplet and contact). - Properly doff and dispose/clean and disinfect PPE when leaving the patient care area (e.g., at end of shift, during breaks or mealtimes).
Access to additional PPE, such as respirators, will be provided in circumstances where a HCW determines there is elevated risk of COVID-19 transmission through patient interaction.
a Patient cohort refers to a group of patients with the same diagnosis or suspected diagnosis. In the case of COVID-19, patients with a confirmed COVID-19 diagnosis, patients suspected to have COVID-19 (diagnosis not yet confirmed), and patients without symptoms suggestive of COVID-19, can each be a respective patient cohort. Decisions regarding cohorting should be made in consultation between facility director/administrator, medical health officer or designate and client care leader.
When Wearing PPE - Avoid touching your mask or eye protection. If you must touch or adjust your mask or eye protection, perform hand hygiene immediately before and after adjusting. - Leave the patient care area if you need to remove your mask (e.g., at end of shift or during a break) and ensure two metres distance from patient or exit exam room; do not re-use a doffed mask.
- Change PPE if it becomes damaged or visibly soiled.
- Use extreme care when taking off/doffing PPE and always perform hand hygiene after removing each individual piece of PPE and before putting on/donning new PPE. - In the context of COVID-19, use of an N95 respirator or equivalent is required when performing AGMPs on a person with suspected or confirmed COVID-19.
- Use an N95 respirator or equivalent and eye protection (e.g., goggles or face shield), gloves and gown for AGMPs for patients with suspected or confirmed COVID-19. o In addition, adhere to routine institutional IPC and workplace safety guidelines and practices. - Eye protection must be a well-fitting device that covers the front and sides of the face.
- Regular eyeglasses are not sufficient to protect from all splashes or droplet spray and are not considered adequate protection. o Eye protection, such as goggles, safety glasses or combination medical mask with attached visor, need to cover from the eyebrow to the cheekbone, and across from the nose to the boney area on the outside of the face and eyes. Eye protection should be fitted so that gaps between the edges of the eye protection and the face are kept to a minimum. o Full face shields should extend below the chin to cover the face, to the ears at both sides of the head, and there should be no exposed gap between the forehead and the shield's headpiece. o For tasks with significant risk of splash, like AGMPs, a full-face shield or goggles must be used. o When reusable eye protection is used for multiple patient encounters, it should be cleaned and disinfected as per the guidance found on BCCDC's webpage. o Properly doff, clean and disinfect your eye protection when visibly soiled and when leaving the patient care area (e.g., at end of shift or during a break).
Putting On (Donning) and Taking Off (Doffing) PPE For up-to-date information on PPE including putting on and taking off, as well as posters and signage, please refer to the BCCDC's personal protective equipment webpage.
# Discontinuation of Droplet and Contact Precautions
For patients in the community, discontinuation of droplet and contact precautions should be aligned with the requirements for self-isolation as per public health guidance for management of cases and contacts associated with COVID-19 in the community. This guidance supports a preference for a nontest-based strategy.
For management of patients in acute care settings, the strategies for discontinuation of additional precautions for patients may be different due to a risk assessment of their patient population. For these recommendations follow provincial guidance for discontinuing additional precautions related to COVID-19 for admitted patients in acute care and decision tree.
# PPE Guidance for Patients and Visitors
Please refer to Mask Use in Health Care Facilities During the COVID-19 Pandemic for guidance on mask use for patients and visitors in all health-care settings.
Visitors accompanying patients with symptoms of, or a diagnosis of, COVID-19 should follow droplet and contact precautions.
Patients and visitors must also follow routine practices and any additional precautions that are in place for non-COVID-19 reasons. Develop or update a clinic response strategy to ensure that all staff roles are clearly defined, and that information and decision-making pathways are identified. Designate one qualified office member as the lead for coordinating COVID-19 response at the practice level, including staff responsibilities, information gathering and dissemination, and developing a preparedness plan for the clinic.
Please see a sample COVID-19 community clinic care preparedness checklist in appendix A of this document to aid planning.
# Staff Education and Communication
Develop or update a communication strategy to ensure HCWs and staff have the most up-to-date information. Please see the key resources section for links to the latest information on COVID-19.
Ensure staff have clear, up-to-date information for communicating with patients. Provide appropriate education and training on the following topics, monitor for compliance, and take immediate corrective action when needed:
- Hand hygiene.
- Environmental cleaning and disinfection.
- How to conduct a PCRA prior to each patient interaction.
- Appropriate handling of HCW work clothing/uniforms. Work clothes must be laundered after each shift. - Respiratory protection, proper selection and use of PPE, and putting on (donning) and taking off (doffing) of PPE.
Ensure there is a process for reporting health and safety concerns.
Prior to any patient interaction, perform a PCRA to assess the likelihood of exposure to infectious agents. Implement medical mask use for HCWs (clinical and non-clinical), patients and visitors entering the facility in accordance with the B.C. Ministry of Health Policy Communiqué: Mask Use in Health Care Facilities During the COVID-19 Pandemic Eye protection use is recommended based on a PCRA and per additional precautions. Wear recommended PPE for droplet and contact precautions (medical mask, eye protection, gown and gloves) for any direct contact with patients with suspected or confirmed COVID-19. Use an N95 respirator or equivalent and eye protection (e.g., goggles or face shield), gloves and gown for aerosol generating medical procedures (AGMPs) on patients with suspected or confirmed COVID-19. Properly doff and dispose of PPE when leaving patient care area (e.g., at end of shift or during a break) or when PPE is visibly soiled or damaged. Plan for the disposition of all patients following their office visit. Options for disposition include:
Arrange testing per current guidelines (if suspected COVID-19) Sending home with self-care guide Referral to alternate-care site Admission to acute care When referring patients with suspected or confirmed COVID-19, notify receiving facility in advance. Monitor staff illness and ensure staff with COVID-19 infection follow appropriate guidance.
# Cleaning and Disinfection
Inform all staff regarding current cleaning and disinfection guidelines, including approved cleaning products. Clean and disinfect shared reusable medical equipment (e.g., stethoscopes, blood pressure cuffs, etc.) in between patients and at the end of each shift. Clean and disinfect exam rooms at least once a day (e.g., chairs, tables, floors). Clean and disinfect frequently touched surfaces at least twice a day (e.g., workstations, cell phones, doorknobs). Maintain a minimum two-week supply of plain soap, paper towels, hand sanitizer, cleaning supplies and medical masks, if possible.
# Psychosocial Support
BCCDC offers guidance for psychosocial planning for HCWs during the COVID-19 pandemic. Please see the key resources section of this document for further information.
# Staff Scheduling and Reassignments
Develop a contingency plan for staff illnesses and shortages, with consideration given to staff scheduling:
- Consider adjusting clinic hours to accommodate patient and staffing needs, while supporting IPC measures. - Assess employee availability when greater staffing needs and employee absences for family or self-care are expected.
# Sick Leave Policy
Have open and frank dialogue with all HCWs and staff about sick leave policy prior to any staff illness or time away from work due to self-isolation or quarantine.
Clearly communicate that HCWs and staff who have suspected or confirmed COVID-19 must self-isolate at home, as well as those who have had a test and are waiting for their results.
Some staff might be only mildly ill or already recovering and/or caring for others and still able to perform some of their duties remotely by Internet or telephone, depending on how a clinic is set up.
# I. Key Resources
Information is Available on the Following Topics Relating to COVID-19: Educate yourself and all staff about current information on the recognition, treatment and prevention of transmission of communicable respiratory illnesses including COVID-19. Develop a contingency plan for staff illnesses and shortages. Assign a staff member to coordinate pandemic planning and monitor public health advisories. Make copies of pandemic educational materials and self-care guides available to patients (provided by public health). Place appropriate COVID-19 posters and signage at entrance doors, in reception areas and in exam rooms. Post signage and create voicemail message advising patients to check in by phone before coming to in-person appointments. Ensure alcohol-based hand sanitizer (with at least 70% alcohol) is available at multiple locations: office entrance, reception counter, waiting room, at point of care and by every exam room for use before entering and upon exit. Remove difficult to clean items (e.g., plush toys) from the waiting area. Replace cloth-covered furnishings with easy-to-clean furniture where possible. Provide disposable tissues and no-touch waste receptacles in waiting area and exam rooms. Provide plain soap and paper towels in patient washrooms and at staff sinks with clear instructions on hand hygiene. Display personal protective equipment (PPE) donning (putting on) and doffing (taking off) instructions in locations available to all health-care staff. Empty exam rooms of all but bare minimum of equipment (e.g., exam table, chair, blood pressure cuff, lights). Provide paper sheeting for exam tables and change between patients.
# Patient and Staff Management
Where possible and appropriate, triage all patients over the phone. In group practices, consider having one care provider or one team see all patients with communicable respiratory illnesses, including suspected or confirmed COVID-19. If possible, schedule patients with symptoms associated with communicable respiratory illnesses, including COVID-19, during designated time slots. Advise patients and accompanying visitors to practice diligent hand hygiene and respiratory etiquette. If possible, designate one exam room for all patients with symptoms associated with communicable respiratory illnesses, including COVID-19, as close to the entrance as possible to minimize patient travel. Minimize the number of tasks that have to be done in the exam room (e.g., chart completion). Perform hand hygiene before and after each patient contact. | # A. Introduction
This document provides a practical guide for primary care practitioners, community-based physicians, nurse practitioners, nurses and midwives as well as related staff in clinics and urgent and primary care centres to support appropriate office-based infection prevention and control (IPC) practices to mitigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. This guidance outlines the IPC measures to provide care safely in these settings, including patients with confirmed COVID-19 and suspected COVID-19 cases (e.g., having symptoms of COVID-19 or required to self-isolate following close contact with a confirmed case or travel outside of Canada).
This guidance is based on the latest best practice and scientific evidence. The guidance may change as new information becomes available. Please see appendix A for a COVID-19 community clinic care preparedness checklist to assist with implementing this guidance.
All practitioners and related staff in clinics must follow all orders from the provincial health officer (PHO) and their local medical health officer (MHO).
# COVID-19 Immunization
Approved COVID-19 vaccines in Canada are safe and effective against COVID-19. We are continuing to learn about the impact that immunization has on SARS-CoV-2 transmission, and the effectiveness of vaccines against certain variants of concern. As the evidence evolves, public health and IPC guidance for individuals who have received their COVID-19 immunizations will be updated as needed.
For COVID-19 variants of concern, recommendations for IPC measures remain the same and should be strictly followed and reinforced. See guidance on SARS-CoV-2 variants of concern for more information. Some of the side effects from COVID-19 vaccines are similar to the common symptoms of COVID-19. Individuals experiencing any symptoms of COVID-19 after receiving their immunizations are to continue to use the BC COVID-19 self-assessment tool to determine if testing for COVID-19 is required.
In health-care facilities, regardless of whether an individual (e.g., patient, health-care worker, visitor) has received a COVID-19 vaccine and when they received it, they must continue to follow local processes for COVID-19 screening and managing COVID-19 like symptoms. When providing care to symptomatic patients, health-care workers (HCWs) must continue to conduct point-of-care risk assessments (PCRAs) and implement additional precautions as needed to prevent the transmission of SARS-CoV-2.
# B. Infection Prevention and Control Measures
Implementation of IPC measures help create a safe environment for health-care providers, staff and patients. A hierarchy of infection prevention and exposure control measures for communicable disease describes the measures that can be taken to reduce the transmission of COVID-19. Control measures at the top are more effective and protective than those at the bottom. By implementing a combination of measures at each level, the risk of COVID-19 is substantially reduced.
Public health measures are society-wide actions to limit the spread of the SARS-CoV-2 virus and reduce the impact of COVID-19. The provincial health officer has implemented public health orders, including capacity limits for indoor and outdoor events, effective testing, case finding and contact tracing, and emphasizing the need for people to stay home when they are sick. Please see the Office of the Provincial Health Officer's website for more information related to COVID-19 orders and notices.
Environmental measures are physical changes in a setting that reduce the risk of exposure by isolation or ventilation. Examples include being in outdoor spaces, having suitable ventilation and air exchange, and frequent cleaning and disinfection of work and living spaces.
Administrative measures are the implementation of policies, procedures, training and education. Examples of these include implementing facility or organizational infection prevention and control policies and procedures (e.g., screening for symptoms and risk factors, use of appropriate signage), as well as HCW training.
Personal measures are actions individuals can take to both protect themselves, as well as to prevent the spread to others. Examples include respecting personal space, washing hands frequently, coughing into an elbow, staying home from work when sick and ensuring immunizations are up-to-date.
# Personal protective equipment (PPE)
is the last and least effective of the infection prevention and exposure control measures. It is not effective as a stand-alone preventive measure and should only be considered after implementing all other measures. PPE must be suited to the task and must be worn and disposed of properly.
Clinics can implement a combination of measures from the different levels described above to protect against COVID-19 as detailed below.
# C. Public Health Measures 2. Case Finding, Contact Tracing and Outbreak Management
When a COVID-19 positive person is identified by public health staff, significant efforts are undertaken to determine if that person is part of a cluster of cases or a local outbreak. Specific public health measures are implemented in facilities where an outbreak occurs to prevent further transmission of COVID-19 and keep others safe in the workplace.
Operators should maintain an updated list of staff and patients' first and last names, their phone numbers or emails, and the dates of clinic attendance, to support public health staff in potential contact tracing efforts.
# Self-Isolation
HCWs and staff with common cold, influenza or symptoms of COVID-19 should stay home, get assessed by their health-care provider and get tested for COVID-19 if their symptoms warrant, in accordance with provincial COVID-19 testing criteria.
When someone has symptoms of COVID-19, they should self-isolate and follow directions provided by their health-care provider. Self-isolation may be advised for those who are considered a close-contact of a confirmed case. Follow public health direction on contact management.
# D. Environmental Measures 4. Cleaning and Disinfection
Regular cleaning and disinfection are essential for preventing the transmission of COVID-19 from contaminated objects and surfaces. Clinic spaces should be cleaned and disinfected in accordance with BCCDC's environmental cleaning and disinfectants for clinic settings document.
# This includes the following:
Minimize equipment brought into the exam room. Clean and disinfect shared reusable equipment between patients.
o This includes stethoscopes, blood pressure cuffs, otoscopes, baby scales, tables and examination beds. Clean and disinfect frequently touched surfaces at least twice a day.
o These include medical equipment, doorknobs, light switches, telephones, keyboards, mice, toys and all hard surfaces in bathrooms (e.g., sinks, faucets, handles). Establish clear roles and responsibilities for those responsible for cleaning and disinfecting each piece of medical or non-medical equipment, and environmental surfaces. Clean and disinfect the procedure and examination rooms at least once a day. Clean and disinfect all surfaces that are visibly dirty. Use a hospital grade disinfectant with a drug identification number, in accordance with manufacturer's instructions, and contact (wet) time requirements to ensure pathogens have been killed. Limit items that are not easily cleaned (e.g., fabric or soft items). Follow routine procedures for waste disposal and laundry management. Empty garbage containers daily. Wear disposable gloves when cleaning blood or body fluids (e.g., runny nose, vomit, stool, urine). Perform hand hygiene before wearing and after removing gloves.
The risk of transmission of COVID-19 via paper or other paper-based products is low. 1,2 As such, there is no need to limit the distribution of paper resources, such as leaflets, to patients because of COVID-19.
# Physical Changes to the Clinic
Facilities may not be able to adopt all of the following measures; however, consideration should be given to incorporating as many measures as possible:
• Consider having a process and designated space for triage, waiting areas and examination rooms, for the management of patients presenting with communicable respiratory illnesses, including suspected or confirmed COVID-19.
o For clinics seeing patients on a walk-in basis, consider setting up communicable respiratory illness and COVID-19 screening stations for all individuals entering the facility at each designated entry point. • Maintain existing physical barrier(s) installed during COVID-19 pandemic if they do not impede normal operations. • Physical distancing or maintaining a distance of two metres between two or more people is no longer required. • Capacity limits for higher occupancy waiting rooms/areas are no longer required.
• Exam rooms:
o The exam room(s) closest to the entrance should be designated for patients with respiratory symptoms in order to allow rapid isolation pending formal assessment. o Exam rooms should be emptied of all but the bare minimum equipment (e.g., exam
# Patient and Visitor Screening
Before each appointment, every patient must be screened for symptoms and risk factors associated with COVID-19 and communicable respiratory illness using the COVID-19 patient screening tool for direct care interactions.
For clinics seeing patients on a walk-in basis, screen patients for COVID-19 and communicable respiratory illness symptoms and risk factors upon entry to the clinic using the COVID-19 entrance screening tool for health-care facilities.
All visitors/support-persons accompanying patients must be actively screened for symptoms and risk factors associated with COVID-19 and communicable respiratory illness on every visit. See COVID-19 entrance screening tool for health-care facilities for more information.
# Patient Management
Plan for patient scheduling, patient flow and triage. Consideration should be given to the management of patients presenting with communicable respiratory illnesses including suspected or confirmed COVID-19 cases in the clinic. Options include having dedicated areas for COVID-19 and communicable respiratory illness patients and/or scheduling appointments for these patients later in the day; as well as seeing high-risk patients (e.g., elderly and those with chronic illnesses) as the first appointments of the day.
# Pre-Visit Messaging
Office telephone message/voice mail and the health-care practice website(s) should clearly instruct patients where to seek up-to-date instructions on assessment for COVID-19. For assessment, patients can be directed to the BC COVID-19 self-assessment tool and BCCDC's website for information on lab testing.
# Pre-Appointment Triage
A comprehensive triage process starts prior to a patient arriving at the clinic. When booking a patient's appointment:
Ask the COVID-19 screening questions (see BCCDC's website for a sample COVID-19 patient screening tool for direct care interactions), including whether the patient has symptoms of COVID-19 or has been confirmed to have COVID-19. Advise patients to self-monitor for COVID-19 symptoms and notify staff of any change in their health prior to coming into the clinic.
Ensure the patient is informed of the recommended precautions and requirements such as wearing a medical mask, practicing hand hygiene and respiratory etiquette.
# F. Personal Measures 9. Staff Safety
HCWs and staff are encouraged to become fully immunized against COVID-19 to protect themselves, patients, and others.
All HCWs and staff must stay home and self-isolate:
• if experiencing symptoms of COVID-19 OR • if required by public health following close contact exposure.
To determine the need for testing and whether to self-isolate, direct staff to the BC COVID-19 selfassessment tool.
If concerned, staff can be advised to contact 8-1-1, their health-care provider or the local public health unit to seek further advice.
See the BCCDC's exposures and return to work for health-care workers guidance on HCWs exposed to COVID-19 while at work, what to do if a staff member becomes ill, how long to self-isolate and criteria for return to work for those with symptoms. Please see the sample COVID-19 health-care worker selfcheck and safety checklist for more information.
# Routine Practices
Routine practices should be in place at all times in all health-care settings. This includes performing diligent hand hygiene, adhering to respiratory hygiene, conducting a point of care risk assessment (PCRA) before every patient care interaction and appropriate use of PPE.
# Hand Hygiene
Rigorous hand hygiene with plain soap and water or ABHR is the most effective way to reduce the spread of illness.
• Wash hands with plain soap and water for at least 20 seconds. Antibacterial soap is not needed for COVID-19. If sinks are not available, use ABHR containing at least 70% alcohol. • If hands are visibly soiled, ABHR may not be effective at eliminating respiratory viruses. Soap and water are preferred when hands are visibly dirty.
• To learn about how to perform hand hygiene, please refer to BCCDC's website for a hand hygiene poster.
Strategies to support and promote diligent hand hygiene:
• Hand hygiene stations should be set up at the clinic entrance, so everyone can perform hand hygiene when they enter; • Hand hygiene sinks, plain soap dispensers, paper towel holders, hand sanitizer dispensers, and related supplies, should be readily available throughout the facility; • Post signs or posters to promote regular hand hygiene; and • Paper towels should be disposed of in non-touch waste baskets lined with a garbage bag.
For patients, visitors, HCWs and staff, hand hygiene must be performed:
• On entering the clinic;
• On entering the examination room;
• On leaving the examination room;
• After using the washroom;
• After using a tissue for their face; and • After coughing or sneezing.
For HCWs and staff, hand hygiene must also be performed:
• Before and after contact with patient or the patient care environment;
• Before and after breaks;
• Before clean or sterile procedures;
• After risk of body fluid exposure;
• Before putting on/donning PPE; and • In between each step when taking off/doffing PPE.
# Respiratory Etiquette
Respiratory etiquette is also known as respiratory and cough hygiene.
Patients, HCWs and staff must cough or sneeze into their elbow sleeve or a tissue; throw away used tissues and immediately perform hand hygiene; refrain from touching their eyes, nose or mouth with unwashed hands. They must not share any food, drinks, unwashed utensils, cigarettes or vaping devices.
# Point-of-Care Risk Assessment
Prior to any patient interaction, all HCWs must assess the infectious risks posed to themselves, other HCWs, patients and visitors, the situation or the procedure.
The PCRA is based on professional judgment about the clinical situation, as well as up-to-date information on how the specific health-care facility has designed and implemented appropriate physical (engineering) and administrative controls, and the use and availability of PPE.
To conduct a PCRA, evaluate the likelihood of exposure to COVID-19:
• From a specific interaction (e.g., performing or assisting with aerosol generating medical procedures (AGMPs), non-clinical interactions, direct face-to-face interactions with patients); • With a specific patient (e.g., infants or young children, patients not able to practice hand hygiene or respiratory etiquette, frequent coughing or sneezing); • In a specific environment (e.g., patient is in a shared room).
See the BCCDC's website for a sample COVID-19 PCRA tool.
# G. Guidance for Personal Protective Equipment
# Key PPE Recommendations
HCWs and non-clinical staff must follow provincial guidance for Mask Use in Health-Care Facilities During the COVID-19 Pandemic in all health-care settings.
Use appropriate eye protection based on a PCRA and per additional precautions, where indicated.
For direct care of patients with suspected COVID-19 illness (e.g., patients with risk factors and/or symptoms of COVID-19) or a diagnosis of COVID-19, follow droplet and contact precautions. This includes wearing a medical mask, eye protection, gloves and gown.
Extend the use of PPE wherever possible. This includes:
• In the same patient cohort,0 F a keep PPE on between patient encounters unless damaged or visibly soiled. The exception is gloves, which must be changed between each patient. • Change PPE if moving from patients with confirmed COVID-19 to patients with suspected COVID-19. • Change PPE if moving between patients on additional precautions for non-COVID-19 reasons (e.g., airborne, droplet and contact). • Properly doff and dispose/clean and disinfect PPE when leaving the patient care area (e.g., at end of shift, during breaks or mealtimes).
Access to additional PPE, such as respirators, will be provided in circumstances where a HCW determines there is elevated risk of COVID-19 transmission through patient interaction.
a Patient cohort refers to a group of patients with the same diagnosis or suspected diagnosis. In the case of COVID-19, patients with a confirmed COVID-19 diagnosis, patients suspected to have COVID-19 (diagnosis not yet confirmed), and patients without symptoms suggestive of COVID-19, can each be a respective patient cohort. Decisions regarding cohorting should be made in consultation between facility director/administrator, medical health officer or designate and client care leader.
When Wearing PPE • Avoid touching your mask or eye protection. If you must touch or adjust your mask or eye protection, perform hand hygiene immediately before and after adjusting. • Leave the patient care area if you need to remove your mask (e.g., at end of shift or during a break) and ensure two metres distance from patient or exit exam room; do not re-use a doffed mask.
• Change PPE if it becomes damaged or visibly soiled.
• Use extreme care when taking off/doffing PPE and always perform hand hygiene after removing each individual piece of PPE and before putting on/donning new PPE. • In the context of COVID-19, use of an N95 respirator or equivalent is required when performing AGMPs on a person with suspected or confirmed COVID-19.
o Use an N95 respirator or equivalent and eye protection (e.g., goggles or face shield), gloves and gown for AGMPs for patients with suspected or confirmed COVID-19. o In addition, adhere to routine institutional IPC and workplace safety guidelines and practices. • Eye protection must be a well-fitting device that covers the front and sides of the face.
o Regular eyeglasses are not sufficient to protect from all splashes or droplet spray and are not considered adequate protection. o Eye protection, such as goggles, safety glasses or combination medical mask with attached visor, need to cover from the eyebrow to the cheekbone, and across from the nose to the boney area on the outside of the face and eyes. Eye protection should be fitted so that gaps between the edges of the eye protection and the face are kept to a minimum. o Full face shields should extend below the chin to cover the face, to the ears at both sides of the head, and there should be no exposed gap between the forehead and the shield's headpiece. o For tasks with significant risk of splash, like AGMPs, a full-face shield or goggles must be used. o When reusable eye protection is used for multiple patient encounters, it should be cleaned and disinfected as per the guidance found on BCCDC's webpage. o Properly doff, clean and disinfect your eye protection when visibly soiled and when leaving the patient care area (e.g., at end of shift or during a break).
Putting On (Donning) and Taking Off (Doffing) PPE For up-to-date information on PPE including putting on and taking off, as well as posters and signage, please refer to the BCCDC's personal protective equipment webpage.
# Discontinuation of Droplet and Contact Precautions
For patients in the community, discontinuation of droplet and contact precautions should be aligned with the requirements for self-isolation as per public health guidance for management of cases and contacts associated with COVID-19 in the community. This guidance supports a preference for a nontest-based strategy.
For management of patients in acute care settings, the strategies for discontinuation of additional precautions for patients may be different due to a risk assessment of their patient population. For these recommendations follow provincial guidance for discontinuing additional precautions related to COVID-19 for admitted patients in acute care and decision tree.
# PPE Guidance for Patients and Visitors
Please refer to Mask Use in Health Care Facilities During the COVID-19 Pandemic for guidance on mask use for patients and visitors in all health-care settings.
Visitors accompanying patients with symptoms of, or a diagnosis of, COVID-19 should follow droplet and contact precautions.
Patients and visitors must also follow routine practices and any additional precautions that are in place for non-COVID-19 reasons. Develop or update a clinic response strategy to ensure that all staff roles are clearly defined, and that information and decision-making pathways are identified. Designate one qualified office member as the lead for coordinating COVID-19 response at the practice level, including staff responsibilities, information gathering and dissemination, and developing a preparedness plan for the clinic.
Please see a sample COVID-19 community clinic care preparedness checklist in appendix A of this document to aid planning.
# Staff Education and Communication
Develop or update a communication strategy to ensure HCWs and staff have the most up-to-date information. Please see the key resources section for links to the latest information on COVID-19.
Ensure staff have clear, up-to-date information for communicating with patients. Provide appropriate education and training on the following topics, monitor for compliance, and take immediate corrective action when needed:
• Hand hygiene.
• Environmental cleaning and disinfection.
• How to conduct a PCRA prior to each patient interaction.
• Appropriate handling of HCW work clothing/uniforms. Work clothes must be laundered after each shift. • Respiratory protection, proper selection and use of PPE, and putting on (donning) and taking off (doffing) of PPE.
Ensure there is a process for reporting health and safety concerns.
Prior to any patient interaction, perform a PCRA to assess the likelihood of exposure to infectious agents. Implement medical mask use for HCWs (clinical and non-clinical), patients and visitors entering the facility in accordance with the B.C. Ministry of Health Policy Communiqué: Mask Use in Health Care Facilities During the COVID-19 Pandemic Eye protection use is recommended based on a PCRA and per additional precautions. Wear recommended PPE for droplet and contact precautions (medical mask, eye protection, gown and gloves) for any direct contact with patients with suspected or confirmed COVID-19. Use an N95 respirator or equivalent and eye protection (e.g., goggles or face shield), gloves and gown for aerosol generating medical procedures (AGMPs) on patients with suspected or confirmed COVID-19. Properly doff and dispose of PPE when leaving patient care area (e.g., at end of shift or during a break) or when PPE is visibly soiled or damaged. Plan for the disposition of all patients following their office visit. Options for disposition include:
Arrange testing per current guidelines (if suspected COVID-19) Sending home with self-care guide Referral to alternate-care site Admission to acute care When referring patients with suspected or confirmed COVID-19, notify receiving facility in advance. Monitor staff illness and ensure staff with COVID-19 infection follow appropriate guidance.
# Cleaning and Disinfection
Inform all staff regarding current cleaning and disinfection guidelines, including approved cleaning products. Clean and disinfect shared reusable medical equipment (e.g., stethoscopes, blood pressure cuffs, etc.) in between patients and at the end of each shift. Clean and disinfect exam rooms at least once a day (e.g., chairs, tables, floors). Clean and disinfect frequently touched surfaces at least twice a day (e.g., workstations, cell phones, doorknobs). Maintain a minimum two-week supply of plain soap, paper towels, hand sanitizer, cleaning supplies and medical masks, if possible.
# Psychosocial Support
BCCDC offers guidance for psychosocial planning for HCWs during the COVID-19 pandemic. Please see the key resources section of this document for further information.
# Staff Scheduling and Reassignments
Develop a contingency plan for staff illnesses and shortages, with consideration given to staff scheduling:
• Consider adjusting clinic hours to accommodate patient and staffing needs, while supporting IPC measures. • Assess employee availability when greater staffing needs and employee absences for family or self-care are expected.
# Sick Leave Policy
Have open and frank dialogue with all HCWs and staff about sick leave policy prior to any staff illness or time away from work due to self-isolation or quarantine.
Clearly communicate that HCWs and staff who have suspected or confirmed COVID-19 must self-isolate at home, as well as those who have had a test and are waiting for their results.
Some staff might be only mildly ill or already recovering and/or caring for others and still able to perform some of their duties remotely by Internet or telephone, depending on how a clinic is set up.
# I. Key Resources
Information is Available on the Following Topics Relating to COVID-19: Educate yourself and all staff about current information on the recognition, treatment and prevention of transmission of communicable respiratory illnesses including COVID-19. Develop a contingency plan for staff illnesses and shortages. Assign a staff member to coordinate pandemic planning and monitor public health advisories. Make copies of pandemic educational materials and self-care guides available to patients (provided by public health). Place appropriate COVID-19 posters and signage at entrance doors, in reception areas and in exam rooms. Post signage and create voicemail message advising patients to check in by phone before coming to in-person appointments. Ensure alcohol-based hand sanitizer (with at least 70% alcohol) is available at multiple locations: office entrance, reception counter, waiting room, at point of care and by every exam room for use before entering and upon exit. Remove difficult to clean items (e.g., plush toys) from the waiting area. Replace cloth-covered furnishings with easy-to-clean furniture where possible. Provide disposable tissues and no-touch waste receptacles in waiting area and exam rooms. Provide plain soap and paper towels in patient washrooms and at staff sinks with clear instructions on hand hygiene. Display personal protective equipment (PPE) donning (putting on) and doffing (taking off) instructions in locations available to all health-care staff. Empty exam rooms of all but bare minimum of equipment (e.g., exam table, chair, blood pressure cuff, lights). Provide paper sheeting for exam tables and change between patients.
# Patient and Staff Management
Where possible and appropriate, triage all patients over the phone. In group practices, consider having one care provider or one team see all patients with communicable respiratory illnesses, including suspected or confirmed COVID-19. If possible, schedule patients with symptoms associated with communicable respiratory illnesses, including COVID-19, during designated time slots. Advise patients and accompanying visitors to practice diligent hand hygiene and respiratory etiquette. If possible, designate one exam room for all patients with symptoms associated with communicable respiratory illnesses, including COVID-19, as close to the entrance as possible to minimize patient travel. Minimize the number of tasks that have to be done in the exam room (e.g., chart completion). Perform hand hygiene before and after each patient contact. | None | None |
5222745bf083d9cd466a64c1586b24c5af163c4e | cma | None | on behalf of the Drugs & Biologics Clinical Practice Guidelines Working Group and the Ontario COVID-19 Science Advisory TableThis Science Brief provides information for health care professionals about Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT), a rare adverse event following the AstraZeneca COVID-19 vaccine. This brief describes the pathophysiology, presentation, diagnostic work-up and treatment of VIPIT. Figure 1 presents a decision tree for diagnosing and ruling out VIPIT.#
The Drugs & Biologics Clinical Practice Guidelines Working Group is a group of clinicians and scientists with recognized expertise in drugs, biologics, and clinical care. The Working Group will evaluate existing scientific data, disease epidemiology, drug availability, and implementation issues in order to develop Clinical Practice Guidelines for the treatment of COVID-19 using drugs and biologics. The Working Group reports its findings to the public and the Science Table . Its findings are also summarized in Science Briefs.
Correspondence to: Secretariat of the Ontario COVID-19 Science Advisory Table
# SCIENCE BRIEFS
# Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Lay Summary
What do we know so far?
The United Kingdom, European Union, and Scandinavian countries have reported that the AstraZeneca COVID-19 vaccine appears to be associated with rare cases of serious blood clots, including blood clots in the brain. These blood clots have Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Ontario COVID-19 Science Advisory Table ([email protected])
Copyright: 2021 Ontario COVID-19 Science Advisory Table . This is an open access document distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided that the original work is properly cited.
The views and findings expressed in this Science Brief are those of the authors and do not necessarily reflect the views of all of the members of the Ontario COVID-19 Science Advisory Table, its Working Groups, and its partners.
two important features: they occur 4 to 20 days after vaccination, and they are associated with low platelets (tiny blood cells that help form blood clots to stop bleeding). Doctors are calling this "vaccine-induced prothrombotic immune thrombocytopenia" (VIPIT). VIPIT seems to be rare, occurring in anywhere from 1 in every 125,000 to 1 in 1 million people.
Health Canada has stated that the AstraZeneca COVID-19 vaccine continues to be safe and effective at protecting Canadians against COVID-19 and encourages people to get immunized with any of the COVID-19 vaccines that are authorized in Canada.
# Are certain people more likely to get VIPIT?
VIPIT is very rare. At this time, we do not know if certain patients are more likely to get VIPIT. So far, most of the cases from Europe have occurred in women under age 55 -but many of these countries used more of their initial AstraZeneca vaccine supply in women under age 55. We do not believe that VIPIT is more common in people who have had blood clots before, people with a family history of blood clots, people with a low platelets, or pregnant women, because VIPIT does not develop through the same process as usual types of bleeding or clotting problems.
# What should you look out for if you received the AstraZeneca COVID-19 vaccine?
You should speak to a health care professional if you have unusual or severe symptoms after any COVID-19 vaccine. If you experience the following symptoms between 4 and 20 days after vaccination, it might indicate that you have VIPIT: a severe headache that does not go away; a seizure; difficulty moving part of your body; new blurry vision that does not go away; difficulty speaking; shortness of breath; chest pain; severe abdominal pain; new severe swelling, pain, or colour change of an arm or a leg. These symptoms can also be a sign of other serious conditions and should be assessed in an emergency department.
# What should you do if you have concerning symptoms after the AstraZeneca COVID-19 vaccine?
If your symptoms are not severe, you can see (virtually or in-person) your primary care professional. If you have severe symptoms, you should go to the nearest emergency department immediately. You should tell the health care providers who see you that you received the AstraZeneca COVID-19 vaccine and give them the date you got vaccinated. If the healthcare professional who assesses you is concerned, you may have scans and additional bloodwork collected.
# Do healthcare professionals know how to diagnose and treat VIPIT?
Yes. Health care professionals and scientists in Ontario have been working with experts in Canada, and around the world, to better understand VIPIT. The Ontario COVID-19 Science Advisory Table has summarized what we know about VIPIT right now and has published guides for healthcare professionals outside and inside the hospital, to help them diagnose and treat VIPIT.
# Why is Ontario still using the AstraZeneca COVID-19 vaccine?
Health Canada reviewed the AstraZeneca COVID-19 Vaccine, as well as a similar vaccine called COVISHIELD. They have stated that the benefits in protecting Canadians from COVID-19 continue to outweigh the risks and encourage Canadians to get immunized with any of the COVID-19 vaccines that are Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Ontario COVID-19 Science Advisory Table
# Background
The AstraZeneca COVID-19 vaccine appears to be associated with autoimmune thrombosis that mimics heparin-induced thrombocytopenia.
The United Kingdom, European Union, and Scandinavian countries have reported rare cases of cerebral sinus vein thrombosis (CSVT) and thrombocytopenia in patients who received the AstraZeneca COVID-19 vaccine. The majority of affected patients thus far are women under the age of 55 years, and CSVT seems to occur 4 to 20 days after vaccination. The Paul Ehrlich Institute has demonstrated that affected individuals in Germany have antibodies that induce massive platelet activation, reducing the platelet count and causing thrombosis. 1 This phenomenon mimics heparin-induced thrombocytopenia (HIT) yet it does not require heparin as a trigger. It has been named vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).
# Questions
# Findings How frequent is VIPIT?
To date, millions of AstraZeneca COVID-19 vaccine doses have been administered worldwide, with suspected cases of VIPIT occurring in only a small fraction of vaccinated individuals. However, there is growing evidence of a causal link with the vaccine. The incidence of VIPIT appears to be between 1 in 125,000 and 1 in 1 million. 2 There is no evidence that the AstraZeneca COVID-19 vaccine increases the overall risk of thrombosis (e.g., deep vein thromboses, pulmonary emboli, myocardial infarction, stroke) beyond what is seen in the general population despite the authorized in Canada when they are eligible. Keep in mind that COVID-19 has killed over 15,000 Canadians so far, that about 1 in 100 Canadians who get COVID-19 end up needing intensive care, and that 1 in 5 Canadians who are hospitalized with COVID-19 develop blood clots. Currently Canada is experiencing a third wave of COVID-19. VIPIT is very rare, while the AstraZeneca vaccine has proven effective at reducing severe illness from COVID-19. Health care professionals, scientists, and government agencies in Ontario -and around the world -will continue to monitor the safety of this and all vaccines.
# Could other COVID-19 vaccines available in Ontario cause VIPIT?
There have been no confirmed cases of VIPIT with any other COVID-19 vaccine.
Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Ontario COVID-19 Science Advisory Table observed increases in CSVT, as the risk of CSVT is orders of magnitude lower than the risk of other thromboses. The AstraZeneca COVID-19 vaccine is highly effective in preventing COVID-19, which also carries a high risk of thrombosis; 1 in 5 patients hospitalized with COVID-19 develops venous thrombosis. 3 For this reason, Health Canada, the United Kingdom Medicines and Healthcare Products Regulatory Agency, and the European Medicines Agency have recommended to continue administering the AstraZeneca COVID-19 vaccine, and have all made clear statements about their assessment of risks and benefits in the setting of the COVID-19 pandemic. 2,4,5 Physicians, scientists, and regulatory agencies worldwide will continue to carefully monitor the safety of the AstraZeneca vaccine and of COVISHIELD, the version of the AstraZeneca COVID-19 vaccine currently available in Canada.
# Are certain patients predisposed to VIPIT?
At this time, it is not clear if certain patients are predisposed to VIPIT. The cases to date are predominantly in younger women, however these individuals may have been overrepresented in the vaccinated population in European Union countries. 2 Further information from jurisdictions like the United Kingdom that prioritized older adults for early vaccination is pending. Since VIPIT is immune-mediated, an individual with a thrombophilia, a family history of blood clots, or a personal history of arterial or venous clots would likely not be at increased of VIPIT. Accordingly, there are no new contraindications to receiving the AstraZeneca COVID-19 vaccine.
# When should I suspect my patient has VIPIT?
Patients with VIPIT may present with CSVT, or with other arterial or venous clots. Any patient with unusual symptoms following vaccination should be assessed by a health care provider. Some symptoms make it more likely that a patient has VIPIT: persistent and severe headache; focal neurological symptoms (including blurred vision); shortness of breath; abdominal or chest pain; swelling and redness in a limb; or pallor and coldness in a limb. VIPIT seems to occur between 4 to 20 days postvaccination. Symptoms in this time frame should raise the clinical suspicion of VIPIT.
# How do I diagnose VIPIT? How do I rule it out?
Patients with severe symptoms should urgently seek care at their nearest emergency department. Patients with non-severe symptoms may have initial investigations done in the primary care or outpatient setting.
Clinicians should ask patients about their COVID-19 vaccine history and should draw a complete blood count (CBC). VIPIT is unlikely if symptoms of blood clotting fall outside of the 4 to 20 day time frame OR if the platelet count is ≥ 150 x 10 9 /L. 6 VIPIT is more likely if symptoms of blood clotting fall within the 4 to 20 day time frame AND the platelet count is < 150 x 10 9 /L, and such patients should be evaluated at their nearest emergency department for suspected VIPIT. This will expedite further diagnostic workup, treatment, and urgent hematology consultation.
Patients with suspected VIPIT should go on to have blood work drawn including a Ddimer level and a blood film. When there is strong clinical suspicion of VIPIT, patients should also have diagnostic imaging to investigate for blood clots (including appropriate imaging to rule out CSVT, if the patient presents with a persistent and severe headache). It is not known whether VIPIT, like HIT, is associated with arterial thromboses, but arterial clots should be considered if patients have consistent symptoms. An elevated D-dimer, a normal blood film (apart from thrombocytopenia), and confirmation of a blood clot on diagnostic imaging makes the diagnosis of VIPIT presumptive.
The confirmatory diagnosis of VIPIT is made by testing for HIT. This testing should be done even if the patient has had no previous exposure to heparin. HIT testing involves two steps: identification of antibodies against the complex of platelet factor 4 and heparin; and confirmatory functional testing of the antibodies' ability to activate platelets. 7 The HIT antibody test appears very sensitive to VIPIT; if it is positive, VIPIT is confirmed, and if it is negative, VIPIT is unlikely. 1 A number of large hospital laboratories test for HIT antibodies, but only one lab in Canada performs confirmatory functional testing (the McMaster University Platelet Immunology Laboratory). Therefore, presumptive VIPIT should prompt an urgent hematology consultation (in person, virtually, or by phone) to arrange testing and start safe empiric treatment of blood clots (see below).
# How do I treat VIPIT?
Patients with presumptive and confirmed VIPIT should be treated similarly to HIT. The Box presents the treatment principles for patients with presumptive and confirmed VIPIT. Until VIPIT has been ruled out, anticoagulation with heparin (unfractionated heparin and low molecular weight heparins) should be avoided. Platelet transfusions should also not be given.
# Summary Box. Treating Blood Clots in Patients with Presumptive or Confirmed VIPIT
Alternative anticoagulants that are safe to use in HIT, and likely safe to use in VIPIT, include direct thrombin inhibitors and anti-Xa inhibitors. Most clinicians in Ontario will be comfortable using direct oral anti-Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban) empirically while awaiting further advice from a hematologist; these agents are used in the treatment of HIT. The dose of direct oral anti-Xa inhibitor is identical to the dose used to treat uncomplicated deep vein thromboses. If the patient has severe renal impairment that makes direct oral anticoagulants unsafe, advice from a hematologist should be sought to guide use of parenteral anticoagulants that are safe to use in HIT.
# How do I treat VIPIT with life threatening blood clots?
In patients with confirmed VIPIT and severe or life-threatening blood clots (e.g., CSVT, splanchnic vein thrombosis), it is important to dampen the prothrombotic response with intravenous immunoglobulin (IVIG). Administration of high dose IVIG (1 g/kg of body weight daily for two days) is appropriate and can be guided by the consulting hematologist.
# Is VIPIT a reportable event?
All suspected adverse events following immunization (AEFI), including thrombosis, and both presumptive and confirmed VIPIT, should be reported using the provincial AEFI form and sent to the local Public Health Unit. More information on how to report AEFIs can be found on the Public Health Ontario website. Ontario conducts
Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Ontario COVID-19 Science Advisory Table vaccine surveillance safety in collaboration with the Public Health Agency of Canada, and prompt reporting is essential to learn more about this rare but serious thrombotic phenomenon.
# Can patients who develop VIPIT safely receive a second dose of AstraZeneca's COVID-19 vaccine? Can they receive another COVID-19 vaccine?
At this time, we do not know how subsequent doses of COVID-19 vaccines should be managed in individuals who develop VIPIT following their first dose. These cases require consultation with a hematologist. We know that individuals with non-vaccine associated HIT can be safely re-exposed to heparin, under very controlled conditions, but this requires the advice and close monitoring of a hematologist. This is an area of active study. There have been no confirmed cases of VIPIT with any other COVID-19 vaccine. Therefore, a second dose of another COVID-19 vaccine may be safe.
# Interpretation
VIPIT is a rare adverse event following the AstraZeneca COVID-19 vaccine. This brief describes the pathophysiology, presentation, diagnostic work-up and treatment of VIPIT, including a decision tree for diagnosing and ruling out VIPIT.
# Author Contributions
MP, PJ and AMM conceived the Science Brief. MP wrote the first draft of the Science Brief. All authors contributed to the conception of the Science Brief, revised it critically for important intellectual content and approved the final version. | on behalf of the Drugs & Biologics Clinical Practice Guidelines Working Group and the Ontario COVID-19 Science Advisory TableThis Science Brief provides information for health care professionals about Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT), a rare adverse event following the AstraZeneca COVID-19 vaccine. This brief describes the pathophysiology, presentation, diagnostic work-up and treatment of VIPIT. Figure 1 presents a decision tree for diagnosing and ruling out VIPIT.#
The Drugs & Biologics Clinical Practice Guidelines Working Group is a group of clinicians and scientists with recognized expertise in drugs, biologics, and clinical care. The Working Group will evaluate existing scientific data, disease epidemiology, drug availability, and implementation issues in order to develop Clinical Practice Guidelines for the treatment of COVID-19 using drugs and biologics. The Working Group reports its findings to the public and the Science Table . Its findings are also summarized in Science Briefs.
Correspondence to: Secretariat of the Ontario COVID-19 Science Advisory Table
# SCIENCE BRIEFS
# Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Lay Summary
What do we know so far?
The United Kingdom, European Union, and Scandinavian countries have reported that the AstraZeneca COVID-19 vaccine appears to be associated with rare cases of serious blood clots, including blood clots in the brain. These blood clots have Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Ontario COVID-19 Science Advisory Table ([email protected])
Copyright: 2021 Ontario COVID-19 Science Advisory Table . This is an open access document distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided that the original work is properly cited.
The views and findings expressed in this Science Brief are those of the authors and do not necessarily reflect the views of all of the members of the Ontario COVID-19 Science Advisory Table, its Working Groups, and its partners.
two important features: they occur 4 to 20 days after vaccination, and they are associated with low platelets (tiny blood cells that help form blood clots to stop bleeding). Doctors are calling this "vaccine-induced prothrombotic immune thrombocytopenia" (VIPIT). VIPIT seems to be rare, occurring in anywhere from 1 in every 125,000 to 1 in 1 million people.
Health Canada has stated that the AstraZeneca COVID-19 vaccine continues to be safe and effective at protecting Canadians against COVID-19 and encourages people to get immunized with any of the COVID-19 vaccines that are authorized in Canada.
# Are certain people more likely to get VIPIT?
VIPIT is very rare. At this time, we do not know if certain patients are more likely to get VIPIT. So far, most of the cases from Europe have occurred in women under age 55 -but many of these countries used more of their initial AstraZeneca vaccine supply in women under age 55. We do not believe that VIPIT is more common in people who have had blood clots before, people with a family history of blood clots, people with a low platelets, or pregnant women, because VIPIT does not develop through the same process as usual types of bleeding or clotting problems.
# What should you look out for if you received the AstraZeneca COVID-19 vaccine?
You should speak to a health care professional if you have unusual or severe symptoms after any COVID-19 vaccine. If you experience the following symptoms between 4 and 20 days after vaccination, it might indicate that you have VIPIT: a severe headache that does not go away; a seizure; difficulty moving part of your body; new blurry vision that does not go away; difficulty speaking; shortness of breath; chest pain; severe abdominal pain; new severe swelling, pain, or colour change of an arm or a leg. These symptoms can also be a sign of other serious conditions and should be assessed in an emergency department.
# What should you do if you have concerning symptoms after the AstraZeneca COVID-19 vaccine?
If your symptoms are not severe, you can see (virtually or in-person) your primary care professional. If you have severe symptoms, you should go to the nearest emergency department immediately. You should tell the health care providers who see you that you received the AstraZeneca COVID-19 vaccine and give them the date you got vaccinated. If the healthcare professional who assesses you is concerned, you may have scans and additional bloodwork collected.
# Do healthcare professionals know how to diagnose and treat VIPIT?
Yes. Health care professionals and scientists in Ontario have been working with experts in Canada, and around the world, to better understand VIPIT. The Ontario COVID-19 Science Advisory Table has summarized what we know about VIPIT right now and has published guides for healthcare professionals outside and inside the hospital, to help them diagnose and treat VIPIT.
# Why is Ontario still using the AstraZeneca COVID-19 vaccine?
Health Canada reviewed the AstraZeneca COVID-19 Vaccine, as well as a similar vaccine called COVISHIELD. They have stated that the benefits in protecting Canadians from COVID-19 continue to outweigh the risks and encourage Canadians to get immunized with any of the COVID-19 vaccines that are Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Ontario COVID-19 Science Advisory Table
# Background
The AstraZeneca COVID-19 vaccine appears to be associated with autoimmune thrombosis that mimics heparin-induced thrombocytopenia.
The United Kingdom, European Union, and Scandinavian countries have reported rare cases of cerebral sinus vein thrombosis (CSVT) and thrombocytopenia in patients who received the AstraZeneca COVID-19 vaccine. The majority of affected patients thus far are women under the age of 55 years, and CSVT seems to occur 4 to 20 days after vaccination. The Paul Ehrlich Institute has demonstrated that affected individuals in Germany have antibodies that induce massive platelet activation, reducing the platelet count and causing thrombosis. 1 This phenomenon mimics heparin-induced thrombocytopenia (HIT) yet it does not require heparin as a trigger. It has been named vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).
# Questions
# Findings How frequent is VIPIT?
To date, millions of AstraZeneca COVID-19 vaccine doses have been administered worldwide, with suspected cases of VIPIT occurring in only a small fraction of vaccinated individuals. However, there is growing evidence of a causal link with the vaccine. The incidence of VIPIT appears to be between 1 in 125,000 and 1 in 1 million. 2 There is no evidence that the AstraZeneca COVID-19 vaccine increases the overall risk of thrombosis (e.g., deep vein thromboses, pulmonary emboli, myocardial infarction, stroke) beyond what is seen in the general population despite the authorized in Canada when they are eligible. Keep in mind that COVID-19 has killed over 15,000 Canadians so far, that about 1 in 100 Canadians who get COVID-19 end up needing intensive care, and that 1 in 5 Canadians who are hospitalized with COVID-19 develop blood clots. Currently Canada is experiencing a third wave of COVID-19. VIPIT is very rare, while the AstraZeneca vaccine has proven effective at reducing severe illness from COVID-19. Health care professionals, scientists, and government agencies in Ontario -and around the world -will continue to monitor the safety of this and all vaccines.
# Could other COVID-19 vaccines available in Ontario cause VIPIT?
There have been no confirmed cases of VIPIT with any other COVID-19 vaccine.
Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Ontario COVID-19 Science Advisory Table observed increases in CSVT, as the risk of CSVT is orders of magnitude lower than the risk of other thromboses. The AstraZeneca COVID-19 vaccine is highly effective in preventing COVID-19, which also carries a high risk of thrombosis; 1 in 5 patients hospitalized with COVID-19 develops venous thrombosis. 3 For this reason, Health Canada, the United Kingdom Medicines and Healthcare Products Regulatory Agency, and the European Medicines Agency have recommended to continue administering the AstraZeneca COVID-19 vaccine, and have all made clear statements about their assessment of risks and benefits in the setting of the COVID-19 pandemic. 2,4,5 Physicians, scientists, and regulatory agencies worldwide will continue to carefully monitor the safety of the AstraZeneca vaccine and of COVISHIELD, the version of the AstraZeneca COVID-19 vaccine currently available in Canada.
# Are certain patients predisposed to VIPIT?
At this time, it is not clear if certain patients are predisposed to VIPIT. The cases to date are predominantly in younger women, however these individuals may have been overrepresented in the vaccinated population in European Union countries. 2 Further information from jurisdictions like the United Kingdom that prioritized older adults for early vaccination is pending. Since VIPIT is immune-mediated, an individual with a thrombophilia, a family history of blood clots, or a personal history of arterial or venous clots would likely not be at increased of VIPIT. Accordingly, there are no new contraindications to receiving the AstraZeneca COVID-19 vaccine.
# When should I suspect my patient has VIPIT?
Patients with VIPIT may present with CSVT, or with other arterial or venous clots. Any patient with unusual symptoms following vaccination should be assessed by a health care provider. Some symptoms make it more likely that a patient has VIPIT: persistent and severe headache; focal neurological symptoms (including blurred vision); shortness of breath; abdominal or chest pain; swelling and redness in a limb; or pallor and coldness in a limb. VIPIT seems to occur between 4 to 20 days postvaccination. Symptoms in this time frame should raise the clinical suspicion of VIPIT.
# How do I diagnose VIPIT? How do I rule it out?
Patients with severe symptoms should urgently seek care at their nearest emergency department. Patients with non-severe symptoms may have initial investigations done in the primary care or outpatient setting.
Clinicians should ask patients about their COVID-19 vaccine history and should draw a complete blood count (CBC). VIPIT is unlikely if symptoms of blood clotting fall outside of the 4 to 20 day time frame OR if the platelet count is ≥ 150 x 10 9 /L. 6 VIPIT is more likely if symptoms of blood clotting fall within the 4 to 20 day time frame AND the platelet count is < 150 x 10 9 /L, and such patients should be evaluated at their nearest emergency department for suspected VIPIT. This will expedite further diagnostic workup, treatment, and urgent hematology consultation.
Patients with suspected VIPIT should go on to have blood work drawn including a Ddimer level and a blood film. When there is strong clinical suspicion of VIPIT, patients should also have diagnostic imaging to investigate for blood clots (including appropriate imaging to rule out CSVT, if the patient presents with a persistent and severe headache). It is not known whether VIPIT, like HIT, is associated with arterial thromboses, but arterial clots should be considered if patients have consistent symptoms. An elevated D-dimer, a normal blood film (apart from thrombocytopenia), and confirmation of a blood clot on diagnostic imaging makes the diagnosis of VIPIT presumptive.
The confirmatory diagnosis of VIPIT is made by testing for HIT. This testing should be done even if the patient has had no previous exposure to heparin. HIT testing involves two steps: identification of antibodies against the complex of platelet factor 4 and heparin; and confirmatory functional testing of the antibodies' ability to activate platelets. 7 The HIT antibody test appears very sensitive to VIPIT; if it is positive, VIPIT is confirmed, and if it is negative, VIPIT is unlikely. 1 A number of large hospital laboratories test for HIT antibodies, but only one lab in Canada performs confirmatory functional testing (the McMaster University Platelet Immunology Laboratory). Therefore, presumptive VIPIT should prompt an urgent hematology consultation (in person, virtually, or by phone) to arrange testing and start safe empiric treatment of blood clots (see below).
# How do I treat VIPIT?
Patients with presumptive and confirmed VIPIT should be treated similarly to HIT. The Box presents the treatment principles for patients with presumptive and confirmed VIPIT. Until VIPIT has been ruled out, anticoagulation with heparin (unfractionated heparin and low molecular weight heparins) should be avoided. Platelet transfusions should also not be given.
# Summary Box. Treating Blood Clots in Patients with Presumptive or Confirmed VIPIT
Alternative anticoagulants that are safe to use in HIT, and likely safe to use in VIPIT, include direct thrombin inhibitors and anti-Xa inhibitors. Most clinicians in Ontario will be comfortable using direct oral anti-Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban) empirically while awaiting further advice from a hematologist; these agents are used in the treatment of HIT. The dose of direct oral anti-Xa inhibitor is identical to the dose used to treat uncomplicated deep vein thromboses. If the patient has severe renal impairment that makes direct oral anticoagulants unsafe, advice from a hematologist should be sought to guide use of parenteral anticoagulants that are safe to use in HIT.
# How do I treat VIPIT with life threatening blood clots?
In patients with confirmed VIPIT and severe or life-threatening blood clots (e.g., CSVT, splanchnic vein thrombosis), it is important to dampen the prothrombotic response with intravenous immunoglobulin (IVIG). Administration of high dose IVIG (1 g/kg of body weight daily for two days) is appropriate and can be guided by the consulting hematologist.
# Is VIPIT a reportable event?
All suspected adverse events following immunization (AEFI), including thrombosis, and both presumptive and confirmed VIPIT, should be reported using the provincial AEFI form and sent to the local Public Health Unit. More information on how to report AEFIs can be found on the Public Health Ontario website. Ontario conducts
#
Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination Ontario COVID-19 Science Advisory Table vaccine surveillance safety in collaboration with the Public Health Agency of Canada, and prompt reporting is essential to learn more about this rare but serious thrombotic phenomenon.
# Can patients who develop VIPIT safely receive a second dose of AstraZeneca's COVID-19 vaccine? Can they receive another COVID-19 vaccine?
At this time, we do not know how subsequent doses of COVID-19 vaccines should be managed in individuals who develop VIPIT following their first dose. These cases require consultation with a hematologist. We know that individuals with non-vaccine associated HIT can be safely re-exposed to heparin, under very controlled conditions, but this requires the advice and close monitoring of a hematologist. This is an area of active study. There have been no confirmed cases of VIPIT with any other COVID-19 vaccine. Therefore, a second dose of another COVID-19 vaccine may be safe.
# Interpretation
VIPIT is a rare adverse event following the AstraZeneca COVID-19 vaccine. This brief describes the pathophysiology, presentation, diagnostic work-up and treatment of VIPIT, including a decision tree for diagnosing and ruling out VIPIT.
# Author Contributions
MP, PJ and AMM conceived the Science Brief. MP wrote the first draft of the Science Brief. All authors contributed to the conception of the Science Brief, revised it critically for important intellectual content and approved the final version. | None | None |
330bba51350c70476afbb657e27aa6e5852753d7 | cma | None | The information contained in this document has been reaffirmed for scientific validity. While this document is no longer identified to be clinically useful for the Canadian health care provider, it may be relevant to providers abroad. The COVID-19 pandemic has affected all Canadian jurisdictions, and community spread of the virus is now common. Physical distancing, hand hygiene and engineering controls remain the most effective measures for prevention of infection. All workers 1 are strongly recommended to adhere to personal protective equipment (PPE) guidelines to avoid infection, however PPE continues to be the lowest intervention on the hierarchy of controls. In particular, when working in healthcare, it is critical that safe donning and doffing of PPE is taught and practiced. This document is intended to provide prenatal care providers with guidance about additional considerations for the pregnant workforce. Available evidence on the impact of COVID-19 infection during pregnancy is growing. We now have evidence available from large datasets and systematic reviews on which to guide practice. These now report on over 20,000 people diagnosed as having suspected or confirmed COVID-19 during pregnancy. The available evidence continues to demonstrate that the majority of pregnant individuals infected with COVID-19 will experience mild to moderate illness. Compared to non-pregnant individuals with COVID-19, pregnant individuals appear to be at increased risk of admission to the intensive care unit (OR 1.62, 95% CI 1.33 to 1.96) and invasive ventilation (OR 1.88, 95% 1.32 to 2.60), but the absolute risks remain low, 4% and 3% among pregnant individuals with COVID-19 in the same study. 2 Importantly, risk of severe morbidity from COVID-19 in pregnant people appears to be strongly associated with risk factors including: age ≥ 35 years old, asthma, obesity, preexisting diabetes, preexisting hypertension and heart disease. 1,2 In published international data, mortality from COVID-19 does not appear to be higher for pregnant individuals with COVID-19 infection, compared to those not pregnant (OR 0.81, 95% CI 0.49 to 1.33). 2 Maternal mortality is multifactorial and highly variable, both within and between countries across the#
globe. Disparities in maternal mortality can be explained by differences in baseline health, access to healthcare services, and socioeconomic inequalities. Similarly, mortality rates from COVID-19 during pregnancy are being influenced by these same factors across the globe, and we are likely to see significant inequities emerge for COVID-19 mortality rates among pregnant people, both within and between countries.
The data available on pregnancy outcomes has been largely reassuring with most infants from COVID-19 affected pregnancies born healthy and full term. Preterm birth (PTB) appears to be the most commonly reported adverse perinatal outcome among pregnant patients with COVID-19 infection. As the body of data continues to grow, it has revealed that the true rate of PTB among those infected with COVID-19 during the second and third trimester is lower than estimated at the outset of the pandemic, with recent estimates from 6-15%. 2,4 Other adverse pregnancy outcomes reported in the literature appear to be proportional to the degree of respiratory illness in the pregnant individual with COVID-19.
Consistent with our experience with other respiratory viruses such as SARS, MERS and influenza, there is no consistent evidence of vertical transmission of COVID-19 to babies or teratogenic effects. Data related to vertical transmission is limited and continues to be monitored and evaluated.
# Summary of Evidence
1) Current data suggest that most healthy pregnant individuals will experience a mild to moderate course of disease when infected with COVID-19. 2) In pregnancy, there is an increased risk of need for intensive care or invasive ventilation, but the absolute risk remains low. 3) Current data indicate that the majority of infants from pregnancies affected by COVID-19 are born healthy and at term, with risk for preterm birth generally under 15%.
4) Comorbidities during pregnancy, such as preexisting diabetes, preexisting hypertension, asthma, age > 35 years, and obesity are all independent risk factors for sepsis and should be considered as risk factors for severe COVID-19 infection in pregnancy.
While the data about infection with COVID-19 during pregnancy provide reassurance that the risk of adverse maternal and fetal outcomes is low, it is preferable for a pregnant person, as it is for all people, to avoid infection. As such, for the duration of the pandemic, discussions about strategies to minimize risk of infection with COVID-19 should be incorporated into prenatal care. For pregnant workers, the workplace will be relevant to this discussion. It is worth noting that overall, the majority of cases of COVID-19 in Canada presently are acquired through community exposure rather than workplace exposure. As such, risk mitigation strategies should focus on both risk of infection in the community and in the workplace.
# Recommendations
1) Strategies to minimize the risk of infection with COVID-19 should be incorporated into guidance discussions during prenatal care for all pregnant patients, with education about the risk of community transmission of the virus. 2) Physical distancing of 2 meters, careful hand hygiene, and engineering controls (such as physical barriers when physical distancing cannot be applied), while seemingly simplistic, are the most impactful risk reducing strategies to decrease infection for all patients.
Each pregnant person's workplace circumstances are different and should be considered individually while respecting their autonomy to make informed decisions about their health. Decisions about continuing to work during the pandemic should take into consideration (a) local epidemiology, (b) workrelated exposure, PPE access, and risk for infection, (c) an individual's personal risk for COVID-related morbidity based on their health status and relevant comorbidities, and (d) an individual's ability to advocate for risk reduction strategies, especially for higher risk encounters, without risking lost income or employment.
# Recommendations
3) Pregnant individuals and their prenatal care providers should discuss an individualized plan related to working during the COVID-19 pandemic. That discussion should consider local epidemiology, work-related risk of infection, individual risk for COVID-related morbidity, and an individual's ability to advocate for safer work conditions or accommodations, without risking lost income or employment. The discussion might also consider a patient's mental health and anxiety related to workplace exposure and infection with COVID-19 during pregnancy. 4) In situations where work-related exposure is substantive and not able to be modified with a safe work plan or an individual's risk for severe COVID-related morbidity is high, it may be appropriate to advocate for accommodations or excused absence from work for pregnant workers. In these situations, a pregnant person's autonomy to make informed decisions about their health, balanced with their other priorities, should be respected.
Physical distancing, engineering controls and handwashing continue to be the most effective method at reducing spread of COVID 19.
No additional PPE measures are recommended for pregnant workers beyond those that are advised for non-pregnant workers. However, it should be recognized that PPE is not infallible and certain workrelated encounters are inherently higher risk for exposure to COVID-19. These include situations where appropriate PPE is substandard; situations where physical distancing cannot be achieved and situations with repeated exposure to persons with COVID-19 (e.g. COVID-positive wards in the healthcare setting). Importantly, it should be recognized that changes in local epidemiology can modify work-related risk dramatically, and decisions should be reassessed if there is significant change in local epidemiology (e.g. an outbreak in the workplace).
# Recommendations:
5) Pregnant workers identified to be at increased risk for severe illness should have reasonable workplace accommodations made to reduce exposures from the public and/or from those with active COVID-19 infection. 6) It is incumbent on employers to provide adequate physical distancing and PPE. A pregnant worker (or indeed any employee) with exposure risk from potentially infected members of the public, should be excused from work if appropriate PPE or physical distancing cannot be ensured in the workplace. 7) A pregnant healthcare worker who is required to wear an N95 respirator, and who has experienced significant weight changes during pregnancy, must ensure that their N95 respirator fit-test is up to date.
The Society of Obstetricians and Gynaecologists of Canada commits to reviewing the available literature on a regular basis and will alter recommendations if appropriate as the body of medical knowledge grows throughout the COVID-19 pandemic. | The information contained in this document has been reaffirmed for scientific validity. While this document is no longer identified to be clinically useful for the Canadian health care provider, it may be relevant to providers abroad. The COVID-19 pandemic has affected all Canadian jurisdictions, and community spread of the virus is now common. Physical distancing, hand hygiene and engineering controls remain the most effective measures for prevention of infection. All workers 1 are strongly recommended to adhere to personal protective equipment (PPE) guidelines to avoid infection, however PPE continues to be the lowest intervention on the hierarchy of controls. In particular, when working in healthcare, it is critical that safe donning and doffing of PPE is taught and practiced. This document is intended to provide prenatal care providers with guidance about additional considerations for the pregnant workforce. Available evidence on the impact of COVID-19 infection during pregnancy is growing. We now have evidence available from large datasets and systematic reviews on which to guide practice. [1][2][3] These now report on over 20,000 people diagnosed as having suspected or confirmed COVID-19 during pregnancy. The available evidence continues to demonstrate that the majority of pregnant individuals infected with COVID-19 will experience mild to moderate illness. Compared to non-pregnant individuals with COVID-19, pregnant individuals appear to be at increased risk of admission to the intensive care unit (OR 1.62, 95% CI 1.33 to 1.96) and invasive ventilation (OR 1.88, 95% 1.32 to 2.60), but the absolute risks remain low, 4% and 3% among pregnant individuals with COVID-19 in the same study. 2 Importantly, risk of severe morbidity from COVID-19 in pregnant people appears to be strongly associated with risk factors including: age ≥ 35 years old, asthma, obesity, preexisting diabetes, preexisting hypertension and heart disease. 1,2 In published international data, mortality from COVID-19 does not appear to be higher for pregnant individuals with COVID-19 infection, compared to those not pregnant (OR 0.81, 95% CI 0.49 to 1.33). 2 Maternal mortality is multifactorial and highly variable, both within and between countries across the#
globe. Disparities in maternal mortality can be explained by differences in baseline health, access to healthcare services, and socioeconomic inequalities. Similarly, mortality rates from COVID-19 during pregnancy are being influenced by these same factors across the globe, and we are likely to see significant inequities emerge for COVID-19 mortality rates among pregnant people, both within and between countries.
The data available on pregnancy outcomes has been largely reassuring with most infants from COVID-19 affected pregnancies born healthy and full term. Preterm birth (PTB) appears to be the most commonly reported adverse perinatal outcome among pregnant patients with COVID-19 infection. As the body of data continues to grow, it has revealed that the true rate of PTB among those infected with COVID-19 during the second and third trimester is lower than estimated at the outset of the pandemic, with recent estimates from 6-15%. 2,4 Other adverse pregnancy outcomes reported in the literature appear to be proportional to the degree of respiratory illness in the pregnant individual with COVID-19.
Consistent with our experience with other respiratory viruses such as SARS, MERS and influenza, there is no consistent evidence of vertical transmission of COVID-19 to babies or teratogenic effects. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Data related to vertical transmission is limited and continues to be monitored and evaluated.
# Summary of Evidence
1) Current data suggest that most healthy pregnant individuals will experience a mild to moderate course of disease when infected with COVID-19. 2) In pregnancy, there is an increased risk of need for intensive care or invasive ventilation, but the absolute risk remains low. 3) Current data indicate that the majority of infants from pregnancies affected by COVID-19 are born healthy and at term, with risk for preterm birth generally under 15%.
4) Comorbidities during pregnancy, such as preexisting diabetes, preexisting hypertension, asthma, age > 35 years, and obesity are all independent risk factors for sepsis and should be considered as risk factors for severe COVID-19 infection in pregnancy.
While the data about infection with COVID-19 during pregnancy provide reassurance that the risk of adverse maternal and fetal outcomes is low, it is preferable for a pregnant person, as it is for all people, to avoid infection. As such, for the duration of the pandemic, discussions about strategies to minimize risk of infection with COVID-19 should be incorporated into prenatal care. For pregnant workers, the workplace will be relevant to this discussion. It is worth noting that overall, the majority of cases of COVID-19 in Canada presently are acquired through community exposure rather than workplace exposure. As such, risk mitigation strategies should focus on both risk of infection in the community and in the workplace.
# Recommendations
1) Strategies to minimize the risk of infection with COVID-19 should be incorporated into guidance discussions during prenatal care for all pregnant patients, with education about the risk of community transmission of the virus. 2) Physical distancing of 2 meters, careful hand hygiene, and engineering controls (such as physical barriers when physical distancing cannot be applied), while seemingly simplistic, are the most impactful risk reducing strategies to decrease infection for all patients.
Each pregnant person's workplace circumstances are different and should be considered individually while respecting their autonomy to make informed decisions about their health. Decisions about continuing to work during the pandemic should take into consideration (a) local epidemiology, (b) workrelated exposure, PPE access, and risk for infection, (c) an individual's personal risk for COVID-related morbidity based on their health status and relevant comorbidities, and (d) an individual's ability to advocate for risk reduction strategies, especially for higher risk encounters, without risking lost income or employment.
# Recommendations
3) Pregnant individuals and their prenatal care providers should discuss an individualized plan related to working during the COVID-19 pandemic. That discussion should consider local epidemiology, work-related risk of infection, individual risk for COVID-related morbidity, and an individual's ability to advocate for safer work conditions or accommodations, without risking lost income or employment. The discussion might also consider a patient's mental health and anxiety related to workplace exposure and infection with COVID-19 during pregnancy. 4) In situations where work-related exposure is substantive and not able to be modified with a safe work plan or an individual's risk for severe COVID-related morbidity is high, it may be appropriate to advocate for accommodations or excused absence from work for pregnant workers. In these situations, a pregnant person's autonomy to make informed decisions about their health, balanced with their other priorities, should be respected.
Physical distancing, engineering controls and handwashing continue to be the most effective method at reducing spread of COVID 19.
No additional PPE measures are recommended for pregnant workers beyond those that are advised for non-pregnant workers. However, it should be recognized that PPE is not infallible and certain workrelated encounters are inherently higher risk for exposure to COVID-19. These include situations where appropriate PPE is substandard; situations where physical distancing cannot be achieved and situations with repeated exposure to persons with COVID-19 (e.g. COVID-positive wards in the healthcare setting). Importantly, it should be recognized that changes in local epidemiology can modify work-related risk dramatically, and decisions should be reassessed if there is significant change in local epidemiology (e.g. an outbreak in the workplace).
# Recommendations:
5) Pregnant workers identified to be at increased risk for severe illness should have reasonable workplace accommodations made to reduce exposures from the public and/or from those with active COVID-19 infection. 6) It is incumbent on employers to provide adequate physical distancing and PPE. A pregnant worker (or indeed any employee) with exposure risk from potentially infected members of the public, should be excused from work if appropriate PPE or physical distancing cannot be ensured in the workplace. 7) A pregnant healthcare worker who is required to wear an N95 respirator, and who has experienced significant weight changes during pregnancy, must ensure that their N95 respirator fit-test is up to date.
The Society of Obstetricians and Gynaecologists of Canada commits to reviewing the available literature on a regular basis and will alter recommendations if appropriate as the body of medical knowledge grows throughout the COVID-19 pandemic. | None | None |
f4b3e76bcd1ab14e01265860fe6d8170d9c4ba46 | cma | None | To provide guidance to clinicians, based on the Canadian Cardiovascular Society recommendations, for the perioperative management of patients on antiplatelet therapy who require non-cardiac or cardiac surgery.Antiplatelet drugs are commonly used in the primary and secondary prevention of cardiovascular disease. Patients receiving antiplatelet therapy have a broad range of cardiovascular risk depending on the clinical indication for treatment.#
With over 200 million noncardiac surgical procedures performed worldwide each year, clinicians face unique challenges regarding the perioperative management of patients with coronary artery disease who are receiving acetylsalicylic acid (ASA) alone; clopidogrel alone; or any combination of ASA and a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor). Clinicians must balance the risks of major adverse cardiovascular events associated with interrupting these therapies against the risk of bleeding from continuing these therapies in the perioperative period. Additionally, other factors including the pharmacokinetic actions of antiplatelet drugs and the optimal timing of surgery in patients with coronary stenting must be considered. The latter group of patients requires special consideration due to the increased risks and significant mortality of stent thrombosis.
# RISK STRATIFICATION FOR PERIOPERATIVE THROMBOSIS AND BLEEDING
Risk stratification for thrombosis and bleeding is largely empiric in patients who are receiving antiplatelet therapy. Patients considered at highest risk for cardiovascular events in the perioperative period include those with recently (i.e. within one year) implanted bare metal stents (BMS) or drugeluting stents (DES), recent myocardial infarction (MI), those with carotid ulcerating plaque and stroke or aortic ulcerating plaque and systemic embolism. Patients at low risk for perioperative cardiovascular events are those taking antiplatelet therapy for primary prevention of MI, limb ischemia or stroke (although this is rarely indicated). Clinicians must balance these risks against the associated risks of perioperative bleeding (listed in Table 1).
In patients with high thromboembolic risk (e.g. antiphospholipid syndrome), a consultation with a thrombosis expert is recommended.
# DIAGNOSTIC TESTING, ARTHROCENTESIS, AND MINOR DENTAL, SKIN AND EYE PROCEDURES
Patients undergoing arthrocentesis, minor dental (extraction, root canal), eye (cataract) or skin (biopsy, skin cancer excision) procedures, as well as low bleeding risk diagnostic procedures, can continue ASA without interruption. Less is known about the safety of continuing P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel) around minor procedures when taken as monotherapy. It is reasonable to discontinue them for a short period (3-4 days) before the procedure. If patients are also taking ASA (dual antiplatelet therapy), the P2Y12 should be discontinued prior to surgery (clopidogrel and ticagrelor for 5-7 days, prasugrel for 7-10 days) while ASA is continued.
Patients having a diagnostic test associated with a higher risk for bleeding should be managed like higher risk surgeries, as outlined below.
# MANAGEMENT OF PATIENTS WITHOUT CORONARY STENTS UNDERGOING ELECTIVE OR NON-URGENT NONCARDIAC SURGERY
The Perioperative Ischemic Evaluation (POISE) 2 trial is the only randomized trial in noncardiac surgery to assess perioperative antiplatelet drug management. It demonstrated that continuing ASA did not have an effect on the incidence of major adverse cardiovascular events or mortality but increased the risk of major bleeding. Only 4% of patients in this study had a coronary stent and it excluded patients who underwent carotid endarterectomy, received a BMS in the 6 weeks before surgery, or a DES in the 12 months before surgery.
Initiating ASA before surgery to reduce perioperative cardiovascular events is not recommended.
ASA should be discontinued 5-7 days prior to elective or non-urgent non-cardiac surgery except in patients undergoing carotid endarterectomy or with recent coronary artery stenting (see below for approach). Perioperative ASA continuation might also be reasonable for some surgical interventions to prevent local thrombosis (e.g. lower extremity bypass or arterial aneurysm repair).
In patients with an indication for chronic ASA, this medication should be resumed when the risk of bleeding related to surgery has passed, usually between 8-10 days after major noncardiac surgery or after venous thromboembolism prophylaxis has stopped.
# MANAGEMENT OF PATIENTS WITH CORONARY STENTS UNDERGOING ELECTIVE OR NON-URGENT NONCARDIAC SURGERY
A sub-study of the POISE-2 trial involving 470 patients with previous percutaneous coronary intervention (PCI) and cardiac stents revealed that for every 1000 patients with prior PCI, perioperative ASA will prevent 59 myocardial infarctions but cause 8 major bleeds. It is, therefore, viewed that in patients with prior PCI undergoing noncardiac surgery, perioperative ASA may be more likely to benefit than harm patients.
Clinicians must consider the timing of surgery and perioperative dual antiplatelet (DAPT) management in patients being treated with DAPT after PCI with a BMS or DES. Recommended to be discontinued ideally 5 days prior to surgery.
# Clopidogrel
Suggested to discontinue a minimum of 48-72 hours prior to surgery to minimize the risk of bleeding.
Recommended to be discontinued ideally 5 days prior to surgery.
# Prasugrel
Suggested to discontinue a minimum of 5 days prior to surgery to minimize the risk of bleeding.
Recommended to be discontinued ideally 7 days prior to surgery.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES
# Date of Version: 04July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide guidance to clinicians, based on the Canadian Cardiovascular Society recommendations, for the perioperative management of patients on antiplatelet therapy who require non-cardiac or cardiac surgery.Antiplatelet drugs are commonly used in the primary and secondary prevention of cardiovascular disease. Patients receiving antiplatelet therapy have a broad range of cardiovascular risk depending on the clinical indication for treatment.#
With over 200 million noncardiac surgical procedures performed worldwide each year, clinicians face unique challenges regarding the perioperative management of patients with coronary artery disease who are receiving acetylsalicylic acid (ASA) alone; clopidogrel alone; or any combination of ASA and a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor). Clinicians must balance the risks of major adverse cardiovascular events associated with interrupting these therapies against the risk of bleeding from continuing these therapies in the perioperative period. Additionally, other factors including the pharmacokinetic actions of antiplatelet drugs and the optimal timing of surgery in patients with coronary stenting must be considered. The latter group of patients requires special consideration due to the increased risks and significant mortality of stent thrombosis.
# RISK STRATIFICATION FOR PERIOPERATIVE THROMBOSIS AND BLEEDING
Risk stratification for thrombosis and bleeding is largely empiric in patients who are receiving antiplatelet therapy. Patients considered at highest risk for cardiovascular events in the perioperative period include those with recently (i.e. within one year) implanted bare metal stents (BMS) or drugeluting stents (DES), recent myocardial infarction (MI), those with carotid ulcerating plaque and stroke or aortic ulcerating plaque and systemic embolism. Patients at low risk for perioperative cardiovascular events are those taking antiplatelet therapy for primary prevention of MI, limb ischemia or stroke (although this is rarely indicated). Clinicians must balance these risks against the associated risks of perioperative bleeding (listed in Table 1).
In patients with high thromboembolic risk (e.g. antiphospholipid syndrome), a consultation with a thrombosis expert is recommended.
# DIAGNOSTIC TESTING, ARTHROCENTESIS, AND MINOR DENTAL, SKIN AND EYE PROCEDURES
Patients undergoing arthrocentesis, minor dental (extraction, root canal), eye (cataract) or skin (biopsy, skin cancer excision) procedures, as well as low bleeding risk diagnostic procedures, can continue ASA without interruption. Less is known about the safety of continuing P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel) around minor procedures when taken as monotherapy. It is reasonable to discontinue them for a short period (3-4 days) before the procedure. If patients are also taking ASA (dual antiplatelet therapy), the P2Y12 should be discontinued prior to surgery (clopidogrel and ticagrelor for 5-7 days, prasugrel for 7-10 days) while ASA is continued.
Patients having a diagnostic test associated with a higher risk for bleeding should be managed like higher risk surgeries, as outlined below.
# MANAGEMENT OF PATIENTS WITHOUT CORONARY STENTS UNDERGOING ELECTIVE OR NON-URGENT NONCARDIAC SURGERY
The Perioperative Ischemic Evaluation (POISE) 2 trial is the only randomized trial in noncardiac surgery to assess perioperative antiplatelet drug management. It demonstrated that continuing ASA did not have an effect on the incidence of major adverse cardiovascular events or mortality but increased the risk of major bleeding. Only 4% of patients in this study had a coronary stent and it excluded patients who underwent carotid endarterectomy, received a BMS in the 6 weeks before surgery, or a DES in the 12 months before surgery.
Initiating ASA before surgery to reduce perioperative cardiovascular events is not recommended.
ASA should be discontinued 5-7 days prior to elective or non-urgent non-cardiac surgery except in patients undergoing carotid endarterectomy or with recent coronary artery stenting (see below for approach). Perioperative ASA continuation might also be reasonable for some surgical interventions to prevent local thrombosis (e.g. lower extremity bypass or arterial aneurysm repair).
In patients with an indication for chronic ASA, this medication should be resumed when the risk of bleeding related to surgery has passed, usually between 8-10 days after major noncardiac surgery or after venous thromboembolism prophylaxis has stopped.
# MANAGEMENT OF PATIENTS WITH CORONARY STENTS UNDERGOING ELECTIVE OR NON-URGENT NONCARDIAC SURGERY
A sub-study of the POISE-2 trial involving 470 patients with previous percutaneous coronary intervention (PCI) and cardiac stents revealed that for every 1000 patients with prior PCI, perioperative ASA will prevent 59 myocardial infarctions but cause 8 major bleeds. It is, therefore, viewed that in patients with prior PCI undergoing noncardiac surgery, perioperative ASA may be more likely to benefit than harm patients.
Clinicians must consider the timing of surgery and perioperative dual antiplatelet (DAPT) management in patients being treated with DAPT after PCI with a BMS or DES. Recommended to be discontinued ideally 5 days prior to surgery.
# Clopidogrel
Suggested to discontinue a minimum of 48-72 hours prior to surgery to minimize the risk of bleeding.
Recommended to be discontinued ideally 5 days prior to surgery.
# Prasugrel
Suggested to discontinue a minimum of 5 days prior to surgery to minimize the risk of bleeding.
Recommended to be discontinued ideally 7 days prior to surgery.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES
# Date of Version: 04July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
2d034aca61801b15b0a979c98e74d06eb50b2339 | cma | None | # Background
Neuroendocrine tumours (NETs) are a family of tumours, occurring with an incidence of about 5.25 cases per 100,000 1 . The incidence of NETs is increasing over the last 3 decades. NETs can arise in several organs; the most common sites are the ileum and pancreas, followed by other sites within the GI tract, the lungs, thyroid, parathyroid, adrenal glands, and pituitary gland. However, NETS can occur anywhere in the body 2,3 . NETs are often classified as functioning or nonfunctioning tumours, the latter of which do not present with hormone hypersecretion, and are often found as a bulky tumours with metastatic disease. The five-year survival rate for patients with NETs depends largely upon the location of the primary tumour and the extent of disease. Patients with localized disease can expect five-year survival rates ranging from 65% for ileal tumours to 84% for lung tumours and 90% for rectal tumours 4 . As expected, patients with distant disease carry a worse prognosis with five-year survival rates ranging from 24% in the rectum and 27% in the lungs to 54% in the ileum 5 .
Few curative options are available for patients with unresectable, progressive, or metastatic NETs. Peptide receptor radionuclide therapy (PRRT) has been studied in the clinical trial setting since about the year 2000. Several agents are potentially available, including 90Y-DOTAOC 6 , 111ln-DTPAOC 7 , 177Lu-DOTATATE 8 , which are radionuclides bound to the somatostatin analog octreotide. These agents work by binding to the tumour receptors and emitting radiation to the tumour. The Health Canada approved product (Lutathera, 177Lu-DOTATATE) is administered with a dose of 200mCi every 8 weeks for a total of four cycles. Dosing and timing may differ based on a centre's specific clinical research trial protocol. The most common side effects of treatment are nausea /vomiting, fatigue and decreased blood counts. Rare severe toxicities include myelodysplasia, acute leukemia, renal failure and hormonal crisis (if the tumour is secretory). The full listing of adverse events can be viewed further in the Lutathera product monographand/or the centre's trial protocol. The purpose of this guideline is to provide evidence-based recommendations on the use of PRRT for NETs and to define which patients are candidates for this treatment. This guideline will focus on the role of 177Lu-DOTATATE 9,10
# Search Strategy
The National Guidelines Clearinghouse and individual cancer agencies' websites were searched for guidelines on the use of peptide receptor radionuclide therapy. Among the guidelines identified, Cancer Care Ontario's document, Radionuclide Therapy for Neuroendocrine Malignancies (August 15, 2011), was deemed appropriate by the working group for adaptation. The search strategy employed by Cancer Care Ontario was current to 2010 11 . In order to make the guideline adaptation current to 2018, the MEDLINE and EMBASE database was searched (2010 through 2021) using the same search strategy.
The search initially resulted in1530 citations after duplicates were removed. Studies that did not report response rates or survival rates were excluded, as well as prospective studies that included 30 or fewer patients or retrospective studies that included 100 or fewer patients. A total of 60 publications were deemed relevant. Evidence is summarized in the table in Appendix A.
# Target Population
The recommendations in this guideline apply to patients diagnosed with unresectable, progressive, or metastatic neuroendocrine tumours. Recommendations 1. Peptide receptor radionuclide therapy (PRRT) is an appropriate treatment option for patients with unresectable or metastatic; progressive or symptomatic, NETs. Consideration for treatment is to be determined at a multidisciplinary neuroendocrine tumour board.
# Required work up
- Confirm diagnosis and staging of NET with histopathology and biochemical assays. The tumour differentiation must be present on the pathology report: Grade 1 (ki-6720%) tumours 12 . - Images should be reviewed to assess for receptor heterogeneity. If there is discordance between imaging modalities with presence of lesions that are suspected to be dedifferentiated based on absence of uptake on somatostatin receptor imaging or if they exhibit a rapid progression pattern on anatomic imaging, an FDG PET-CT should be performed to exclude aggressive or dedifferentiated disease that would not be amenable to PRRT and for prognostic purposes.
- Baseline tumor markers should be obtained prior to initiating therapy, depending on origin and hormonal secretion status (secreting or not, ex: CgA and 5-HIAA, Insulinemia, etc).
- Somatostatin receptor imaging (SRI) using PET or SPECT, such as Ga68 DOTA PET, octreotide scan or other available SRI imaging , to determine if tumour is somatostatin receptor positive. Sufficient tumour uptake is defined as higher than normal liver uptake.
- For Higher grade tumors: ki67 >10%, it is recommended that Diagnostic imaging (CT and MRI), should be less than 3 months old.
- If PRRT is received within a clinical trial, additional work up may be required based on the study protocol.
- Conduct an appropriate laboratory assessment at baseline and before each cycle (directed at known side effects of treatment) o hematologic: CBCD (complete blood count and differential) o kidney function: electrolytes, creatinine and eGFR o liver function: bilirubin, albumin, INR, ALT o metabolic: fasting glucose - Perform cross sectional imaging (CT and/or MRI) at baseline (within 6 months of therapy initiation or less in case of suspected significant interval changes: significant elevation in tumor markers, clinical deterioration or other imaging showing significant progression) and at follow-up to assess tumour response. If PRRT is offered within a clinical trial, additional imaging may be required for tumour response assessment as per the trial protocol.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Endocrine Tumour Team. Members include . Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Endocrine Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2021.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
# Copyright © (2021) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see /. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner. | # Background
Neuroendocrine tumours (NETs) are a family of tumours, occurring with an incidence of about 5.25 cases per 100,000 1 . The incidence of NETs is increasing over the last 3 decades. NETs can arise in several organs; the most common sites are the ileum and pancreas, followed by other sites within the GI tract, the lungs, thyroid, parathyroid, adrenal glands, and pituitary gland. However, NETS can occur anywhere in the body 2,3 . NETs are often classified as functioning or nonfunctioning tumours, the latter of which do not present with hormone hypersecretion, and are often found as a bulky tumours with metastatic disease. The five-year survival rate for patients with NETs depends largely upon the location of the primary tumour and the extent of disease. Patients with localized disease can expect five-year survival rates ranging from 65% for ileal tumours to 84% for lung tumours and 90% for rectal tumours 4 . As expected, patients with distant disease carry a worse prognosis with five-year survival rates ranging from 24% in the rectum and 27% in the lungs to 54% in the ileum 5 .
Few curative options are available for patients with unresectable, progressive, or metastatic NETs. Peptide receptor radionuclide therapy (PRRT) has been studied in the clinical trial setting since about the year 2000. Several agents are potentially available, including 90Y-DOTAOC 6 , 111ln-DTPAOC 7 , 177Lu-DOTATATE 8 , which are radionuclides bound to the somatostatin analog octreotide. These agents work by binding to the tumour receptors and emitting radiation to the tumour. The Health Canada approved product (Lutathera, 177Lu-DOTATATE) is administered with a dose of 200mCi every 8 weeks for a total of four cycles. Dosing and timing may differ based on a centre's specific clinical research trial protocol. The most common side effects of treatment are nausea /vomiting, fatigue and decreased blood counts. Rare severe toxicities include myelodysplasia, acute leukemia, renal failure and hormonal crisis (if the tumour is secretory). The full listing of adverse events can be viewed further in the Lutathera product monographand/or the centre's trial protocol. The purpose of this guideline is to provide evidence-based recommendations on the use of PRRT for NETs and to define which patients are candidates for this treatment. This guideline will focus on the role of 177Lu-DOTATATE 9,10
# Search Strategy
The National Guidelines Clearinghouse and individual cancer agencies' websites were searched for guidelines on the use of peptide receptor radionuclide therapy. Among the guidelines identified, Cancer Care Ontario's document, Radionuclide Therapy for Neuroendocrine Malignancies (August 15, 2011), was deemed appropriate by the working group for adaptation. The search strategy employed by Cancer Care Ontario was current to 2010 11 . In order to make the guideline adaptation current to 2018, the MEDLINE and EMBASE database was searched (2010 through 2021) using the same search strategy.
The search initially resulted in1530 citations after duplicates were removed. Studies that did not report response rates or survival rates were excluded, as well as prospective studies that included 30 or fewer patients or retrospective studies that included 100 or fewer patients. A total of 60 publications were deemed relevant. Evidence is summarized in the table in Appendix A.
# Target Population
The recommendations in this guideline apply to patients diagnosed with unresectable, progressive, or metastatic neuroendocrine tumours. Recommendations 1. Peptide receptor radionuclide therapy (PRRT) is an appropriate treatment option for patients with unresectable or metastatic; progressive or symptomatic, NETs. Consideration for treatment is to be determined at a multidisciplinary neuroendocrine tumour board.
# Required work up
• Confirm diagnosis and staging of NET with histopathology and biochemical assays. The tumour differentiation must be present on the pathology report: Grade 1 (ki-67<3%) Grade 2 (ki-67 3% -20%), and selected Grade 3 (>20%) tumours 12 . • Images should be reviewed to assess for receptor heterogeneity. If there is discordance between imaging modalities with presence of lesions that are suspected to be dedifferentiated based on absence of uptake on somatostatin receptor imaging or if they exhibit a rapid progression pattern on anatomic imaging, an FDG PET-CT should be performed to exclude aggressive or dedifferentiated disease that would not be amenable to PRRT and for prognostic purposes.
• Baseline tumor markers should be obtained prior to initiating therapy, depending on origin and hormonal secretion status (secreting or not, ex: CgA and 5-HIAA, Insulinemia, etc).
• Somatostatin receptor imaging (SRI) using PET or SPECT, such as Ga68 DOTA PET, octreotide scan or other available SRI imaging , to determine if tumour is somatostatin receptor positive. Sufficient tumour uptake is defined as higher than normal liver uptake.
• For Higher grade tumors: ki67 >10%, it is recommended that Diagnostic imaging (CT and MRI), should be less than 3 months old.
• If PRRT is received within a clinical trial, additional work up may be required based on the study protocol.
• Conduct an appropriate laboratory assessment at baseline and before each cycle (directed at known side effects of treatment) o hematologic: CBCD (complete blood count and differential) o kidney function: electrolytes, creatinine and eGFR o liver function: bilirubin, albumin, INR, ALT o metabolic: fasting glucose • Perform cross sectional imaging (CT and/or MRI) at baseline (within 6 months of therapy initiation or less in case of suspected significant interval changes: significant elevation in tumor markers, clinical deterioration or other imaging showing significant progression) and at follow-up to assess tumour response. If PRRT is offered within a clinical trial, additional imaging may be required for tumour response assessment as per the trial protocol.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Endocrine Tumour Team. Members include [surgical oncologists, radiation oncologists, medical oncologists, dermatologists, nurses, pathologists, and pharmacists]. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Endocrine Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2021.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
# Copyright © (2021) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of Cancer Care Alberta's evidence-based clinical practice guidelines and supporting materials comes from the Cancer Care Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Stella Koumna: has nothing to disclose Dr. Vicky Parkins*: has nothing to disclose Ritu Sharma has nothing to disclose. * Guideline working group lead | None | None |
4a6f74ddbfe1f8afec70fa87ae4f621ea4de63cd | cma | None | Physicians, nurses and nurse practitioners, pharmacists, allied health care professionals, and all other clinical and non-clinical personnel who are involved in the care of pregnant and post-partum individuals who use alcohol.# Disclaimer for Health Care Providers
The recommendations in this guideline supplement represent the view of the provincial guideline supplement committee, arrived at after careful consideration of the available scientific evidence and following external expert peer review. The application of the recommendations in this document does not override the responsibility of health care professionals to make decisions that are appropriate to the needs, preferences, and values of an individual patient, in consultation with that patient and their family members or guardian(s), and, when appropriate, external experts (e.g., specialty consultation). When exercising clinical judgment in the treatment of perinatal alcohol use and alcohol use disorder, BC health care professionals are expected to take this guideline supplement fully into account while upholding their duty to adhere to the fundamental principles and values of the Canadian Medical Association Code of Ethics, especially compassion, beneficence, non-maleficence, respect for persons, justice and accountability, as well as the required standards for good clinical practice as set by the College of Physicians and Surgeons of British Columbia and any other relevant provincial regulatory body. Nothing in this guideline supplement should be interpreted in a way that would be inconsistent with compliance with those duties.
# Legal Disclaimer
While the individuals and groups involved in the production of this document have made every effort to ensure the accuracy of the information contained in this guideline supplement, please note that the information is provided "as is". The Ministry of Health (MoH), Ministry of Mental Health and Addictions (MMHA), and the BCCSU make no representation or warranty of any kind, either expressed or implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest extent possible under applicable law, the MoH, MMHA, and BCCSU disclaim and will not be bound by any express, implied or statutory representation or warranty (including, without limitation, representations or warranties of title or non-infringement).
This guideline supplement is intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. This guideline supplement is not intended as a substitute for the advice or professional judgment of a health care professional, nor is it intended to be the only approach to the management of a clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional. 7.1 Rooming-in and skin-to-skin contact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 7.2 Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 7.2.1 Alcohol and lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 7.2.2 Alcohol withdrawal pharmacotherapy and lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 7.2.3 AUD pharmacotherapy and lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 8. Child Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Appendix 1: Alcohol Use Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Summary of principles of care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 3 Comparative specifications of alcohol screening tools validated for pregnancy . . Table 4 The 5A's model for delivering alcohol use brief intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 5 Comparative features of pharmacotherapy options for management of alcohol withdrawal during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 6 Comparison of pharmacotherapies for AUD during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . .
# Table of Contents
Executive
# List of Tables
# Executive Summary
This document is intended to supplement the BCCSU Provincial Guideline for the Clinical Management of High-Risk Drinking and Alcohol Use Disorder (Guideline) with clinical guidance specific to pregnant and post-partum patients. While the Guideline has provided a comprehensive description of the harms of highrisk drinking and alcohol use disorder (AUD) in general adult and youth populations, it is recognized that pregnant individuals who use alcohol face an additional set of obstetrical risks. Some of the negative pregnancy outcomes associated with alcohol use during pregnancy include spontaneous abortion, intrauterine growth restriction, preterm birth, and fetal alcohol spectrum disorder.
Increased frequency of healthcare service use during pregnancy and post-partum periods present a unique opportunity for clinicians to identify and address alcohol use; however, stigma regarding substance use during pregnancy and lack of knowledge regarding appropriate screening and treatment options present barriers to early detection and treatment of alcohol use and AUD in this population.
To address this discrepancy, this guideline supplement reviews the evidence pertaining to care principles, screening and risk assessment methods, and treatment and continuing care options for pregnant individuals with high risk alcohol use and AUD. This document emphasises the need for a non-judgmental, inclusive, trauma-informed, and culturally safe approach to care that accommodates patients' individual choices and circumstances. Within this framework, the present document recommends a holistic and integrated care plan with appropriate use of the full range of available treatment options and harm reduction services. A summary of the clinical recommendations outlined in this supplement is provided in Table 1.
# Table 1 Summary of Clinical Recommendations
# Screening and Brief Intervention 1
Annual alcohol use screening for all patients of childbearing capacity should include education on Canada's Low-Risk Alcohol Drinking Guidelines and the risks of alcohol use during pregnancy.
Healthcare providers should screen pregnant and post-partum patients for alcohol use at the earliest opportunity. Screening should be repeated routinely throughout pregnancy and post-partum.
All pregnant and post-partum patients who screen positive for alcohol use should receive brief counselling intervention and advice for discontinuing alcohol use.
All pregnant and post-partum patients with AUD should be offered, or referred to, appropriate treatment interventions and support services.
# Withdrawal Management
Where possible, alcohol withdrawal management for pregnant patients should be conducted in inpatient settings where patients can receive symptom-triggered treatment with close monitoring of withdrawal symptoms. a 6 Clinicians should consider the use of the Prediction of Alcohol Withdrawal Severity Scale (PAWSS), in combination with best clinical judgement, to select the appropriate withdrawal management pharmacotherapy based on the risk of severe complications of withdrawal.
Pregnant patients who develop alcohol withdrawal symptoms should be offered pharmacotherapy for alcohol withdrawal management.
A. Either benzodiazepines or gabapentin may be offered to pregnant patients at low risk of severe complications of withdrawal (PAWSS<4).
B. Benzodiazepines are recommended for patients at high risk of severe complications of withdrawal (PAWSS>4).
All pregnant and post-partum patients who undergo withdrawal management should be connected to continuing AUD care.
# Continuing Care 9
All pregnant and post-partum patients with AUD should be offered, or referred to, psychosocial treatment interventions.
Healthcare providers should consider offering pharmacotherapy with naltrexone, acamprosate, or gabapentin to prevent relapse to alcohol use in pregnant patients with moderate to severe AUD. b
# Post-partum considerations 11
Healthcare providers should facilitate rooming in and encourage skin-to-skin contact to promote parent-neonate bonding and, in turn, improve maternal and neonatal outcomes.
Nursing parents should be strongly encouraged to discontinue alcohol use while lactating. Patients who continue using alcohol during this period should receive advice and support to reduce drinking and schedule feeding and alcohol use to ensure alcohol is eliminated from breastmilk by the time of feeding or storage of milk.
For patients who are stable on AUD pharmacotherapy (i.e., naltrexone, acamprosate, or gabapentin), decisions regarding breastfeeding c should be made on a case-by-case basis with the knowledge and involvement of the patient. The possible neonatal risks of these medications should be weighed against the well-established benefits of breastfeeding for mother and neonate.
1 Introduction
# Background
Alcohol is a known teratogen, and its use during pregnancy is associated with a wide range of negative pregnancy outcomes collectively referred to as fetal alcohol spectrum disorder (FASD), as well as spontaneous abortion and stillbirth. 1,2 According to recent Canadian estimates, FASD affects approximately 4% of the Canadian population and includes fetal growth restriction, developmental delay, neurological abnormalities, and behavioral and cognitive issues throughout life. 1,2 While a number of meta-analyses have demonstrated that the likelihood and severity of physiologic, cognitive, and behavioural sequalae of in utero alcohol exposure are dose-dependent, no consensus has emerged concerning the specific cut-off blood alcohol level below which alcohol use would be considered "low-risk" for the pregnant person and fetus. 1,3 Therefore, most jurisdictions, including Canada, strongly recommend abstinence from alcohol use during pregnancy. 4,5 Despite this unequivocal recommendation, alcohol use during pregnancy is not uncommon. According to a 2019 report by the US Centers for Disease Control and Prevention, the overall estimates of alcohol consumption and binge drinking rates among pregnant women during 2015-2017 were 11.5% and 4% respectively, marking a slight increase since the 2011-2013 period (10.2% and 3.1%, respectively). 6 Data from the 2009 Canadian Maternity Experiences Survey indicated that 62.4% of survey respondents reported drinking alcohol during the three months prior to pregnancy, and 10.5% reported that they consumed alcohol during pregnancy. 5,7 These data are likely an underestimation of the true prevalence of alcohol use in pregnancy, as the experience of stigma and fear of judgement and child apprehension can lead to significant under-reporting of alcohol use in this population. 5,8 Nevertheless, available data suggest that the prevalence of alcohol use during pregnancy is comparable to, or higher than, that of many conditions routinely screened for and addressed during prenatal care, such as cystic fibrosis, gestational diabetes, post-partum depression, and preeclampsia. Increased frequency of healthcare service use in the prenatal period and elevated motivation for delivering a healthy baby present a unique opportunity for clinicians, particularly primary care providers, to screen pregnant patients for alcohol use and provide appropriate advice, care, and referrals to address high risk alcohol use and alcohol use disorder (AUD). 12,13 Yet, alcohol use among pregnant patients frequently goes unrecognized. The lack of clear clinical guidelines for screening, assessment, and management of alcohol use and AUD during pregnancy is a commonly cited barrier to seizing this opportunity for early detection and intervention. 3,5,9 In response to this discrepancy, a committee of experts was assembled to supplement the BCCSU, MOH, and MMHA Provincial Guideline for the Clinical Management of High Risk Drinking and Alcohol Use Disorder ("Guideline") with clinical recommendations based on a review of evidence for screening and brief intervention, withdrawal management, and continuing AUD care specifically pertaining to pregnant individuals. The following text provides a summary of research evidence from which the committee has derived the clinical recommendations and principles of care presented in this guideline supplement.
# Objectives and scope of the guideline supplement
This guideline supplement primarily focuses on the identification, assessment, and clinical management of high-risk alcohol use and AUD in pregnant and post-partum individuals. To support transition from prenatal care to post-partum care for this population, the committee has also provided a review of available evidence on the implications of alcohol use, AUD, and AUD treatment on immediate post-partum care and breastfeeding.
This supplement is intended to serve as a companion document to the Guideline which provides a comprehensive review of the evidence on high risk-alcohol use and AUD treatment, clinical recommendations, and a general framework of care for the treatment of AUD; readers are encouraged to also refer to the Guideline for broadly applicable guidance in this area.
The objectives of this document are to address barriers to routine screening for the early identification of alcohol use and AUD among pregnant patients and to promote the uptake of evidence-based prevention, risk reduction, and treatment interventions appropriate for pregnant patients within primary care and other clinical settings.
Specifically, these guidelines aim to:
- Describe the principles of care and general considerations for screening, diagnosis, and management of high-risk drinking and AUD for pregnant and post-partum patients.
- Review specific strategies for alcohol use screening and brief intervention for pregnant patients.
- Recommend a clinical pathway for alcohol withdrawal management, whereby appropriate withdrawal risk and severity assessment facilitates tailored treatment selection and symptom-triggered approach that minimizes harm to the patient and fetus.
- Review and recommend pharmacotherapeutic and psychosocial alcohol withdrawal management options that are safe and suitable for the pregnant patient and the fetus.
- Review and recommend strategies for continuing AUD care with demonstrated maternal and fetal safety, including use of pharmacotherapy, psychosocial treatment interventions, and community-based treatment and support geared towards this population.
- Provide an overview of relevant care and safety considerations for patients with AUD and alcohol-exposed infants in the immediate post-partum period.
- Provide guidance on the potential impact of alcohol consumption and the safety considerations of alcohol withdrawal and AUD pharmacotherapy on lactation and breastfeeding.
# Guideline development process
Between January 2017 and November 2018, the guideline committee for the pregnancy supplement to the Provincial Guideline for the Clinical Management of High-Risk Drinking and Alcohol Use Disorder conferred through email, teleconferences, and three face-to-face meetings. At the first committee meeting, the purpose, scope, and outline of the guideline were provisionally approved by committee consensus in accordance with the AGREE-II reporting checklist for development of clinical practice guidelines.
From May 2019 to January 2020, guidance committee members conferred over email and teleconference, and held two in-person meetings to review and approve evidence summaries prepared by the medical writer and draft guideline contents and recommendations.
# Development and approval of recommendations
The recommendations for the pregnancy supplement were developed in reference to the broadly applicable recommendations of the Guideline, which were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool to develop and score recommendations. In view of limited volume and low quality of evidence focused on pregnant patients, recommendations specific to pregnant and postpartum populations were developed through committee consensus after rigorous review and discussion of prepared evidence summaries. In addition to the safety and efficacy data pertaining to both pregnant and non-pregnant populations, a range of factors, such as clinician, patient, and policy makers' values and preferences, costs, risk-benefit ratios, and feasibility were considered in the process of recommendation development.
The draft supplement and recommendations were compiled and circulated to the full committee to provide feedback on contents and recommendations. The committee was given four weeks to submit written feedback on the draft supplement. Feedback was collated and incorporated into a revised draft which was then circulated to the committee for additional feedback. Further feedback was collated and incorporated into a second revised draft for external review
# External review
The draft guideline supplement was circulated for review and comment to relevant experts and stakeholders as identified by the committee. Feedback from the external reviewers was reviewed and incorporated into the final draft of the supplement and external reviewers approved this draft. The final draft was then circulated to the committee for final approval.
# Principles of Care
As outlined in detail in the Guideline, healthcare providers are encouraged to observe a set of overarching principles of care that inform a collaborative, equitable, and effective therapeutic relationship with patients and, where appropriate, families affected by high-risk alcohol use and AUD. These principles enable clinicians and care teams to meet the healthcare needs of patients within a patient-centred framework and along an integrated continuum of addiction care. This section highlights a number of care principles and practices with particular practical relevance to the care of pregnant and post-partum individuals who use alcohol. Table 2 provides a summary of the key care principles described in this section.
# Respect for the autonomy, agency, and individuality of patients
As with all patients, pregnant individuals who use alcohol should be empowered to take an active role in decisions concerning their own health and well-being; this includes making informed decisions concerning the fetus. While patients should be provided with clinical recommendations to improve pregnancy outcomes, clinicians' concern for the health of the fetus should not override the patient's individual preferences and values. 4 Securing the patient's informed consent prior to implementing clinical decisions, and non-judgemental and informative dialogue are among the key aspects of respectful and effective care.
# Privacy and consent
Assuring patients of the confidentiality of the information they disclose helps establish a trusting and open therapeutic relationship. Care providers should inform patients of the relevant aspects of their duty to report and emphasize that there is no legal obligation to report substance use and risks to the fetus during the course of pregnancy to Child Protection Services (see the Child Protection section). This is an important detail to include in the initial discussion as, according to numerous studies, the fear of intervention by child welfare services and losing custody of a child is a major barrier to seeking treatment for pregnant people who use substances. 14,15 Respect for the privacy of patients extends to the involvement of family members or other support resources in their care. While a patient's family and social circle can have a key role in supporting the patient's care, healthcare providers should avoid assuming that involving a family member is always in the best interest of every patient.
# Information sharing and education
Continuous education and sharing of relevant information with patients are the cornerstones of collaborative and empowering care. Lack of knowledge about available treatment options and their implications for the health of the patient and the fetus may act as a barrier to accessing substance use care and engaging in treatment. 16 Thus, it is imperative that clinicians discuss the risks and benefits of available clinical care options for the patient and fetus, and provide referrals to educational and support resources that enhance patients' self-efficacy and independence in improving their health. 16 For example, clinicians should combine alcohol screening for pregnant patients and patients of childbearing capacity with a conversation regarding the risks of alcohol use during pregnancy and post-partum using the recommendations of Canada's Low Risk Alcohol Drinking Guidelines for this population. 5
# Gender-inclusive and non-judgemental language
While the majority of pregnant people identify as women, some pregnant people, including those who are transgender, transsexual, nonbinary, genderqueer, gender neutral, agender, Two-Spirit, and gender nonconforming (also collectively referred to as "trans" individuals) do not identify as women. Historically, clinical interventions for alcohol use during pregnancy have been designed and evaluated with insufficient awareness or understanding of the diversity of pregnant patients in terms of gender and reproductive intentions. 17 A 2018 commentary on gender-inclusive alcohol interventions for pregnant people argues that the assumption that all pregnant people are women creates gaps in services for people who are both trans and pregnant. 17 For many pregnant patients, the prospect of parenthood is an important source of motivation for positive change. However, care approaches and discourses that do not take into account gender diversity among pregnant people may render alcohol use interventions inapplicable, inaccessible, ineffective, and potentially harmful for pregnant patients who do not identify as women or do not intend to assume the role of mother (e.g., surrogates, patients who choose adoption, expecting parents who do not identify as "mothers"). It should be noted that normative pressures are cited as risk factors for problematic substance use among trans individuals, as they may lead to feelings of guilt, isolation, and inadequacy that, in turn, increase the risk for excessive alcohol consumption and reluctance to access care. 17,18 Clinicians should respect the identities of patients by using appropriate terminology and pronouns according to each individual's identity and preference. 19 In cases where clinicians require clarity, it is appropriate to ask the patient regarding pronouns and terminology that corresponds with their identity. Where possible and appropriate, care providers should also accommodate the gender identities and reproductive intentions of their patients in care plans and offer to connect patients with support resources. These measures have a significant role in ensuring the engagement and retention of trans patients in care.
# Awareness of social determinants of health
Healthcare providers should view and address alcohol use and AUD during pregnancy within the broader context of social determinants of health. Social determinants of health are defined as "the economic and social conditions that shape the health of individuals, communities, and jurisdictions as a whole. " 20 The distribution of resources and opportunities that a society makes available to its members (e.g., food, income, housing, education, and healthcare) is affected by a range of factors including socioeconomic class; gender; sexual orientation; race and ethnicity; refugee, migrant or immigrant status; and disability status. 21,22 The intersection of multiple factors (e.g., gender, race, sexual orientation) informs each individual's social identity and, access to resources, and, in turn, health outcomes. 23 People who belong to marginalized groups experience the most significant barriers to accessing resources, and, thus, have the poorest health outcomes. 21 Cited determinants of high-risk drinking and AUD include negative childhood experiences; 24 lower socioeconomic status; 25 living in poorer neighbourhoods; 26 and being a member of a racial, ethnic, gender, or sexual orientation minority. 27 In addition, race, history of physical abuse, general health status, and, to a lesser extent, education have been identified as some of the social determinants of alcohol use during pregnancy. 28 Lack of awareness of the complexity of socioeconomic factors contributing to alcohol use among pregnant individuals may lead to further marginalization of this population, and may impede access to adequate care.
In addition to having a basic understanding of how the unequal distribution of opportunity and resources in the Canadian society impacts the health of individuals, clinicians and care teams should endeavour to identify and remove barriers to accessing care. Clinicians should also aim to address disparities that may exist in the social determinants of health by offering to connect patients to resources that help meet their social and survival needs (e.g., housing, food/nutrition, child care, financial assistance).
# Trauma-and violence-informed care
Alcohol use disorder has been associated with a high lifetime prevalence of trauma including physical and sexual abuse, and pregnancy is a period of particular vulnerability for individuals who have experienced trauma. 29,30 It is also noteworthy that pregnant individuals are at an increased risk of intimate partner violence, particularly in the case of unplanned pregnancies. 31,32 Clinicians involved in the care of pregnant patients with AUD should be familiar with the principles of trauma-informed practice (e.g., trauma awareness; safety and trustworthiness; choice, collaboration and connection; strengths-based approaches and skill building). The provincial Trauma-informed Practice (TIP) Guide may be a useful resource when working with this patient population. 33 Healthcare providers serving this population should also be equipped to identify and respond to gender-based violence; to this end, the Provincial Health Services Authority (PHSA) offers a brief online course series entitled "Gender-Based Violence: We All Can Help Improving the Health Sector's Response", which may serve as a helpful resource.
# Integrated medical management
Care for pregnant individuals with AUD should reach beyond a strictly substance-focused approach in order to improve long-term outcomes for the patient and fetus. As the standard of care for the management of any complex or chronic medical condition, thorough medical management should be provided to pregnant patients with AUD. In this context, medical management is defined as informal medically-focused counselling that includes, but is not limited to, conducting health and mental wellness checks; offering non-judgmental support and advice; assessing motivation and exploring ideas for change; developing a holistic treatment plan; promoting alternative strategies for managing stress; and providing appropriate referrals to health and social services with the consent and input of the patient. Clinicians should also ascertain patients' housing, food/nutrition, and security needs and make necessary referrals to address them, with the consent and input of the patient. 29,30
# Harm reduction during pregnancy and post-partum
Harm reduction is commonly defined as policies, programs, and practices aimed at minimizing the negative impact of substance use on the individual and the society without necessarily stopping or reducing substance use. 34,35 In essence, a harm reduction-oriented approach seeks to meet patients "where they are at" and supports any step or behaviour that enhances the health and safety of patients and their communities. This fundamental framework of care requires particular attention in the context of pregnancy, given that recommended AUD interventions for pregnant patients are mainly aimed at abstinence.
While recognizing that discontinuing alcohol use is the only means of fully eliminating alcohol-related risks to the patient and the fetus, this supplement strongly emphasises that the provision of comprehensive and continued care should never be contingent on a pregnant patient's willingness to discontinue alcohol use. Clinicians providing care for pregnant or lactating individuals who continue drinking alcohol should adopt appropriate harm reduction strategies such as promoting safer alcohol use (e.g., reduced drinking, refraining from drinking and driving, discontinuing non-beverage alcohol use) and providing referrals to resources that address social determinants of health (e.g., housing, nutrition, legal services, financial assistance, child care). 35,36 Harm reduction measures have been shown to contribute to reduced drinking, improved nutrition, and improved overall health outcomes for the patient and fetus. 35,36 For additional information on evidence-based harm reduction strategies geared towards pregnant patients who use substances, see Harm Reduction and Pregnancy: Community-based Approaches to Prenatal Substance Use in Western Canada. 3
Clinicians should incorporate the principles of trauma-and violence-informed care in the care and clinical management of pregnant and post-partum patients who use alcohol and those with AUD.
Alcohol use and AUD in pregnant patients should be managed within the framework of comprehensive medical care and support, including routine and ongoing medical, mental health, and psychosocial assessments.
Provision of comprehensive and continued care should never be contingent on a pregnant patient's willingness to discontinue alcohol use. Clinicians providing care for pregnant individuals who continue drinking alcohol should adopt appropriate harm reduction strategies.
3 Screening and Brief Intervention
# Considerations for alcohol screening during pregnancy
Regular substance use screening is widely recommended for patients who are or may become pregnant, in order to identify risk and prevent or minimize harm to the patient and the fetus. 4,5,11 Substance use screening should be included in the first prenatal assessment, or at the first available opportunity, and conducted routinely throughout pregnancy and post-partum and when clinically relevant and necessary. 37 Research has suggested that patient self-reports are a reasonably reliable measure of alcohol use during pregnancy; however, clinicians should be sensitive to factors that may deter patients from providing accurate responses to screening questions, such as stigma and fear of child apprehension. 38,39,40 To address these concerns, it is crucial to establish comfort and trust by securing the patient's informed consent prior to screening, and to assure them of confidentiality and other rights in accordance with the standards of medical practice. 41,42 It is also helpful to mention that all patients are periodically asked about substance use as a standard of primary care provision. Some guidelines recommend that care providers ask pregnant individuals about alcohol consumption at every visit as patients are more likely to disclose alcohol use after a therapeutic relationship has been established. 41 Additionally continuous documentation of alcohol use patterns in pregnant patients with AUD is instrumental to the early identification and management of FASD. 5
# Initiating a dialogue about alcohol use and pregnancy
Screening and assessment for all patients of childbearing capacity should be combined with education about Canada's Low-Risk Alcohol Drinking Guidelines 3 , which recommends abstinence from alcohol use during pregnancy and outlines low-risk drinking limits for adults. In addition to raising awareness of these guidelines, introducing the topic of alcohol use in a general and conversational manner can also help build rapport and facilitate a natural transition to questions regarding personal alcohol use. For example, alcohol screening can be initiated by asking: "Have you heard about Canada's Low-Risk Alcohol Drinking Guidelines? I talk to all my patients about these guidelines. They contain important information about safer alcohol use that everyone should know. It also offers recommendations for people who are or may become pregnant. "
Where appropriate, clinicians should also discuss effective contraceptive methods and how to access them with patients of childbearing capacity. This is in consideration of the persistently high prevalence of unplanned pregnancies in Canada. 8,43 Contraceptive counselling services and supplies should also be offered to patients who are currently pregnant in order to reduce the likelihood of a subsequent unplanned pregnancy as short intervals between pregnancies may disrupt ongoing treatment and amplify potential risks to recovery and long-term health. 44,45 3.3 A simplified screening method to address time constraints Despite the well-established utility of regular alcohol screening for early detection of alcohol use and AUD, and the secondary prevention or minimization of harm to the patient and fetus, many pregnant patients are not screened for alcohol use. 5,11 Time constraints are frequently cited as a key barrier to adequate screening; primary care clinicians often report being overwhelmed by the number of conditions for which they are required to screen pregnant patients. The duration of the average primary care visit is often insufficient to accommodate a thorough screening process which ideally involves an introductory conversation about the maternal and fetal risks of alcohol use. 5,11 To counteract this barrier, a simplified and stepped alcohol screening process is recommended for pregnant patients, involving a single alcohol screening question (SASQ) to identify alcohol use in pregnant individuals. Patients who screen positive should be offered brief intervention and further assessment with validated screening and/or a diagnostic interview using the DSM-5 criteria for AUD. 5 See Appendix 1 for an instructive overview of alcohol use screening for pregnant patients.
A recommended screening method in the general population, the SASQ is typically constructed in reference to low-risk drinking limits in order to determine if, and how frequently, the patient's alcohol consumption has exceeded these limits. For example, an adult patient would screen negative for high-risk alcohol use if their response to the following question was "zero" or "never":
"In the past year, how often have you consumed more than 3 drinks (for adult women) or 4 drinks (for adult men) on any one occasion?"
In the context of pregnancy, the SASQ may be modified to identify any alcohol use in accordance with the Low-Risk Alcohol Drinking Guideline recommendation for this population:
"Do you sometimes drink beer, wine, or other alcoholic drinks?" 46 An affirmative response indicates the need for brief intervention and further assessment.
Studies have found that the sensitivity of the SASQ ranges from 60-90%, and systematic reviews involving non-pregnant patient populations have validated this option for clinical settings where time and patient interactions are limited, notwithstanding its slightly lower sensitivity than structured screening instruments for the detection of high-risk drinking behaviours. 51,52 Although the SASQ has not been explicitly validated for screening pregnant patients, it has been recommended as the first step in alcohol use screening in this population by the Society of Obstetricians and Gynaecologists of Canada 5 and the U.S. Preventive Health Services Task Force on account of its brevity and sufficient sensitivity and specificity. 53 Another advantage of the SASQ is that it can be integrated into an informative conversation without disrupting the flow of the appointment.
# Additional validated screening tools for pregnant patients
Studies involving pregnant participants support the effectiveness of a range of screening tools validated for the general population, such as the AUDIT, AUDIT-C, CAGE, and CRAFFT methods. 4,46 Additionally there are a number of screening tools specifically developed for detecting high-risk drinking and AUD among pregnant patients, including the T-ACE, and TWEAK tools. This guideline supplement presents AUDIT, AUDIT-C, TWEAK, and T-ACE, commonly recommended screening tools which have been validated for use during pregnancy. (See Appendix 1)
Table 3 provides a comparative overview of pregnancy-validated tools in terms of selectivity, specificity, time and expertise required, and other factors informing usefulness. Refer to the Guideline for screening tools not presented in this document.
# Diagnosis of AUD
Pregnant patients who screen positive for alcohol use during pregnancy should undergo further assessment to confirm or exclude AUD. As with the non-pregnant population, this assessment may be conducted through a structured interview using the DSM-5 criteria for the diagnosis and severity of AUD. Confirmation or exclusion of an AUD largely determines subsequent steps in the treatment pathway. Appendix 1 presents the diagnostic criteria for AUD.
While all pregnant individuals who screen positive for alcohol use should receive brief counselling intervention and routine follow-ups (see next section, Brief intervention), brief intervention alone is not effective for individuals with AUD. 4,55 Patients who are diagnosed with an AUD should be offered evidencebased treatment for AUD. (See Withdrawal Management and Continuing Care Sections for an overview of evidence-based interventions)
# Brief intervention
Brief intervention is a time-limited single-session counselling dialogue that typically follows a positive screen for alcohol use during pregnancy. The aim of this intervention is to assess, strengthen, and mobilize patients' motivation for change in order to help them reduce or discontinue alcohol use. There are a number of different approaches and models for delivering brief intervention for alcohol use in primary care settings, but most are variations of motivational interviewing (MI), a psychosocial intervention which empowers patients to make positive behavioural changes. 5,56 Key components of brief intervention are exploring and discussing motivations for or against reducing alcohol use, identifying barriers and facilitators to change and available treatment and supports, assisting the patient to set goals, and providing non-judgmental encouragement and support. Brief intervention also serves as an opportunity to offer referrals to community-based resources or supports. An advantage of brief intervention is that it can be easily implemented by a range of health care providers including physicians, nurse practitioners, nurses and other allied health professionals who may not have specialized training in addiction medicine.
As with the non-pregnant population, brief intervention is widely recommended for pregnant patients and supported by a number of clinical trials. A 2009 systematic review (n=4 studies; 715 participants) of randomized controlled trials (RCTs) examining the effectiveness of psychosocial treatment interventions found that brief psychosocial or educational interventions may motivate pregnant patients to reduce or discontinue alcohol use, although the authors found the data insufficient for performing a meta-analysis. 57 A number of individual studies have reported significant results in favor of BIs in this population. For example, in a randomized study comparing brief intervention (n=162) to assessment only, O'Conner and Whaley (2007) reported that pregnant individuals in the brief intervention treatment group were 5 times more likely than participants in the control group to report that they abstained from alcohol use throughout pregnancy. The infant mortality rate in the brief intervention group was 3 times lower than the rate in the control group, and newborns from the brief intervention group had greater birth length and weight than control subjects. 58 A practical example of brief intervention that has been well studied in primary care and used for various specific populations is the 5As (Ask, Advise, Assess, Assist, and Arrange) model for behavioural change. 59 Ease of recall, brevity, and adaptability are practice-relevant strengths of this approach. This model is presented in Table 4. Appendix 2 provides general instructions for conducting brief intervention with a trauma-informed approach.
It should be noted that, while guidelines endorse a range of validated brief intervention methods, research has shown that simply asking patients in a detailed manner about the extent of their alcohol use, discussing potential risks, and offering brief non-judgmental advice may help raise awareness about their actual levels of alcohol consumption and modify behavior. 53,60 Table 4 The 5A's Model for Delivering Alcohol Use Brief Intervention 61,62 (modified for pregnancy)
# Ask
Screen pregnant patients in a conversational and non-judgmental manner with awareness of the stigma affecting this population. Acknowledge the patient's existing knowledge about the risks of alcohol use during pregnancy and any changes they have already made to mitigate this risk.
# Advise
In a clear and personalized manner, inform patients of the risks of alcohol use during pregnancy and postpartum and advise them to discontinue alcohol use during this period.
# Assess
Assess and record patients' readiness to discontinue or reduce alcohol use at this time.
At this stage, it is advised to conduct a diagnostic interview to confirm/exclude AUD, as brief intervention alone is not effective for individuals with AUD.
# Assist
Work with the patient to develop a treatment plan that accommodates their level of readiness and motivation. Offer supportive counselling and advice, provide a menu of options for treatment and referrals to community resources.
Arrange Schedule follow-up contact, preferably within a week of the intended "change date".
4 Withdrawal Management
# Overview
Alcohol withdrawal occurs with the sudden cessation or significant reduction of alcohol use after a period of chronic heavy alcohol consumption. These symptoms are believed to result from the hyperactivity of glutamate, the main excitatory neurotransmitter of the central nervous system (CNS), upon the sudden reduction in the blood alcohol level. 3,63,64 In normal conditions, the brain maintains a balance between the effects of GABA, a major inhibitory neurotransmitter, and glutamate. Alcohol disrupts this balance by increasing the inhibitory effect of GABA and suppressing the excitatory effects of glutamate. Chronic alcohol consumption causes the CNS to compensate for the inhibitory effects of alcohol by upregulating glutamate transmission in order to restore neurochemical equilibrium. When suddenly unopposed by the inhibitory effects of alcohol, the upregulated excitatory system results in overall CNS hyperactivity, which manifests as a range of withdrawal symptoms in up to 50% of individuals with long-term alcohol dependence. 3,63,64 Common alcohol withdrawal symptoms include tachycardia, pyrexia, tremor, nausea, vomiting, and sweating, which may also be accompanied by psychological distress in the form of anxiety, agitation, and sleep disturbance or insomnia. Symptoms of alcohol withdrawal typically begin 6-24 hours after the last intake of alcohol and reach peak intensity at 24-48 hours, with resolution of symptoms within 5-7 days. 65 Additionally, a small percentage of symptomatic patients may experience severe complications of withdrawal consisting of tonic-clonic seizures and delirium tremens which are life-threatening if left untreated. The data available on the specific effects of acute withdrawal on the pregnant patient are sparse; however, some have extrapolated that pregnant individuals may be particularly vulnerable to the withdrawal symptoms listed above due to their well-documented increased susceptibility to physiological and environmental stress. 3, Acute maternal alcohol withdrawal may, in turn, lead to a host of adverse effects on the fetus including fetal distress, placental abruption, preterm labour, and fetal demise. 3 In view of the added risks of alcohol withdrawal during pregnancy, it is recommended that, where possible, pregnant patients with AUD undergo withdrawal management in inpatient settings where patients can receive symptom-triggered treatment with close monitoring of withdrawal symptoms and fetal health. 3,4,9 It should also be noted that available studies on withdrawal management for this specific population have been conducted in inpatient settings. However, if inpatient withdrawal management is not an option due to patient preference or lack of timely access to available beds, outpatient treatment with close monitoring may be offered to pregnant patients who otherwise meet the criteria for this setting (e.g., low risk of severe complications of withdrawal, family or community-based support, ability to attend medical visits, absence of other conditions requiring inpatient care). For instructions on outpatient withdrawal management, see Appendix 3, Patient Criteria and Considerations for Outpatient Alcohol Withdrawal Management.
It should be emphasised that withdrawal management alone does not constitute treatment for AUD. Studies report high post-withdrawal relapse rates and suggest that sustained abstinence and reductions in alcohol use are unlikely without provision of continuing AUD care. 73,74 Patients should be connected to continuing care following the completion of withdrawal management. See the Continuing Care section in this supplement for an overview of evidence-based treatment interventions. This section provides a review of the efficacy and safety of clinical withdrawal assessment and management options with a focus on fetal and neonatal outcomes.
Refer to Section 3 of the Guideline for a comprehensive review of all common withdrawal management treatment options for the general population of patients with AUD.
# Assessment
# The Prediction of Alcohol Withdrawal Severity Scale (PAWSS)
The Prediction of Alcohol Withdrawal Severity Scale (PAWSS) is a validated score-based tool for estimating the risk of developing severe complications of withdrawal (i.e., seizures and delirium tremens), which facilitates the selection of appropriate withdrawal management interventions. 75 The PAWSS incorporates the evidence-based risk factors of developing severe complications of withdrawal into a 10-item cumulative scale with a maximum score of 10, wherein a score of <4 indicates low risk and a score of ≥4 denotes high risk for severe complications of withdrawal. 75 While this tool has not yet been validated specifically for use in pregnant patients, its accuracy and usefulness in inpatient settings was validated in a 2018 systematic review of 14 studies (n=71,295) evaluating single and composite measures of severe withdrawal risk. 76 The authors demonstrated that composite scales that measured multiple signs and symptoms were more useful in predicting an individual's risk than individual signs or symptoms. Of these composite scales, the PAWSS was found to have the highest sensitivity (93%, ) in assessing the risk of severe complications of withdrawal. 76 Recommended preliminary assessment for alcohol withdrawal in non-pregnant populations involves the administration of the PAWSS tool in order to select the appropriate treatment setting based on their risk of developing severe complications of withdrawal. 75,76 Given the recommendation that all pregnant patients requiring withdrawal management undergo treatment in an inpatient setting, assessment for the purpose of selecting the treatment setting may not be indicated in this population unless strong patient preference or scarcity of beds prompts risk assessment for outpatient treatment. However, the PAWSS is also a useful means of selecting the appropriate withdrawal management pharmacotherapy, as non-benzodiazepine withdrawal management medications may not be appropriate for individuals at high risk of experiencing severe complications of alcohol withdrawal. 9 As such, this supplement recommends that clinicians consider the use of this tool to help select between gabapentin and benzodiazepines for withdrawal management in pregnant patients.
For more information see Pharmacotherapies for withdrawal management. If clinicians elect to administer the PAWSS tool to inform medication selection, its result should be combined with additional clinical assessment and observation.9 The PAWSS tool and corresponding instructions will be produced in Appendix 3.B.
# Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)
The CIWA-Ar is considered the gold standard for assessing withdrawal symptom severity in a range of clinical care settings for the general patient population, with demonstrated inter-rater reliability and validity. 77 This tool is commonly used to determine and adjust symptom-triggered dosing schedules. Studies have shown that using the CIWA-Ar in this context minimizes both under-and over-medicating patients while mitigating the risk of severe symptoms. 78,79 The CIWA-Ar involves the assessment of 10 individual symptoms and signs of alcohol withdrawal including anxiety and agitation; auditory, visual, and tactile disturbances; tremor; sweating; nausea; headache; and clouding of sensorium, which are assigned a numerical score based on objective and subjective measures of severity. A score <15 indicates mild withdrawal symptoms while scores ≥15 and ≥20 are indicative of moderate and severe withdrawal symptoms respectively. 77 Due to the wide recognition of the CIWA-Ar scale, the terms "mild", "moderate", and "severe" withdrawal used in this supplement are defined according to these numerical scores.
Although the CIWA-Ar has not been validated for pregnant patients, its use is common for alcohol withdrawal symptom assessment during pregnancy and has been described in a case report. 80 The authors reported the utility of this tool in devising a symptom-triggered withdrawal management regimen and minimizing the exposure of the patient and fetus to potentially harmful medications.80 Clinicians using this tool for withdrawal symptom severity assessment should be mindful that some of the CIWA-Ar criteria (e.g., nausea and headache) overlap with common symptoms of pregnancy. Thus, CIWA-Ar results should be interpreted with clinical judgment and in communication with the patient to distinguish between pregnancy and withdrawal symptoms. 80 The CIWA-Ar tool and corresponding instructions are presented in Appendix 3.B.
# Management of negligible to mild withdrawal symptoms
In consideration of the significant risks of acute withdrawal to the patient and fetus, all pregnant patients diagnosed with AUD should be offered medication for withdrawal management. However, patients with mild AUD may experience negligible withdrawal symptoms and may prefer to receive supportive therapy and continuing care without pharmacological detoxification.
There is a lack of consistent guidance regarding the non-pharmacological management of mild withdrawal symptoms among non-pregnant and pregnant patients alike. Many practice guidelines pertaining to the general population recommend provision of supportive care alone until withdrawal symptoms subside (e.g., supportive environment; close monitoring with the involvement family where possible; adequate nutrition and hydration; encouragement and positive reinforcement; referrals to psychosocial treatment interventions and communitybased support resources). 8,81 If not contraindicated, over-the-counter pain relievers, anti-emetics, and antidiarrheal medications approved for use during pregnancy and lactation may also be prescribed for management of mild symptoms. This is based on early studies involving non-pregnant populations that found supportive care was sufficient for approximately 75% of patients with no psychiatric or medical comorbidities. 82,83 Clinical experience suggests that pregnant patients are more likely than other populations to opt for nonpharmacological treatment options due to heightened motivation to minimize possible risks of pharmacotherapy to the fetus. 84,85 While patient preference and motivation are among the predictors of treatment success and key factors in treatment selection, patients should be clearly informed of the risks of maternal withdrawal symptoms, and offered frequent monitoring and reassessment.
# Pharmacotherapies for withdrawal management
Common pharmacotherapies for alcohol withdrawal in non-pregnant patients consist of benzodiazepines; anticonvulsants including carbamazepine, gabapentin, and valproic acid; and alpha-2 adrenergic agonists. There is a dearth of research and evidence-based guidance pertaining to pharmacotherapeutic withdrawal management in pregnant individuals. This is partly due to the ethical concerns restricting clinical investigation in this population, particularly given the suggested risk of teratogenicity associated with a number of common withdrawal management medications in animal studies. 9 A 2009 Cochrane review of pharmacotherapies found no randomized or quasi-randomized studies of pharmacologic interventions for pregnant participants enrolled in alcohol treatment programs and concluded that considerably more research was needed to assess the safety of available treatments in this population. 86 As reviewed below, the limited research on the safety of pharmacological options for withdrawal management during pregnancy has been focused almost exclusively on benzodiazepines. However, in response to emerging evidence in support of gabapentin for this indication, this supplement also provides a brief overview of the safety and efficacy of this medication. Considered as an aggregate, the literature summarized in this section suggests that the harms of acute alcohol withdrawal surpass the potential risks associated with its pharmacological treatment with these agents. See Table 5 below for a comparative overview of the clinically relevant characteristics of benzodiazepines and gabapentin. Appendix 3.C provides general prescribing information and sample dosing protocols for the medications reviewed in this section.
Refer to the Guideline for a comprehensive review of evidence concerning all evidence-based pharmacotherapies for alcohol withdrawal in the general population.
# Benzodiazepines
Benzodiazepines have the most substantial history and supportive evidence in alcohol withdrawal management for pregnant and non-pregnant populations. 4,87 Numerous systematic reviews have established the superior efficacy of this class of medications in suppressing alcohol withdrawal symptoms and preventing withdrawal seizures and delirium tremens. 4, Early case-control studies on the use of benzodiazepines in pregnancy suggested that these medications may be associated with increased risk of fetal malformations. 3,80 However, a number of more recent cohort studies found no increased risk of congenital malformations, cardiac defects, or neurobehavioural problems among children born to people who used benzodiazepines during pregnancy in comparison to the general population. 3,91,92 A 2011 systematic review and meta-analysis including nine case-control and cohort studies also examined the correlation between maternal benzodiazepine use and major fetal malformation. 93 The authors also concluded that, in sum, benzodiazepines did not appear to increase teratogenic risk (OR, 1.07 ), although the case-control studies demonstrated an increased risk of cleft lip. 93 Currently, the use of benzodiazepines during pregnancy holds a category D designation by the US Food and Drug Administration (FDA), which denotes evidence of risk to human fetuses with prolonged use. 9 This categorization is attributed to evidence suggesting an increased risk of cleft lip.9 However, it is important to note that the duration of alcohol withdrawal management is typically 5-7 days, which does not constitute prolonged use. Additionally, the majority of studies concerning the fetal safety of benzodiazepine treatment in pregnancy do not account for the purpose, duration, and dose of maternal benzodiazepine use. 3 One case-control study examining the fetal outcomes of short-term (generally 3 weeks) diazepam treatment during pregnancy found that short-term exposure to this medication presented no detectable teratogenic risk to the fetus. 94 Additional considerations for benzodiazepine use during the final trimester of pregnancy include "floppy infant syndrome" and neonatal benzodiazepine withdrawal. Floppy infant syndrome is characterized by a constellation of treatable symptoms such as mild sedation, hypotonia, reluctance to suck, apneic spells, and cyanosis that can persist for hours to months after birth.3 Neonatal benzodiazepine withdrawal symptoms may include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, diarrhea, and vomiting. 3,95 While there is no conclusive data regarding the specific type of benzodiazepine that would prevent the development of these symptoms, some reports suggest that short acting benzodiazepines (e.g., lorazepam) may be preferable in the third trimester for minimizing the duration and severity of neonatal benzodiazepine withdrawal. 80,95 Overall, considering the well-established risks of untreated withdrawal, the literature suggests that potential benefits of benzodiazepine use for the treatment of acute alcohol withdrawal outweigh its risks, particularly in the case of severe AUD where the prevention of seizures and delirium tremens is a key consideration. In reference to these findings, the 2014 World Health Organization guidelines recommend management with a benzodiazepine, titrated to the severity of withdrawal. 4
# Gabapentin
The effectiveness of gabapentin for alcohol withdrawal management in non-pregnant patients at low risk of developing seizures and delirium tremens is demonstrated by a growing evidence base. To date, results from two RCTs (n=126) indicate that gabapentin (at total doses of 1200mg/day) is as effective as benzodiazepines for the outpatient management of mild to moderate alcohol withdrawal symptoms, and may yield additional benefits in terms of improved daytime alertness, sleep quality, anxiety, and mood. 96,97 With respect to safety for use during pregnancy, gabapentin is listed as a category C drug by the FDA; there is no evidence suggesting that this medication is teratogenic in humans, though some dose-dependent adverse effects to the fetus have been observed in animal studies. 9,98 Recent evidence suggests that the use of this medication for withdrawal management during pregnancy is safe. 9,45 Clinicians should be mindful that this medication is not suitable for preventing severe complications of withdrawal (i.e., seizures and delirium tremens). Therefore, it is recommended to assess the patient's risk of severe complications of withdrawal using the PAWSS tool prior to selecting between benzodiazepines and gabapentin.
# Caution regarding other agents
Alternative options for the management of alcohol withdrawal in the non-pregnant population include other anticonvulsants (i.e., carbamazepine, valproic acid) and alpha-adrenergic agonists including clonidine (See Guideline Chapter 4). However, due to the lack of sufficient supporting evidence, and reported risk of teratogenicity, these agents should not be considered for pregnant patients unless acute withdrawal constitutes a life-threatening emergency and the use of recommended options is contraindicated. 9 Safety for use during pregnancy 9 FDA category D:
- Evidence of cleft lip and "floppy infant syndrome" in human studies
- Potential benefits may outweigh risks FDA category C:
- No adequate human studies
- Possible risk extrapolated from animal models include preterm birth, low birth weight, and neonatal withdrawal symptoms
- Potential benefits may outweigh risks
# Efficacy
Superior efficacy for suppression of withdrawal symptoms compared to placebo and other active treatments. 90 Superior efficacy for prevention of seizures compared to placebo and active treatments. Emerging data (2 RCTs) showing equal efficacy to benzodiazepines in suppressing mild to moderate withdrawal.
May be superior for treatment of insomnia and anxiety symptoms. 96,97 Insufficient evidence for prevention of seizures or delirium tremens. Less common side effects include changes in skin colour, nausea, headache, blurred vision, tremors, hypotension, GI disturbances. Memory loss may also occur.
Higher doses may cause ataxia, slurred speech and drowsiness.
Favourable side effect profile in comparison to other anticonvulsants.
# Safety for breastfeeding
Sedation and poor weight gain in infants have been rarely reported. Short acting agents (e.g., lorazepam, oxazepam) may be preferable. Overall, deemed compatible with breastfeeding by WHO and ACGC. 4,101 Small number of case reports reported no adverse neonatal effects. Infants should be monitored for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. 102 Other considerations
Potential for non-medical use, diversion, and dependence.
Potential for drug-drug interactions leading to excess sedation, impaired psychomotor and cognitive functioning.
Potential for non-medical use, diversion, and dependence.
Toxicity profile parallels that of alcohol.
Easy to transition from withdrawal management to long-term relapse prevention.
- Note: This information is directly adapted from the product monographs of these medications. The fact that benzodiazepines are excreted into human milk was cited as a reason for caution during breastfeeding. See Section 7.2.2 for a summary of evidence supporting the compatibility of these medications with breastfeeding.
5 Continuing Care
# Pharmacotherapy
There are no clinical trials evaluating the possible options for the pharmacological management of AUD during pregnancy. The meagre existing literature on this topic is extrapolated from animal studies and evidence pertaining to non-pregnant populations. A recent practice guideline by the American Psychiatric Association recommends against pharmacotherapeutic interventions for AUD during pregnancy, except for the management of alcohol withdrawal. 9,45 This is due to the risk of teratogenicity associated with many evidencebased AUD medications. In line with available guidelines, all patients with AUD should be offered evidencebased psychosocial treatment interventions and supports for AUD. However, the risks of pharmacotherapy to the fetus should be weighed against risk of relapse to alcohol use in the case of pregnant patients with moderate to severe AUD.
Naltrexone and acamprosate are considered first-line AUD treatment agents for non-pregnant patients. This section provides an overview of the safety and efficacy of these treatments for pregnant individuals in reference to available literature. Gabapentin is also reviewed as a potential alternative option for this population. Overall, it is suggested that the benefits of preventing relapse outweigh the risk of possible effects of these agents on the fetus. 9 See Table 6 below for a comparative summary of the characteristics of these medications. Sample dosing protocols and PharmaCare coverage information are provided in Appendix 4. Additionally, please refer to the Guideline for a comprehensive review of all evidence-based AUD pharmacotherapies for the general population.
# Naltrexone
Naltrexone is a mu-opioid receptor antagonist shown to block euphoria associated with alcohol consumption. 103 It is hypothesized to work by diminishing the rewarding effect of alcohol in the brain following its consumption, as well as reducing cravings for alcohol in some individuals. 103 This blunting effect on neural reward pathways is consistent with research findings that naltrexone is particularly effective in preventing a return to heavy or ongoing drinking. 104 Naltrexone has a well-established evidence base for safety and efficacy in the treatment of AUD among non-pregnant populations. 105 Notably, a 2010 meta-analysis including 50 RCTs (n=7793 participants) reported that 17% fewer participants treated with naltrexone engaged in heavy drinking, and had 4% fewer drinking days per month when compared to the placebo group. 104 Participants treated with naltrexone also showed a greater reduction in heavy drinking days (-3.25%) and the amount of alcohol consumed (-10.83g) compared to the placebo group. 104 The FDA has classified naltrexone as a category C medication for use during pregnancy, meaning that there are no adequate human studies on the effects of naltrexone on the fetus, while animal studies have demonstrated mild adverse effects on the fetus. 3,9 Animal studies on in utero exposure to naltrexone have found that this medication crossed the placenta and was associated with reduced sensitivity of the offspring to morphine, and possibly with early fetal loss and increased birth weight. 9 However, limited evidence pertaining to the use of naltrexone for the treatment of opioid use disorder has demonstrated no adverse effects on pregnancy outcomes, although the long-term developmental effects of in utero exposure to this medication are not known. 106,107
# Acamprosate
Acamprosate is believed to restore the balance between glutamate-mediated excitation and GABA-mediated inhibition of neural activity, and reduce general neuronal hyperexcitability. 103 Together, these modify responses to alcohol-related cognitive cues. 103 Acamprosate has been used for the treatment of AUD for several decades in Europe prior to its approval in North America, and has an established evidence base for safety and efficacy in non-pregnant populations. A 2010 meta-analysis including 24 RCTs (n=6915) reported that acamprosate reduced the risk of return to any drinking by 14% and increased the cumulative duration of abstinence by 11 days compared to placebo. 111 In addition, the authors found that the treatment effects of acamprosate persisted at 3-12 months after treatment discontinuation. 111 Acamprosate is classified as a category C medication. Until recently, human data on the impact of in utero exposure to acamprosate was limited to one observational personal communication reporting one case of cleft lip among 18 pregnancies, while animal studies show dose-related defects in offspring including retinal dysplasia, iris malformation, hydronephrosis, and increased rate of stillbirth. 9,114 However, more comprehensive supportive evidence was presented by a 2019 population-based retroactive cohort study from New South Wales, Australia, comparing maternal and neonatal health outcomes of acamprosate-exposed pregnancies (n=54) to those of untreated alcohol-exposed (alcohol comparison group; n=162) and non-exposed (community comparison group; n=162) pregnancies. 115 Authors reported that rates of hospital admissions during pregnancy and 42 days post-partum in acamprosate-treated individuals were not significantly different from the community comparison group (adjusted rate ratio = 0.85, 95% CI = 0.65-1.11), but were significantly lower compared with the alcohol comparison group (adjusted RR = 1.26, 95% CI = 1.00-1.60).115 Acamprosateexposed neonates were not significantly different from the alcohol comparison group or the community comparison group in terms of birth weight, proportion of small-for-gestational-age neonates, or incidence of congenital abnormalities (including FASD). 115 It should also be noted that this study only included individuals who were exposed to acamprosate for more than 30 days during pregnancy in the case group, so that the results would be applicable to patients receiving pharmacotherapy for continuing AUD care. Available data suggests that the benefits associated with the use of this medication during pregnancy may outweigh the risks of continued alcohol consumption during this period. 9,114,115
# Gabapentin
Emerging evidence for the efficacy of gabapentin in preventing relapse in non-pregnant populations is derived primarily from three placebo-controlled clinical trials. Two RCTs comparing 7-day gabapentin treatment to placebo found that gabapentin was more effective in reducing alcohol craving, the number of drinks per day, and percentage of heavy drinking days, and increasing the number of days abstinent. 116,117 Most recently, a 12-week trial of 150 participants in an outpatient setting demonstrated that gabapentin significantly improved rates of cumulative abstinence (estimated number needed to treat of 8) and heavy drinking (estimated NNT of 5), with no difference in adverse events compared to placebo. 118 A distinctive advantage of gabapentin is that it has been found effective for outpatient withdrawal management in patients at low risk of developing severe complications of withdrawal (PAWSS<4), and patients who complete withdrawal using this medication may have the option to continue its use beyond the acute withdrawal period as part of a long-term treatment strategy without the risk of disruption to care. 119 In terms of safety for use during pregnancy, gabapentin is a category C medication which indicates evidence of risk to the fetus in animal studies. Available animal models reveal a higher risk of embryotoxicity during organogenesis, but this is purported to occur at supratherapeutic doses that would not typically be seen in humans. 120 In a limited 2013 prospective cohort study with pregnant participants, no fetal malformations were observed, but the authors reported a possible association with preterm birth and low birth weight. 121 Clinicians considering gabapentin for pregnant patients should be mindful of the risk of non-medical use and dependence associated with this medication. It is also important to note that concurrent use of alcohol, opioids, or other CNS depressants with higher doses of gabapentin increases the risk of respiratory depression, profound sedation, syncope, and death. 100 While available evidence suggests that these risks are significantly lower than those associated with untreated AUD, clinicians should arrange frequent follow-ups and monitor patients for non-medical use, dependence, diversion, and concurrent alcohol or opioid use. Particular attention is advisable in the case of patients who are prescribed multiple medications for concurrent conditions. 123 Gabapentin withdrawal has also been reported in a number of infants born to patients who used gabapentin; this condition is treatable, though it may require admission to the neonatal intensive care unit. 9,130
# Caution regarding other agents
The use of other AUD medications, such as topiramate and disulfiram, during pregnancy is not recommended.
A preliminary report on 203 prospectively followed pregnancies exposed to topiramate found a high rate of major congenital malformations among neonates. 131 Similarly, sparse evidence associates maternal disulfiram use with fetal limb reduction. 132 There is no evidence-based guidance regarding patients who are stable on one of these medications prior to becoming pregnant. In these cases, clinicians should carefully consider the risks and benefits of transitioning patients to alternative treatment options in communication with an addiction specialist and the patient. 45 Where possible, transitioning the patient to safer pharmacotherapies (i.e., naltrexone, acamprosate, or gabapentin) or psychosocial treatment interventions and supports may be appropriate. Additionally, patients of childbearing capacity who are prescribed one of these medications should be informed of possible risks in the event of pregnancy and advised of the importance of contraception in the course of treatment. Higher doses may cause ataxia, slurred speech, or drowsiness.
Favourable side effect profile in comparison to other anticonvulsants.
# Concurrent alcohol use
Safe to start while patients are using alcohol, but may be more effective and side effects minimized if started following completion of withdrawal.
Safe to start while patients are using alcohol, but may be more effective if started following completion of withdrawal management.
Higher than therapeutic dose and use concurrent with alcohol increases the risk of respiratory depression, profound sedation, syncope, and death.
# Breastfeeding
Minimally excreted into breast milk. Limited case studies show no adverse neonatal effects. 135,136 Not a barrier to breastfeeding.
No adequate human studies.
Deemed "probably safe" in pharmacokinetic investigations. 45,137 Small number of case reports reported no adverse neonatal effects.
Infants should be monitored for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. 102 - This information is directly adapted from the product monographs of these medications, where lack of sufficient data pertaining to pregnancy and lactation was cited as cause for caution. Section 7.2.3 for a review of available information on the safety of AUD pharmacotherapy for breastfeeding.
# Psychosocial treatment interventions
Validated psychosocial treatment interventions for AUD in pregnancy do not differ from those offered to the general population. There is modest RCT evidence supporting the effectiveness of cognitive behavioural therapy (CBT), motivational interviewing (MI), and contingency management during pregnancy. 3 A 2009 Cochrane review of psychological and educational interventions for reducing alcohol use in pregnancy (4 RCTs, n=715) concluded that there was insufficient data on the effectiveness of these interventions for reducing alcohol consumption or supporting abstinence. 57 However, the authors cited inconsistent results, small sample sizes, high risk of bias, and heterogeneity in intervention types and outcomes assessed across trials as confounding factors hindering evidence synthesis. The authors also acknowledged that the existing literature supports the usefulness of these psychosocial interventions in increasing abstinence from alcohol use and reducing alcohol consumption among pregnant individuals. 57 Accordingly, most clinical practice guidelines recommend that all pregnant individuals with AUD be offered psychosocial treatment interventions to support abstinence or reduced alcohol consumption. 138 It is important to note that MI, CBT, and CM are well-studied in the context of substance use disorders among the general populations, and have a significant track record of use in a wide range of settings and patient populations. 139,140 For a comprehensive review of evidence on the efficacy of these interventions, see the corresponding sections of the Guideline. See Appendix 5 for an instructive overview of MI.
# Considerations for Bed-Based Treatment Facilities
Although the evidence supporting the efficacy of bed-based treatment facilities e for substance use disorder is relatively limited, guidelines pertaining to pregnant individuals cite residential settings as potentially beneficial for patients who require more intensive medical care and support to improve health and pregnancy outcomes. 120,141 These facilities may also be appropriate for patients with comorbidities and complex medical and psychosocial needs, as well as those who have unstable housing and social circumstances. Decisions regarding the selection of this treatment setting should be made in collaboration with, and with the consent of, the patient.
The following factors should be considered when selecting a treatment facility for pregnant patients:
- Capacity to provide pharmacological treatment for AUD as directed by the patient's prescriber
- Capacity to provide wraparound medical and psychosocial support for concurrent conditions as well as AUD
- Access to comprehensive specialist pregnancy and prenatal care
- If applicable, access to post-partum and neonatal care, as well as onsite accommodation or visitation provision for patient's child(ren) and family. 142 Keeping parents and children together should be among primary considerations when selecting a treatment setting for this population.
Effective discharge planning is also crucial to ensure positive long-term bed-based treatment outcomes. 143,144 The treatment facility should communicate with outpatient care providers and relevant community-based services to ensure the continuation of care and support after discharge. It may be necessary to intensify support and monitoring during transition between settings as patients are particularly vulnerable to relapse to alcohol use in these periods. Every effort should be made to ensure patient's access to safe and stable housing prior to discharge. 142 Several systematic reviews have concluded that there is insufficient research evidence to recommend an optimal screening/rescreening interval for alcohol use in adults and youth. 127 In the absence of robust evidence, most public health agencies, including the Canadian Task Force on Preventive Health Care 139 and the Canadian Paediatric Society, 140,141 recommend screening adults and youth on an annual basis. This is for reasons of convenience -alcohol screening can be combined with other components of a routine medical exam or preventive health screening -and to detect changes, as an individual's alcohol use can shift from low-to high-risk over a one-year period. In line with this, a U.S. study found that use of annual substance use screening intervals identifies a modest number of incident cases of high-risk use in adult primary care patients. 142 Of 1014 patients who initially screened negative for high-risk alcohol or drug use, 34 (3.4%) screened positive for high-risk use when screened again one year later, with the majority (23/34) meeting criteria for high-risk alcohol use. 142
e Also referred to as "residential treatment" or "inpatient treatment" facilities in the literature.
7 Post-partum Considerations
# Rooming-in and skin-to-skin contact
Rooming-in and skin-to-skin contact during the immediate post-partum period is associated with healthy parent-infant bonding leading to improved long-term developmental outcomes, higher likelihood of breastfeeding, improved access to integrated care and initial childcare education in a family-centered setting, and reduction of maternal and neonatal distress and alcohol withdrawal symptoms. 4,145,146 Skin-to-skin contact and gentle rocking of the infant in a quiet environment are also widely recommended interventions for management of neonatal withdrawal symptoms. 4,136 Thus, in line with standards of care pertaining to the general populations, healthcare facilities providing obstetric care should have a rooming-in protocol in place whereby the monitoring and treatment of patients with AUD and their infants can take place without interrupting nursing and parent-infant contact.
# Breastfeeding
Breastfeeding f is consistently recommended in guidelines pertaining to neonatal care, including care for infants born to parents in treatment for substance use disorders. 4 This is in view of a robust evidence base demonstrating that breastfeeding is the ideal means of supporting the healthy growth and development of a child while promoting parent-infant bonding and reducing maternal stress. 4 In the case of nursing parents who use alcohol or are receiving pharmacotherapy for AUD, the risks and benefits of breastfeeding should be considered on an individual basis. This section provides a brief overview of the pharmacokinetics of alcohol and AUD pharmacotherapies (i.e., naltrexone, acamprosate, and gabapentin) during lactation and discusses neonatal and developmental safety concerns associated with the maternal use of these agents while breastfeeding.
# Alcohol and lactation
Available research on the effects of maternal alcohol use during lactation on the neonate is limited and contradictory. While there is some evidence suggesting that occasional drinking while breastfeeding does not have significant adverse effects on nursing infants, there is insufficient investigation and lack of consensus regarding the long-term consequences of heavy maternal alcohol use during breastfeeding. Alcohol is transferred into breast milk; the alcohol concentration in breast milk is known to resemble that in maternal blood, and the amount of alcohol transferred to nursing infants during feeding is approximately 5 to 6% of the weight-adjusted dose consumed by the nursing parent. 147,148 Thus, some studies have suggested that, even in the case of binge drinking, the infants may not be subjected to clinically relevant amounts of alcohol 148,149 while others associate heavy maternal alcohol use during lactation with decreased rate of infant growth and psychomotor development. 149,150 A systematic review of 11 studies (n=36) investigating alcohol's effect on nursing neonates found that infants breastfed by mothers who had consumed alcohol prior to feeding temporarily ingested 20% less milk, arguably as a result of reduced milk ejection reflex. 148 Temporary sedation and changes in sleeping patterns in the neonate have also been documented. 4,148 In view of these effects and the lack of conclusive evidence on the possibility of long-term developmental risk, most guidelines strongly recommend that breastfeeding mothers refrain from consuming alcohol during lactation. 4,147 However, many guidelines also emphasise that alcohol use is not necessarily a contraindication to breastfeeding. For example, the World Health Organization lists alcohol use among maternal conditions during which breastfeeding may still continue based on a case-by-case analysis of benefits and risks. 151 Breastfeeding patients who continue consuming alcohol should be strongly advised to reduce drinking and provided with education to schedule breastfeeding and alcohol use to ensure alcohol is eliminated from breastmilk at the time of feeding or storage of breastmilk. In the case of moderate drinking (i.e., 1-2 standard drinks in a day), guidelines generally recommend waiting 2-2.5 hours after drinking to store breastmilk or breastfeed. 4 However, the time required for the elimination of alcohol is dependent on the amount of alcohol consumed; alcohol appears to be eliminated from breastmilk more slowly in the case of daily heavy alcohol use (i.e., more than two standard drinks per day), and there is a decrease in the length of time that mothers can breastfeed their infants, resulting in significant risk. 152 Therefore, the risk of breastfeeding may outweigh its benefits in the case of chronic heavy maternal alcohol use.
See Appendix 6 for a sample patient information handout of alcohol use and safer nursing practices.
# Alcohol withdrawal pharmacotherapy and lactation
Benzodiazepines: All major classes of benzodiazepines are known to be excreted into human milk in varying but generally low concentrations. 95 Limited evidence characterises possible adverse effects of neonatal exposure to benzodiazepines through human milk as lethargy, sedation, and reduced sucking ability which may lead to poor weight gain. 95, However, available literature suggests that these adverse effects are rare and mild. For example, in a 2012 retrospective cohort study (n=124) examining the neonatal impact of maternal benzodiazepine use during lactation, adverse outcomes-namely sedation-were observed in two (1.6%) infants, both of whom were breastfed by participants who used benzodiazepines in conjunction with other CNS depressants. 154 Similarly, a 2014 review of 16 studies on the impact of neonatal benzodiazepine exposure found rare reports of sedation, predominantly associated with longer-acting benzodiazepines (e.g., diazepam, clonazepam). 155 The authors emphasize the absence of serious negative effects among infants exposed to relatively short acting drugs and suggest that lorazepam and oxazepam may be among preferable agents for breastfeeding patients.
There findings are in line with guidelines by the WHO and the American College of Obstetricians and Gynecologists which deem benzodiazepines compatible with breastfeeding unless the infant's ability to metabolize the medication is impaired. 4,101 Gabapentin: The safety of gabapentin for breastfeeding has been investigated by a small number of case reports involving a range of doses and durations of treatment, and no significant adverse effects were reported. 102,156 Limited information indicates that maternal doses of gabapentin up to 2.1g daily produce relatively low levels in infant serum. 102 Accordingly, an expert consensus guideline indicates that gabapentin is an acceptable medication during lactation. 102 However, the authors advise to monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. 102
# AUD pharmacotherapy and lactation
There are no controlled studies and limited human data on the safety of maternal use of naltrexone, acamprosate, and gabapentin during breastfeeding. On account of this lack of evidence, careful assessment of benefits and risks, fully informed patient consent, and close monitoring of the infant is advised when considering these medications for nursing parents.
Naltrexone: Limited data indicate that naltrexone is minimally excreted into human milk. A case study cited by the Drugs and Lactation Database involves two 1.5-month-old infants breastfed by individuals who were receiving 50mg of oral naltrexone daily during pregnancy and lactation. 135,136 The authors reported no naltrexone-related adverse effects in the infants. Accordingly, while the Health Canada-approved product monograph for naltrexone recommends caution with regards to the use of this medication by nursing parents, 133 the benefits of breastfeeding may outweigh potential risks of neonatal exposure to naltrexone.
Acamprosate: Acamprosate's effect on human breastmilk has not been studied. In animal studies, this medication was excreted in the milk of lactating rats. In reference to this lack of evidence, the product monograph of acamprosate lists pregnancy and breastfeeding among contraindications to the use of this medication. 134 However, available guidance on the neonatal risks of pharmacotherapies during lactation suggests that the use of this medication during breastfeeding is "probably safe" for neonates. 45,137 Gabapentin: Please Section 7.2.2, Alcohol withdrawal pharmacotherapy and lactation for a summary of evidence supporting the compatibility of gabapentin with breastfeeding.
# Child Protection
The prenatal period:
Clinicians in Canada do not have a legal obligation to report prenatal substance use or substance use during the course of pregnancy. Any antenatal referrals or reports should be made with the informed consent of the patient.
Integrated care programs and collaborative long-term support planning in the course of pregnancy may foster family stability and enable new parents to play an active role in their child's care with the help of resources available in her family and community. 157,158 The involvement of expecting parents, supportive family members, public health and community-based resources, and services provided by the BC Ministry of Children and Family Development (MCFD) prior to childbirth can help improve pregnancy outcomes. However, the involvement of these services should be considered on a case-by-case basis with the collaboration and consent of the pregnant patient.
# The neonate (and other children in the custody of patient):
Maternal substance use alone is not grounds for the apprehension of an infant or referral to MCFD. However, the health care team is legally obligated under Section 14 of the Child and Family and Community Service Act (CFCSA) to report child protection concerns to the MCFD. Prior to making a report, clinicians should refer to Section 13 of the CFCSA for a comprehensive outline of circumstances under which notifying MCFD is warranted. The decision to report should be made on a case-by-case basis in consultation with the full health care team. It should be noted that the apprehension of infants is associated with a range of negative long-term social and health outcomes for the mother and child. If a child is temporarily apprehended during the immediate post-partum period, mothers should be offered appropriate supports to ensure that the outcomes they experience after the loss of their child do not become barriers to reunification. 159
# Appendices Preface
The following appendices have been provided to support clinical practice and were developed through discussion and consensus of the guideline committee. The practice guidance herein was informed by review of existing national and international evidence-based clinical practice guidelines issued by recognized addiction medicine organizations and authorities. Where appropriate, Health Canada-approved drug product monographs were consulted to ensure compliance with provincial and national safety regulations and standards for practice.
Recommendations adhere to the CPSBC Professional Standards and Guidelines for Safe Prescribing of Drugs with the Potential for Misuse/Diversion (www.cpsbc.ca/files/pdf/PSG-Safe-Prescribing.pdf).
# Appendix 1 Alcohol Use Screening
In line with available guidelines, this document emphasises the key role of universal and regular substance use screening in health promotion, and specifically recommends screening pregnant patients for alcohol use in the first prenatal assessment (or at the first available opportunity) and re-screening routinely throughout pregnancy and post-partum and as clinically relevant. This appendix provides an instructive overview of the screening process in three steps: Step 1-Starting the Conversation using the Low-Risk Alcohol Drinking Guidelines, Step 2-Screening for High-Risk Alcohol Use, and Step 3 -Assessment and Diagnosis of an AUD.
# Step 1 Starting the Conversation
Introducing the topic of alcohol use to patients in a non-judgmental, conversational, and clear manner can foster a candid conversation and improve the accuracy of self-reported alcohol use. The following strategies are recommended to establish comfort and trust prior to beginning screening questions.
# Use Canada's Low-Risk Alcohol Drinking Guidelines as a Communication Tool
Briefly reviewing Canada's Low-Risk Alcohol Drinking Guidelines (LRADG) handout can help guide conversations toward alcohol use screening. Clinicians may use the LRADG handouts to provide patients with general information regarding the risks of alcohol use to the patient and fetus while clarifying concepts that would enhance the accuracy of alcohol screening, such as what is meant by "alcoholic beverages" and standard drink sizes.
# Sample Script:
" Have you heard about Canada's Low-Risk Alcohol Drinking Guidelines? I talk to all of my patients about these guidelines. They contain important information about safer alcohol use that everyone needs to know. "
# Secure consent and assure the patient of the confidentiality of the conversation
Patients' reluctance to share information about their alcohol use can be a barrier to obtaining accurate screening results and establishing an effective therapeutic relationship for next steps. It is important to::
- Ask the patient's permission before screening - Assure the patient of the confidentiality of the information they share - Emphasize that you ask all your patients about alcohol use
# Sample Script:
" I regularly ask my patients about alcohol and other substance use. Would it be alright for us to talk about this now?"
" Now that we've talked about some of the effects of alcohol, would you mind if I ask you some questions about your alcohol use?"
Step 2 Screening for High-Risk Alcohol Use
In consideration of the time constraints reported by clinicians providing prenatal care, this guideline has recommended a simplified and stepped screening method using a single alcohol screening question (SASQ) to identify alcohol use in pregnant individuals. In addition to a brief sample script for this abbreviated screening process, this appendix presents alternative screening methods validated for pregnant patients. Clinicians are encouraged to select a screening approach based on their clinical experience and judgement.
# SASQ sample script
" Do you sometimes drink beer, wine, or other alcoholic beverages?"
No: Screening is complete.
- Offer encouragement.
- Review the LRADG, emphasising that abstinence is recommended during pregnancy.
- If patient reports not drinking, ask about their alcohol use history:
- Offer encouragement to patients with a personal or family history of AUD who have stopped drinking since they have become pregnant; ask if they have encountered challenges in the process, and offer encouragement and support as needed.
- Rescreen annually frequently depending on personal and family history.
# Yes:
Positive result for high-risk drinking.
- Ask about the patient's average weekly alcohol consumption in standard drinks over the past three months to assess risk and determine whether a diagnostic test is needed (record amounts for follow-up sessions):
- Ask patient: "On average, how many days a week do you drink alcohol?"
- Ask patient: "On a typical drinking day, how many drinks do you have?"
- (Drinking days x number of drinks per drinking day = weekly average).
- If deemed useful, clinicians may choose to use an additional pregnancy-validated screening tool (e.g., AUDIT, AUDIT-C, T-ACE, TWEAK) to assess risk prior conducting the diagnostic test (See below for a review of additional screening tools).
- If patient's self-reported drinking is above low-risk limits for non-pregnant female adults, or if their responses are vague or inconsistent with the clinician's observations, proceed to diagnosis and assessment for AUD (Step 3).
- All patients screening positive for alcohol use should receive brief intervention (Appendix 2).
# Additional screening tools AUDIT and AUDIT-C
The Alcohol Use Disorders Identification Test (AUDIT) was developed by the World Health Organization (WHO) to assist in the early identification of "hazardous" g or "harmful" h alcohol consumption. The AUDIT is a well-studied and commonly used alcohol screening tool which has been validated for a wide range of settings and populations, including pregnant individuals. This tool consists of 10 questions that may enable the administrator to obtain relatively comprehensive information about a patient's alcohol consumption patterns at present and over the past year. 5 Each question is assigned a score between 0-4 that corresponds to frequency of occurrence, resulting in a total score ranging from 0 to 40 points. For adult patients, a score of 8 or higher is associated with "problem drinking, " while 13 or more indicates alcohol dependence. This AUDIT questionnaire takes approximately 3-4 minutes to complete and score.
The condensed AUDIT-Consumption (AUDIT-C) tool, which consists of three questions focusing on frequency and quantity of alcohol use, uses sex-specific cut-off points: in adult patients who were assigned female at birth, a score of 3 or higher indicates hazardous or harmful drinking. This condensed questionnaire takes approximately one minute to complete and score.
The WHO and the US Preventive Health Services Task Force recommend use of the AUDIT or AUDIT-C for detection of hazardous or harmful drinking in all adult primary care patient populations. 61,162,163 Similarly, a recent article examining the potential of adequate alcohol screening and harmonized data collection for the prevention of FASD has found that the AUDIT-C contains the required elements for clinicians to ascertain pregnant patients' pattern of alcohol use in a relatively compact format. 164 However, provider-level barriers, including lack of experience and time constraints (which are of particular concern in the context of pregnancy), have been cited as barriers to more widespread uptake and use of these tools in primary care. 11,48, As an alternative, self-administered print and electronic versions of these questionnaires are available and can be provided to patients to complete in advance of scheduled clinical appointments or while they are waiting to be seen. Self-administered versions of the AUDIT and AUDIT-C appear to be as effective as clinician-administered screening for the identification of hazardous or harmful alcohol use. 168 Another potential limitation of the AUDIT and AUDIT-C is that the low-risk limits and standard drink sizes used in these instruments are slightly different from those indicated in Canada's Low-Risk Alcohol Drinking Guidelines. The US Centers for Disease Control and Prevention have made adaptations in the standard drink size and cut-off points for use in the United States of America; a similar adjustment in accordance to the LRADG would significantly enhance the utility of AUDIT-C as a validated compact tool for alcohol screening during pregnancy. 164 The AUDIT and AUDIT-C questionnaires are provided in Boxes 1 and 2 below.
g Hazardous use: A pattern of alcohol use that increases the risk of harmful physical and/or mental health consequences as well as social consequences for the individual. Hazardous use occurs in the absence of addiction or alcohol use disorder. h Harmful use: A pattern of alcohol use associated with health consequences and/or that causes damage to health. Damage may be physical or mental.
Harmful use commonly, but not invariably, has adverse social consequences, but social consequences alone are not sufficient to justify a diagnosis of harmful use. Harmful use occurs in the absence of addiction or alcohol use disorder. (ICD-10 code, previously known as "non-dependent use" in .
# Box 1 The Alcohol Use Disorders Identification Test ( AUDIT ) 169
Read questions as written. Record answers carefully. Begin the AUDIT by saying "Now I am going to ask you some questions about your use of alcoholic beverages during this past year." Explain what is meant by "alcoholic beverages" by using local examples of beer, wine, vodka, etc. Code answers in terms of "standard drinks". Place the correct answer number in the box at the right.
- How often do you have a drink containing alcohol? In female patients, a score of 3 or more is considered positive for hazardous drinking.
If score is positive, proceed to diagnosis and assessment for AUD.
Total score:
# T-ACE
The Tolerance, Annoyed, Cut down, Eye opener (T-ACE) is the first screening tool validated for pregnant patients, and is currently recommended by the American College of Obstetrics and Gynecology and the National Institute of Alcohol Abuse and Alcoholism. 60 This tool is regularly used as a part of primary care for this population due to its brevity, clarity, and ease of administration. 60 The T-ACE was developed through a substantial simplification of the 25-question Michigan Alcohol Screening Test (MAST) into a 4-item questionnaire which has a similar structure to the CAGE tool. 171 The T-ACE takes approximately one minute to conduct and score. The T-ACE questionnaire is provided in Box 3.
# Box 3 The T-ACE Tool T-ACE
# Questions Points
Tolerance How many drinks does it take to make you feel the first effect (before pregnancy)? 3 or more = 2 points
# Annoyed
Have people ever annoyed you by criticizing you about your drinking?
Yes = 1 point
# Cut down
Do you sometimes feel the need to cut down your drinking? Yes = 1 point Eye Opener Do you sometimes take a drink in the morning when you first get up?
Yes = 1 point Patients who score 2 or higher on the T-ACE should be referred for further assessment for alcohol use disorder.
# TWEAK
Tolerance, Worry, Eye-opener, Amnesia, Cut down (TWEAK) is a 5-question screening tool developed specifically for pregnant patients. As a slight variation of the T-ACE, TWEAK combines features from CAGE and MAST. This method is suitable for use in primary care settings and takes less than 2 minutes to administer and score. The result is calculated on a 7-point scale, and a score of 2 or higher indicates high risk drinking.5,54
The TWEAK questionnaire is provided in Box 4.
# Worried
Have close friends or relatives worried or complained about your drinking in the past year?
Yes = 2 points Eye Opener Do you sometimes take a drink in the morning when you first get up?
Yes = 1 point Amnesia (stands for blackouts)
Has a friend or family member ever told you about things you said or did while you were drinking that you could not remember?
Yes = 1 point Eye Opener Do you sometimes feel the need to cut down on your drinking?
Yes = 1 point
Step 3 Assessment and Diagnosis of an Alcohol Use Disorder
Any continued alcohol use in the course of pregnancy constitutes high-risk drinking and indicates the need for further assessment, and, if appropriate, a structured interview using the DSM-5 criteria to confirm the diagnosis and severity of AUD (see Box 5 below).
Patients who are drinking above low-risk limits but do not have an AUD should receive a brief counselling intervention and be encouraged to discontinue alcohol consumption during pregnancy(see Appendix 2).
Brief intervention alone is not an effective intervention for individuals with an AUD.172 Patients who are diagnosed with an AUD should be offered treatment and care options for withdrawal management and continuing care. Baseline assessment and other withdrawal management considerations, including sample dosing schedules, are outlined in Appendix 3. Appendix 4 offers an instructive overview of continuing AUD pharmacotherapies while Appendix 5 outlines the key principles and considerations for motivational interviewing, a recommended evidence-based psychosocial intervention for AUD.
# Box 5 DSM-5 Diagnostic Criteria for Alcohol Use Disorder 173
A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period, indicates presence of an AUD.
# Sample Clinical Interview Questions 174
In the past year (12 months), have you...
Alcohol is often taken in larger amounts or over a longer period than was intended Had times when you ended up drinking more, or longer, than you intended?
There is a persistent desire or unsuccessful efforts to cut down or control alcohol use More than once wanted to cut down or stop drinking, or tried to, but couldn't?
Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol Continued to drink even though it was making you feel depressed or anxious, or adding to another health problem? Or, continued drinking after having a memory blackout?
Tolerance, as defined by either of the following: a) A need for markedly increased amounts of alcohol to achieve intoxication or desired effect b) A markedly diminished effect with continued use of the same amount of alcohol Had to drink much more than you once did to get the effect you want? Or found that your usual number of drinks had much less effect than before?
Withdrawal, as manifested by either of the following: a) The characteristic withdrawal syndrome for alcohol b) Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms
Found that when the effects of alcohol were wearing off, you had withdrawal symptoms, such as trouble sleeping, shakiness, restlessness, nausea, sweating, a racing heart, or a seizure? Or sensed things that were not there?
Severity: MILD: presence of 2-3 symptoms, MODERATE: presence of 4-5 symptoms, SEVERE: presence of 6 or more symptoms.
Modifiers for the diagnosis include:
- Early remission: After full criteria for AUD were previously met, none of the criteria for AUD have been met (with the exception of craving) for at least 3 months but less than 12 months. - Sustained remission: After full criteria for AUD were previously met, none of the criteria for AUD have been met
(with the exception of craving) during a period of 12 months or longer. - Controlled environment: If the individual is in an environment where access to alcohol is restricted.
Ask Be mindful of the impact our behaviors can have on people with a history of trauma:
- Utilize universal precautions for creating a calm and welcoming environment. This includes minimizing noise, decreasing clutter, maintaining a comfortable temperature
- Be aware of internal emotions and thoughts and focus on those that bolster support for the patient - Be aware of your tone of voice and physical space as you introduce yourself and your role and explain the collaborative process planned (Practical note: ensure that you do not physically block the patent's pathway to the door)
- Respond and communicate respectfully (e.g., ask what name they would like to be called, their gender, their partner's gender, and what pronouns they prefer. Validate patient's gender identity, sexual orientation, and preferences for how they wish to be addressed)
- Listen intently to understand responses and their context
- Commit to setting aside your own judgements and thoughts about screening results
- Maintain awareness of your language and tone of voice when responding.
- Screen patient for alcohol use. See Appendix 1 for detailed guidance on screening
- Express appreciation for answering sensitive screening questions
# Advise
- Clearly describe the screening result and its implications on the health of the patient and fetus
- Provide direct personalized recommendations
- Where possible, relay relevant health risks in reference to patient's concerns, including risks to the fetus:
"You are drinking more than is medically safe, and this is putting your health (and the health of the fetus) at risk…."
"I recommend that you cut down or stop drinking."
# Assess
- Engage patient in a brief conversation to assess and encourage motivation, ability to reduce or discontinue their alcohol use at this time - Identifying strengths rather than deficits will enhance change talk; use this approach when discussing how to achieve a higher number if that's their goal
- Recognize that anything the patient is willing to do to address the issue is a step in the right direction
- Connect the patient to others who may be able to meet any needs that are outside your scope of practice
- Reinforce that you are here to help and that this is an ongoing discussion. Ideally, you want patients to always feel comfortable to discuss these issues with you during visits
- Document the agreed upon plan so you can engage in informed follow-up during the next appointment
# Arrange
If patient has met, or made progress towards, planned intervention goal:
- Congratulate, reinforce, and support continued change
- Coordinate care with referral partners if the patient has accessed additional support. Communicate with external/community agencies on patient's progress
- Assess and address any co-occurring medical conditions and mental health symptoms (e.g., insomnia, depression, anxiety) noting that these may improve with reduction in alcohol use
- With the patient's consent, assist with identifying new goals according to patient's intentions, and schedule follow-up appointments
If patient has been unable to meet planned intervention goal: | Physicians, nurses and nurse practitioners, pharmacists, allied health care professionals, and all other clinical and non-clinical personnel who are involved in the care of pregnant and post-partum individuals who use alcohol.# Disclaimer for Health Care Providers
The recommendations in this guideline supplement represent the view of the provincial guideline supplement committee, arrived at after careful consideration of the available scientific evidence and following external expert peer review. The application of the recommendations in this document does not override the responsibility of health care professionals to make decisions that are appropriate to the needs, preferences, and values of an individual patient, in consultation with that patient and their family members or guardian(s), and, when appropriate, external experts (e.g., specialty consultation). When exercising clinical judgment in the treatment of perinatal alcohol use and alcohol use disorder, BC health care professionals are expected to take this guideline supplement fully into account while upholding their duty to adhere to the fundamental principles and values of the Canadian Medical Association Code of Ethics, especially compassion, beneficence, non-maleficence, respect for persons, justice and accountability, as well as the required standards for good clinical practice as set by the College of Physicians and Surgeons of British Columbia and any other relevant provincial regulatory body. Nothing in this guideline supplement should be interpreted in a way that would be inconsistent with compliance with those duties.
# Legal Disclaimer
While the individuals and groups involved in the production of this document have made every effort to ensure the accuracy of the information contained in this guideline supplement, please note that the information is provided "as is". The Ministry of Health (MoH), Ministry of Mental Health and Addictions (MMHA), and the BCCSU make no representation or warranty of any kind, either expressed or implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest extent possible under applicable law, the MoH, MMHA, and BCCSU disclaim and will not be bound by any express, implied or statutory representation or warranty (including, without limitation, representations or warranties of title or non-infringement).
This guideline supplement is intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. This guideline supplement is not intended as a substitute for the advice or professional judgment of a health care professional, nor is it intended to be the only approach to the management of a clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional. 7.1 Rooming-in and skin-to-skin contact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 7.2 Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 7.2.1 Alcohol and lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 7.2.2 Alcohol withdrawal pharmacotherapy and lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 7.2.3 AUD pharmacotherapy and lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 8. Child Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Appendix 1: Alcohol Use Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Summary of principles of care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 3 Comparative specifications of alcohol screening tools validated for pregnancy . . Table 4 The 5A's model for delivering alcohol use brief intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 5 Comparative features of pharmacotherapy options for management of alcohol withdrawal during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 6 Comparison of pharmacotherapies for AUD during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . .
# Table of Contents
Executive
# List of Tables
# Executive Summary
This document is intended to supplement the BCCSU Provincial Guideline for the Clinical Management of High-Risk Drinking and Alcohol Use Disorder (Guideline) with clinical guidance specific to pregnant and post-partum patients. While the Guideline has provided a comprehensive description of the harms of highrisk drinking and alcohol use disorder (AUD) in general adult and youth populations, it is recognized that pregnant individuals who use alcohol face an additional set of obstetrical risks. Some of the negative pregnancy outcomes associated with alcohol use during pregnancy include spontaneous abortion, intrauterine growth restriction, preterm birth, and fetal alcohol spectrum disorder.
Increased frequency of healthcare service use during pregnancy and post-partum periods present a unique opportunity for clinicians to identify and address alcohol use; however, stigma regarding substance use during pregnancy and lack of knowledge regarding appropriate screening and treatment options present barriers to early detection and treatment of alcohol use and AUD in this population.
To address this discrepancy, this guideline supplement reviews the evidence pertaining to care principles, screening and risk assessment methods, and treatment and continuing care options for pregnant individuals with high risk alcohol use and AUD. This document emphasises the need for a non-judgmental, inclusive, trauma-informed, and culturally safe approach to care that accommodates patients' individual choices and circumstances. Within this framework, the present document recommends a holistic and integrated care plan with appropriate use of the full range of available treatment options and harm reduction services. A summary of the clinical recommendations outlined in this supplement is provided in Table 1.
# Table 1 Summary of Clinical Recommendations
# Screening and Brief Intervention 1
Annual alcohol use screening for all patients of childbearing capacity should include education on Canada's Low-Risk Alcohol Drinking Guidelines and the risks of alcohol use during pregnancy.
# 2
Healthcare providers should screen pregnant and post-partum patients for alcohol use at the earliest opportunity. Screening should be repeated routinely throughout pregnancy and post-partum.
# 3
All pregnant and post-partum patients who screen positive for alcohol use should receive brief counselling intervention and advice for discontinuing alcohol use.
# 4
All pregnant and post-partum patients with AUD should be offered, or referred to, appropriate treatment interventions and support services.
# Withdrawal Management
# 5
Where possible, alcohol withdrawal management for pregnant patients should be conducted in inpatient settings where patients can receive symptom-triggered treatment with close monitoring of withdrawal symptoms. a 6 Clinicians should consider the use of the Prediction of Alcohol Withdrawal Severity Scale (PAWSS), in combination with best clinical judgement, to select the appropriate withdrawal management pharmacotherapy based on the risk of severe complications of withdrawal.
# 7
Pregnant patients who develop alcohol withdrawal symptoms should be offered pharmacotherapy for alcohol withdrawal management.
A. Either benzodiazepines or gabapentin may be offered to pregnant patients at low risk of severe complications of withdrawal (PAWSS<4).
B. Benzodiazepines are recommended for patients at high risk of severe complications of withdrawal (PAWSS>4).
# 8
All pregnant and post-partum patients who undergo withdrawal management should be connected to continuing AUD care.
# Continuing Care 9
All pregnant and post-partum patients with AUD should be offered, or referred to, psychosocial treatment interventions.
# 10
Healthcare providers should consider offering pharmacotherapy with naltrexone, acamprosate, or gabapentin to prevent relapse to alcohol use in pregnant patients with moderate to severe AUD. b
# Post-partum considerations 11
Healthcare providers should facilitate rooming in and encourage skin-to-skin contact to promote parent-neonate bonding and, in turn, improve maternal and neonatal outcomes.
# 12
Nursing parents should be strongly encouraged to discontinue alcohol use while lactating. Patients who continue using alcohol during this period should receive advice and support to reduce drinking and schedule feeding and alcohol use to ensure alcohol is eliminated from breastmilk by the time of feeding or storage of milk.
# 13
For patients who are stable on AUD pharmacotherapy (i.e., naltrexone, acamprosate, or gabapentin), decisions regarding breastfeeding c should be made on a case-by-case basis with the knowledge and involvement of the patient. The possible neonatal risks of these medications should be weighed against the well-established benefits of breastfeeding for mother and neonate.
1 Introduction
# Background
Alcohol is a known teratogen, and its use during pregnancy is associated with a wide range of negative pregnancy outcomes collectively referred to as fetal alcohol spectrum disorder (FASD), as well as spontaneous abortion and stillbirth. 1,2 According to recent Canadian estimates, FASD affects approximately 4% of the Canadian population and includes fetal growth restriction, developmental delay, neurological abnormalities, and behavioral and cognitive issues throughout life. 1,2 While a number of meta-analyses have demonstrated that the likelihood and severity of physiologic, cognitive, and behavioural sequalae of in utero alcohol exposure are dose-dependent, no consensus has emerged concerning the specific cut-off blood alcohol level below which alcohol use would be considered "low-risk" for the pregnant person and fetus. 1,3 Therefore, most jurisdictions, including Canada, strongly recommend abstinence from alcohol use during pregnancy. 4,5 Despite this unequivocal recommendation, alcohol use during pregnancy is not uncommon. According to a 2019 report by the US Centers for Disease Control and Prevention, the overall estimates of alcohol consumption and binge drinking rates among pregnant women during 2015-2017 were 11.5% and 4% respectively, marking a slight increase since the 2011-2013 period (10.2% and 3.1%, respectively). 6 Data from the 2009 Canadian Maternity Experiences Survey indicated that 62.4% of survey respondents reported drinking alcohol during the three months prior to pregnancy, and 10.5% reported that they consumed alcohol during pregnancy. 5,7 These data are likely an underestimation of the true prevalence of alcohol use in pregnancy, as the experience of stigma and fear of judgement and child apprehension can lead to significant under-reporting of alcohol use in this population. 5,8 Nevertheless, available data suggest that the prevalence of alcohol use during pregnancy is comparable to, or higher than, that of many conditions routinely screened for and addressed during prenatal care, such as cystic fibrosis, gestational diabetes, post-partum depression, and preeclampsia. [9][10][11] Increased frequency of healthcare service use in the prenatal period and elevated motivation for delivering a healthy baby present a unique opportunity for clinicians, particularly primary care providers, to screen pregnant patients for alcohol use and provide appropriate advice, care, and referrals to address high risk alcohol use and alcohol use disorder (AUD). 12,13 Yet, alcohol use among pregnant patients frequently goes unrecognized. The lack of clear clinical guidelines for screening, assessment, and management of alcohol use and AUD during pregnancy is a commonly cited barrier to seizing this opportunity for early detection and intervention. 3,5,9 In response to this discrepancy, a committee of experts was assembled to supplement the BCCSU, MOH, and MMHA Provincial Guideline for the Clinical Management of High Risk Drinking and Alcohol Use Disorder ("Guideline") with clinical recommendations based on a review of evidence for screening and brief intervention, withdrawal management, and continuing AUD care specifically pertaining to pregnant individuals. The following text provides a summary of research evidence from which the committee has derived the clinical recommendations and principles of care presented in this guideline supplement.
# Objectives and scope of the guideline supplement
This guideline supplement primarily focuses on the identification, assessment, and clinical management of high-risk alcohol use and AUD in pregnant and post-partum individuals. To support transition from prenatal care to post-partum care for this population, the committee has also provided a review of available evidence on the implications of alcohol use, AUD, and AUD treatment on immediate post-partum care and breastfeeding.
This supplement is intended to serve as a companion document to the Guideline which provides a comprehensive review of the evidence on high risk-alcohol use and AUD treatment, clinical recommendations, and a general framework of care for the treatment of AUD; readers are encouraged to also refer to the Guideline for broadly applicable guidance in this area.
The objectives of this document are to address barriers to routine screening for the early identification of alcohol use and AUD among pregnant patients and to promote the uptake of evidence-based prevention, risk reduction, and treatment interventions appropriate for pregnant patients within primary care and other clinical settings.
Specifically, these guidelines aim to:
• Describe the principles of care and general considerations for screening, diagnosis, and management of high-risk drinking and AUD for pregnant and post-partum patients.
• Review specific strategies for alcohol use screening and brief intervention for pregnant patients.
• Recommend a clinical pathway for alcohol withdrawal management, whereby appropriate withdrawal risk and severity assessment facilitates tailored treatment selection and symptom-triggered approach that minimizes harm to the patient and fetus.
• Review and recommend pharmacotherapeutic and psychosocial alcohol withdrawal management options that are safe and suitable for the pregnant patient and the fetus.
• Review and recommend strategies for continuing AUD care with demonstrated maternal and fetal safety, including use of pharmacotherapy, psychosocial treatment interventions, and community-based treatment and support geared towards this population.
• Provide an overview of relevant care and safety considerations for patients with AUD and alcohol-exposed infants in the immediate post-partum period.
• Provide guidance on the potential impact of alcohol consumption and the safety considerations of alcohol withdrawal and AUD pharmacotherapy on lactation and breastfeeding.
# Guideline development process
Between January 2017 and November 2018, the guideline committee for the pregnancy supplement to the Provincial Guideline for the Clinical Management of High-Risk Drinking and Alcohol Use Disorder conferred through email, teleconferences, and three face-to-face meetings. At the first committee meeting, the purpose, scope, and outline of the guideline were provisionally approved by committee consensus in accordance with the AGREE-II reporting checklist for development of clinical practice guidelines.
From May 2019 to January 2020, guidance committee members conferred over email and teleconference, and held two in-person meetings to review and approve evidence summaries prepared by the medical writer and draft guideline contents and recommendations.
# Development and approval of recommendations
The recommendations for the pregnancy supplement were developed in reference to the broadly applicable recommendations of the Guideline, which were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool to develop and score recommendations. In view of limited volume and low quality of evidence focused on pregnant patients, recommendations specific to pregnant and postpartum populations were developed through committee consensus after rigorous review and discussion of prepared evidence summaries. In addition to the safety and efficacy data pertaining to both pregnant and non-pregnant populations, a range of factors, such as clinician, patient, and policy makers' values and preferences, costs, risk-benefit ratios, and feasibility were considered in the process of recommendation development.
The draft supplement and recommendations were compiled and circulated to the full committee to provide feedback on contents and recommendations. The committee was given four weeks to submit written feedback on the draft supplement. Feedback was collated and incorporated into a revised draft which was then circulated to the committee for additional feedback. Further feedback was collated and incorporated into a second revised draft for external review
# External review
The draft guideline supplement was circulated for review and comment to relevant experts and stakeholders as identified by the committee. Feedback from the external reviewers was reviewed and incorporated into the final draft of the supplement and external reviewers approved this draft. The final draft was then circulated to the committee for final approval.
# Principles of Care
As outlined in detail in the Guideline, healthcare providers are encouraged to observe a set of overarching principles of care that inform a collaborative, equitable, and effective therapeutic relationship with patients and, where appropriate, families affected by high-risk alcohol use and AUD. These principles enable clinicians and care teams to meet the healthcare needs of patients within a patient-centred framework and along an integrated continuum of addiction care. This section highlights a number of care principles and practices with particular practical relevance to the care of pregnant and post-partum individuals who use alcohol. Table 2 provides a summary of the key care principles described in this section.
# Respect for the autonomy, agency, and individuality of patients
As with all patients, pregnant individuals who use alcohol should be empowered to take an active role in decisions concerning their own health and well-being; this includes making informed decisions concerning the fetus. While patients should be provided with clinical recommendations to improve pregnancy outcomes, clinicians' concern for the health of the fetus should not override the patient's individual preferences and values. 4 Securing the patient's informed consent prior to implementing clinical decisions, and non-judgemental and informative dialogue are among the key aspects of respectful and effective care.
# Privacy and consent
Assuring patients of the confidentiality of the information they disclose helps establish a trusting and open therapeutic relationship. Care providers should inform patients of the relevant aspects of their duty to report and emphasize that there is no legal obligation to report substance use and risks to the fetus during the course of pregnancy to Child Protection Services (see the Child Protection section). This is an important detail to include in the initial discussion as, according to numerous studies, the fear of intervention by child welfare services and losing custody of a child is a major barrier to seeking treatment for pregnant people who use substances. 14,15 Respect for the privacy of patients extends to the involvement of family members or other support resources in their care. While a patient's family and social circle can have a key role in supporting the patient's care, healthcare providers should avoid assuming that involving a family member is always in the best interest of every patient.
# Information sharing and education
Continuous education and sharing of relevant information with patients are the cornerstones of collaborative and empowering care. Lack of knowledge about available treatment options and their implications for the health of the patient and the fetus may act as a barrier to accessing substance use care and engaging in treatment. 16 Thus, it is imperative that clinicians discuss the risks and benefits of available clinical care options for the patient and fetus, and provide referrals to educational and support resources that enhance patients' self-efficacy and independence in improving their health. 16 For example, clinicians should combine alcohol screening for pregnant patients and patients of childbearing capacity with a conversation regarding the risks of alcohol use during pregnancy and post-partum using the recommendations of Canada's Low Risk Alcohol Drinking Guidelines for this population. 5
# Gender-inclusive and non-judgemental language
While the majority of pregnant people identify as women, some pregnant people, including those who are transgender, transsexual, nonbinary, genderqueer, gender neutral, agender, Two-Spirit, and gender nonconforming (also collectively referred to as "trans" individuals) do not identify as women. Historically, clinical interventions for alcohol use during pregnancy have been designed and evaluated with insufficient awareness or understanding of the diversity of pregnant patients in terms of gender and reproductive intentions. 17 A 2018 commentary on gender-inclusive alcohol interventions for pregnant people argues that the assumption that all pregnant people are women creates gaps in services for people who are both trans and pregnant. 17 For many pregnant patients, the prospect of parenthood is an important source of motivation for positive change. However, care approaches and discourses that do not take into account gender diversity among pregnant people may render alcohol use interventions inapplicable, inaccessible, ineffective, and potentially harmful for pregnant patients who do not identify as women or do not intend to assume the role of mother (e.g., surrogates, patients who choose adoption, expecting parents who do not identify as "mothers"). It should be noted that normative pressures are cited as risk factors for problematic substance use among trans individuals, as they may lead to feelings of guilt, isolation, and inadequacy that, in turn, increase the risk for excessive alcohol consumption and reluctance to access care. 17,18 Clinicians should respect the identities of patients by using appropriate terminology and pronouns according to each individual's identity and preference. 19 In cases where clinicians require clarity, it is appropriate to ask the patient regarding pronouns and terminology that corresponds with their identity. Where possible and appropriate, care providers should also accommodate the gender identities and reproductive intentions of their patients in care plans and offer to connect patients with support resources. These measures have a significant role in ensuring the engagement and retention of trans patients in care.
# Awareness of social determinants of health
Healthcare providers should view and address alcohol use and AUD during pregnancy within the broader context of social determinants of health. Social determinants of health are defined as "the economic and social conditions that shape the health of individuals, communities, and jurisdictions as a whole. " 20 The distribution of resources and opportunities that a society makes available to its members (e.g., food, income, housing, education, and healthcare) is affected by a range of factors including socioeconomic class; gender; sexual orientation; race and ethnicity; refugee, migrant or immigrant status; and disability status. 21,22 The intersection of multiple factors (e.g., gender, race, sexual orientation) informs each individual's social identity and, access to resources, and, in turn, health outcomes. 23 People who belong to marginalized groups experience the most significant barriers to accessing resources, and, thus, have the poorest health outcomes. 21 Cited determinants of high-risk drinking and AUD include negative childhood experiences; 24 lower socioeconomic status; 25 living in poorer neighbourhoods; 26 and being a member of a racial, ethnic, gender, or sexual orientation minority. 27 In addition, race, history of physical abuse, general health status, and, to a lesser extent, education have been identified as some of the social determinants of alcohol use during pregnancy. 28 Lack of awareness of the complexity of socioeconomic factors contributing to alcohol use among pregnant individuals may lead to further marginalization of this population, and may impede access to adequate care.
In addition to having a basic understanding of how the unequal distribution of opportunity and resources in the Canadian society impacts the health of individuals, clinicians and care teams should endeavour to identify and remove barriers to accessing care. Clinicians should also aim to address disparities that may exist in the social determinants of health by offering to connect patients to resources that help meet their social and survival needs (e.g., housing, food/nutrition, child care, financial assistance).
# Trauma-and violence-informed care
Alcohol use disorder has been associated with a high lifetime prevalence of trauma including physical and sexual abuse, and pregnancy is a period of particular vulnerability for individuals who have experienced trauma. 29,30 It is also noteworthy that pregnant individuals are at an increased risk of intimate partner violence, particularly in the case of unplanned pregnancies. 31,32 Clinicians involved in the care of pregnant patients with AUD should be familiar with the principles of trauma-informed practice (e.g., trauma awareness; safety and trustworthiness; choice, collaboration and connection; strengths-based approaches and skill building). The provincial Trauma-informed Practice (TIP) Guide may be a useful resource when working with this patient population. 33 Healthcare providers serving this population should also be equipped to identify and respond to gender-based violence; to this end, the Provincial Health Services Authority (PHSA) offers a brief online course series entitled "Gender-Based Violence: We All Can Help Improving the Health Sector's Response", which may serve as a helpful resource.
# Integrated medical management
Care for pregnant individuals with AUD should reach beyond a strictly substance-focused approach in order to improve long-term outcomes for the patient and fetus. As the standard of care for the management of any complex or chronic medical condition, thorough medical management should be provided to pregnant patients with AUD. In this context, medical management is defined as informal medically-focused counselling that includes, but is not limited to, conducting health and mental wellness checks; offering non-judgmental support and advice; assessing motivation and exploring ideas for change; developing a holistic treatment plan; promoting alternative strategies for managing stress; and providing appropriate referrals to health and social services with the consent and input of the patient. Clinicians should also ascertain patients' housing, food/nutrition, and security needs and make necessary referrals to address them, with the consent and input of the patient. 29,30
# Harm reduction during pregnancy and post-partum
Harm reduction is commonly defined as policies, programs, and practices aimed at minimizing the negative impact of substance use on the individual and the society without necessarily stopping or reducing substance use. 34,35 In essence, a harm reduction-oriented approach seeks to meet patients "where they are at" and supports any step or behaviour that enhances the health and safety of patients and their communities. This fundamental framework of care requires particular attention in the context of pregnancy, given that recommended AUD interventions for pregnant patients are mainly aimed at abstinence.
While recognizing that discontinuing alcohol use is the only means of fully eliminating alcohol-related risks to the patient and the fetus, this supplement strongly emphasises that the provision of comprehensive and continued care should never be contingent on a pregnant patient's willingness to discontinue alcohol use. Clinicians providing care for pregnant or lactating individuals who continue drinking alcohol should adopt appropriate harm reduction strategies such as promoting safer alcohol use (e.g., reduced drinking, refraining from drinking and driving, discontinuing non-beverage alcohol use) and providing referrals to resources that address social determinants of health (e.g., housing, nutrition, legal services, financial assistance, child care). 35,36 Harm reduction measures have been shown to contribute to reduced drinking, improved nutrition, and improved overall health outcomes for the patient and fetus. 35,36 For additional information on evidence-based harm reduction strategies geared towards pregnant patients who use substances, see Harm Reduction and Pregnancy: Community-based Approaches to Prenatal Substance Use in Western Canada. 3
Clinicians should incorporate the principles of trauma-and violence-informed care in the care and clinical management of pregnant and post-partum patients who use alcohol and those with AUD.
# 4
Alcohol use and AUD in pregnant patients should be managed within the framework of comprehensive medical care and support, including routine and ongoing medical, mental health, and psychosocial assessments.
# 5
Provision of comprehensive and continued care should never be contingent on a pregnant patient's willingness to discontinue alcohol use. Clinicians providing care for pregnant individuals who continue drinking alcohol should adopt appropriate harm reduction strategies.
3 Screening and Brief Intervention
# Considerations for alcohol screening during pregnancy
Regular substance use screening is widely recommended for patients who are or may become pregnant, in order to identify risk and prevent or minimize harm to the patient and the fetus. 4,5,11 Substance use screening should be included in the first prenatal assessment, or at the first available opportunity, and conducted routinely throughout pregnancy and post-partum and when clinically relevant and necessary. 37 Research has suggested that patient self-reports are a reasonably reliable measure of alcohol use during pregnancy; however, clinicians should be sensitive to factors that may deter patients from providing accurate responses to screening questions, such as stigma and fear of child apprehension. 38,39,40 To address these concerns, it is crucial to establish comfort and trust by securing the patient's informed consent prior to screening, and to assure them of confidentiality and other rights in accordance with the standards of medical practice. 41,42 It is also helpful to mention that all patients are periodically asked about substance use as a standard of primary care provision. Some guidelines recommend that care providers ask pregnant individuals about alcohol consumption at every visit as patients are more likely to disclose alcohol use after a therapeutic relationship has been established. 41 Additionally continuous documentation of alcohol use patterns in pregnant patients with AUD is instrumental to the early identification and management of FASD. 5
# Initiating a dialogue about alcohol use and pregnancy
Screening and assessment for all patients of childbearing capacity should be combined with education about Canada's Low-Risk Alcohol Drinking Guidelines 3 , which recommends abstinence from alcohol use during pregnancy and outlines low-risk drinking limits for adults. In addition to raising awareness of these guidelines, introducing the topic of alcohol use in a general and conversational manner can also help build rapport and facilitate a natural transition to questions regarding personal alcohol use. For example, alcohol screening can be initiated by asking: "Have you heard about Canada's Low-Risk Alcohol Drinking Guidelines? I talk to all my patients about these guidelines. They contain important information about safer alcohol use that everyone should know. It also offers recommendations for people who are or may become pregnant. "
Where appropriate, clinicians should also discuss effective contraceptive methods and how to access them with patients of childbearing capacity. This is in consideration of the persistently high prevalence of unplanned pregnancies in Canada. 8,43 Contraceptive counselling services and supplies should also be offered to patients who are currently pregnant in order to reduce the likelihood of a subsequent unplanned pregnancy as short intervals between pregnancies may disrupt ongoing treatment and amplify potential risks to recovery and long-term health. 44,45 3.3 A simplified screening method to address time constraints Despite the well-established utility of regular alcohol screening for early detection of alcohol use and AUD, and the secondary prevention or minimization of harm to the patient and fetus, many pregnant patients are not screened for alcohol use. 5,11 Time constraints are frequently cited as a key barrier to adequate screening; primary care clinicians often report being overwhelmed by the number of conditions for which they are required to screen pregnant patients. The duration of the average primary care visit is often insufficient to accommodate a thorough screening process which ideally involves an introductory conversation about the maternal and fetal risks of alcohol use. 5,11 To counteract this barrier, a simplified and stepped alcohol screening process is recommended for pregnant patients, involving a single alcohol screening question (SASQ) to identify alcohol use in pregnant individuals. Patients who screen positive should be offered brief intervention and further assessment with validated screening and/or a diagnostic interview using the DSM-5 criteria for AUD. 5 See Appendix 1 for an instructive overview of alcohol use screening for pregnant patients.
A recommended screening method in the general population, the SASQ is typically constructed in reference to low-risk drinking limits in order to determine if, and how frequently, the patient's alcohol consumption has exceeded these limits. For example, an adult patient would screen negative for high-risk alcohol use if their response to the following question was "zero" or "never":
"In the past year, how often have you consumed more than 3 drinks (for adult women) or 4 drinks (for adult men) on any one occasion?"
In the context of pregnancy, the SASQ may be modified to identify any alcohol use in accordance with the Low-Risk Alcohol Drinking Guideline recommendation for this population:
"Do you sometimes drink beer, wine, or other alcoholic drinks?" 46 An affirmative response indicates the need for brief intervention and further assessment.
Studies have found that the sensitivity of the SASQ ranges from 60-90%, [47][48][49][50] and systematic reviews involving non-pregnant patient populations have validated this option for clinical settings where time and patient interactions are limited, notwithstanding its slightly lower sensitivity than structured screening instruments for the detection of high-risk drinking behaviours. 51,52 Although the SASQ has not been explicitly validated for screening pregnant patients, it has been recommended as the first step in alcohol use screening in this population by the Society of Obstetricians and Gynaecologists of Canada 5 and the U.S. Preventive Health Services Task Force on account of its brevity and sufficient sensitivity and specificity. 53 Another advantage of the SASQ is that it can be integrated into an informative conversation without disrupting the flow of the appointment.
# Additional validated screening tools for pregnant patients
Studies involving pregnant participants support the effectiveness of a range of screening tools validated for the general population, such as the AUDIT, AUDIT-C, CAGE, and CRAFFT methods. 4,46 Additionally there are a number of screening tools specifically developed for detecting high-risk drinking and AUD among pregnant patients, including the T-ACE, and TWEAK tools. This guideline supplement presents AUDIT, AUDIT-C, TWEAK, and T-ACE, commonly recommended screening tools which have been validated for use during pregnancy. (See Appendix 1)
Table 3 provides a comparative overview of pregnancy-validated tools in terms of selectivity, specificity, time and expertise required, and other factors informing usefulness. Refer to the Guideline for screening tools not presented in this document.
# Diagnosis of AUD
Pregnant patients who screen positive for alcohol use during pregnancy should undergo further assessment to confirm or exclude AUD. As with the non-pregnant population, this assessment may be conducted through a structured interview using the DSM-5 criteria for the diagnosis and severity of AUD. Confirmation or exclusion of an AUD largely determines subsequent steps in the treatment pathway. Appendix 1 presents the diagnostic criteria for AUD.
While all pregnant individuals who screen positive for alcohol use should receive brief counselling intervention and routine follow-ups (see next section, Brief intervention), brief intervention alone is not effective for individuals with AUD. 4,55 Patients who are diagnosed with an AUD should be offered evidencebased treatment for AUD. (See Withdrawal Management and Continuing Care Sections for an overview of evidence-based interventions)
# Brief intervention
Brief intervention is a time-limited single-session counselling dialogue that typically follows a positive screen for alcohol use during pregnancy. The aim of this intervention is to assess, strengthen, and mobilize patients' motivation for change in order to help them reduce or discontinue alcohol use. There are a number of different approaches and models for delivering brief intervention for alcohol use in primary care settings, but most are variations of motivational interviewing (MI), a psychosocial intervention which empowers patients to make positive behavioural changes. 5,56 Key components of brief intervention are exploring and discussing motivations for or against reducing alcohol use, identifying barriers and facilitators to change and available treatment and supports, assisting the patient to set goals, and providing non-judgmental encouragement and support. Brief intervention also serves as an opportunity to offer referrals to community-based resources or supports. An advantage of brief intervention is that it can be easily implemented by a range of health care providers including physicians, nurse practitioners, nurses and other allied health professionals who may not have specialized training in addiction medicine.
As with the non-pregnant population, brief intervention is widely recommended for pregnant patients and supported by a number of clinical trials. A 2009 systematic review (n=4 studies; 715 participants) of randomized controlled trials (RCTs) examining the effectiveness of psychosocial treatment interventions found that brief psychosocial or educational interventions may motivate pregnant patients to reduce or discontinue alcohol use, although the authors found the data insufficient for performing a meta-analysis. 57 A number of individual studies have reported significant results in favor of BIs in this population. For example, in a randomized study comparing brief intervention (n=162) to assessment only, O'Conner and Whaley (2007) reported that pregnant individuals in the brief intervention treatment group were 5 times more likely than participants in the control group to report that they abstained from alcohol use throughout pregnancy. The infant mortality rate in the brief intervention group was 3 times lower than the rate in the control group, and newborns from the brief intervention group had greater birth length and weight than control subjects. 58 A practical example of brief intervention that has been well studied in primary care and used for various specific populations is the 5As (Ask, Advise, Assess, Assist, and Arrange) model for behavioural change. 59 Ease of recall, brevity, and adaptability are practice-relevant strengths of this approach. This model is presented in Table 4. Appendix 2 provides general instructions for conducting brief intervention with a trauma-informed approach.
It should be noted that, while guidelines endorse a range of validated brief intervention methods, research has shown that simply asking patients in a detailed manner about the extent of their alcohol use, discussing potential risks, and offering brief non-judgmental advice may help raise awareness about their actual levels of alcohol consumption and modify behavior. 53,60 Table 4 The 5A's Model for Delivering Alcohol Use Brief Intervention 61,62 (modified for pregnancy)
# Ask
Screen pregnant patients in a conversational and non-judgmental manner with awareness of the stigma affecting this population. Acknowledge the patient's existing knowledge about the risks of alcohol use during pregnancy and any changes they have already made to mitigate this risk.
# Advise
In a clear and personalized manner, inform patients of the risks of alcohol use during pregnancy and postpartum and advise them to discontinue alcohol use during this period.
# Assess
Assess and record patients' readiness to discontinue or reduce alcohol use at this time.
At this stage, it is advised to conduct a diagnostic interview to confirm/exclude AUD, as brief intervention alone is not effective for individuals with AUD.
# Assist
Work with the patient to develop a treatment plan that accommodates their level of readiness and motivation. Offer supportive counselling and advice, provide a menu of options for treatment and referrals to community resources.
Arrange Schedule follow-up contact, preferably within a week of the intended "change date".
4 Withdrawal Management
# Overview
Alcohol withdrawal occurs with the sudden cessation or significant reduction of alcohol use after a period of chronic heavy alcohol consumption. These symptoms are believed to result from the hyperactivity of glutamate, the main excitatory neurotransmitter of the central nervous system (CNS), upon the sudden reduction in the blood alcohol level. 3,63,64 In normal conditions, the brain maintains a balance between the effects of GABA, a major inhibitory neurotransmitter, and glutamate. Alcohol disrupts this balance by increasing the inhibitory effect of GABA and suppressing the excitatory effects of glutamate. Chronic alcohol consumption causes the CNS to compensate for the inhibitory effects of alcohol by upregulating glutamate transmission in order to restore neurochemical equilibrium. When suddenly unopposed by the inhibitory effects of alcohol, the upregulated excitatory system results in overall CNS hyperactivity, which manifests as a range of withdrawal symptoms in up to 50% of individuals with long-term alcohol dependence. 3,63,64 Common alcohol withdrawal symptoms include tachycardia, pyrexia, tremor, nausea, vomiting, and sweating, which may also be accompanied by psychological distress in the form of anxiety, agitation, and sleep disturbance or insomnia. Symptoms of alcohol withdrawal typically begin 6-24 hours after the last intake of alcohol and reach peak intensity at 24-48 hours, with resolution of symptoms within 5-7 days. 65 Additionally, a small percentage of symptomatic patients may experience severe complications of withdrawal consisting of tonic-clonic seizures and delirium tremens which are life-threatening if left untreated. [66][67][68] The data available on the specific effects of acute withdrawal on the pregnant patient are sparse; however, some have extrapolated that pregnant individuals may be particularly vulnerable to the withdrawal symptoms listed above due to their well-documented increased susceptibility to physiological and environmental stress. 3,[69][70][71][72] Acute maternal alcohol withdrawal may, in turn, lead to a host of adverse effects on the fetus including fetal distress, placental abruption, preterm labour, and fetal demise. 3 In view of the added risks of alcohol withdrawal during pregnancy, it is recommended that, where possible, pregnant patients with AUD undergo withdrawal management in inpatient settings where patients can receive symptom-triggered treatment with close monitoring of withdrawal symptoms and fetal health. 3,4,9 It should also be noted that available studies on withdrawal management for this specific population have been conducted in inpatient settings. However, if inpatient withdrawal management is not an option due to patient preference or lack of timely access to available beds, outpatient treatment with close monitoring may be offered to pregnant patients who otherwise meet the criteria for this setting (e.g., low risk of severe complications of withdrawal, family or community-based support, ability to attend medical visits, absence of other conditions requiring inpatient care). For instructions on outpatient withdrawal management, see Appendix 3, Patient Criteria and Considerations for Outpatient Alcohol Withdrawal Management.
It should be emphasised that withdrawal management alone does not constitute treatment for AUD. Studies report high post-withdrawal relapse rates and suggest that sustained abstinence and reductions in alcohol use are unlikely without provision of continuing AUD care. 73,74 Patients should be connected to continuing care following the completion of withdrawal management. See the Continuing Care section in this supplement for an overview of evidence-based treatment interventions. This section provides a review of the efficacy and safety of clinical withdrawal assessment and management options with a focus on fetal and neonatal outcomes.
Refer to Section 3 of the Guideline for a comprehensive review of all common withdrawal management treatment options for the general population of patients with AUD.
# Assessment
# The Prediction of Alcohol Withdrawal Severity Scale (PAWSS)
The Prediction of Alcohol Withdrawal Severity Scale (PAWSS) is a validated score-based tool for estimating the risk of developing severe complications of withdrawal (i.e., seizures and delirium tremens), which facilitates the selection of appropriate withdrawal management interventions. 75 The PAWSS incorporates the evidence-based risk factors of developing severe complications of withdrawal into a 10-item cumulative scale with a maximum score of 10, wherein a score of <4 indicates low risk and a score of ≥4 denotes high risk for severe complications of withdrawal. 75 While this tool has not yet been validated specifically for use in pregnant patients, its accuracy and usefulness in inpatient settings was validated in a 2018 systematic review of 14 studies (n=71,295) evaluating single and composite measures of severe withdrawal risk. 76 The authors demonstrated that composite scales that measured multiple signs and symptoms were more useful in predicting an individual's risk than individual signs or symptoms. Of these composite scales, the PAWSS was found to have the highest sensitivity (93%, [95% CI, 77%-99%) and specificity (99%, [95% CI, 98%-99%]) in assessing the risk of severe complications of withdrawal. 76 Recommended preliminary assessment for alcohol withdrawal in non-pregnant populations involves the administration of the PAWSS tool in order to select the appropriate treatment setting based on their risk of developing severe complications of withdrawal. 75,76 Given the recommendation that all pregnant patients requiring withdrawal management undergo treatment in an inpatient setting, assessment for the purpose of selecting the treatment setting may not be indicated in this population unless strong patient preference or scarcity of beds prompts risk assessment for outpatient treatment. However, the PAWSS is also a useful means of selecting the appropriate withdrawal management pharmacotherapy, as non-benzodiazepine withdrawal management medications may not be appropriate for individuals at high risk of experiencing severe complications of alcohol withdrawal. 9 As such, this supplement recommends that clinicians consider the use of this tool to help select between gabapentin and benzodiazepines for withdrawal management in pregnant patients.
For more information see Pharmacotherapies for withdrawal management. If clinicians elect to administer the PAWSS tool to inform medication selection, its result should be combined with additional clinical assessment and observation.9 The PAWSS tool and corresponding instructions will be produced in Appendix 3.B.
# Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)
The CIWA-Ar is considered the gold standard for assessing withdrawal symptom severity in a range of clinical care settings for the general patient population, with demonstrated inter-rater reliability and validity. 77 This tool is commonly used to determine and adjust symptom-triggered dosing schedules. Studies have shown that using the CIWA-Ar in this context minimizes both under-and over-medicating patients while mitigating the risk of severe symptoms. 78,79 The CIWA-Ar involves the assessment of 10 individual symptoms and signs of alcohol withdrawal including anxiety and agitation; auditory, visual, and tactile disturbances; tremor; sweating; nausea; headache; and clouding of sensorium, which are assigned a numerical score based on objective and subjective measures of severity. A score <15 indicates mild withdrawal symptoms while scores ≥15 and ≥20 are indicative of moderate and severe withdrawal symptoms respectively. 77 Due to the wide recognition of the CIWA-Ar scale, the terms "mild", "moderate", and "severe" withdrawal used in this supplement are defined according to these numerical scores.
Although the CIWA-Ar has not been validated for pregnant patients, its use is common for alcohol withdrawal symptom assessment during pregnancy and has been described in a case report. 80 The authors reported the utility of this tool in devising a symptom-triggered withdrawal management regimen and minimizing the exposure of the patient and fetus to potentially harmful medications.80 Clinicians using this tool for withdrawal symptom severity assessment should be mindful that some of the CIWA-Ar criteria (e.g., nausea and headache) overlap with common symptoms of pregnancy. Thus, CIWA-Ar results should be interpreted with clinical judgment and in communication with the patient to distinguish between pregnancy and withdrawal symptoms. 80 The CIWA-Ar tool and corresponding instructions are presented in Appendix 3.B.
# Management of negligible to mild withdrawal symptoms
In consideration of the significant risks of acute withdrawal to the patient and fetus, all pregnant patients diagnosed with AUD should be offered medication for withdrawal management. However, patients with mild AUD may experience negligible withdrawal symptoms and may prefer to receive supportive therapy and continuing care without pharmacological detoxification.
There is a lack of consistent guidance regarding the non-pharmacological management of mild withdrawal symptoms among non-pregnant and pregnant patients alike. Many practice guidelines pertaining to the general population recommend provision of supportive care alone until withdrawal symptoms subside (e.g., supportive environment; close monitoring with the involvement family where possible; adequate nutrition and hydration; encouragement and positive reinforcement; referrals to psychosocial treatment interventions and communitybased support resources). 8,81 If not contraindicated, over-the-counter pain relievers, anti-emetics, and antidiarrheal medications approved for use during pregnancy and lactation may also be prescribed for management of mild symptoms. This is based on early studies involving non-pregnant populations that found supportive care was sufficient for approximately 75% of patients with no psychiatric or medical comorbidities. 82,83 Clinical experience suggests that pregnant patients are more likely than other populations to opt for nonpharmacological treatment options due to heightened motivation to minimize possible risks of pharmacotherapy to the fetus. 84,85 While patient preference and motivation are among the predictors of treatment success and key factors in treatment selection, patients should be clearly informed of the risks of maternal withdrawal symptoms, and offered frequent monitoring and reassessment.
# Pharmacotherapies for withdrawal management
Common pharmacotherapies for alcohol withdrawal in non-pregnant patients consist of benzodiazepines; anticonvulsants including carbamazepine, gabapentin, and valproic acid; and alpha-2 adrenergic agonists. There is a dearth of research and evidence-based guidance pertaining to pharmacotherapeutic withdrawal management in pregnant individuals. This is partly due to the ethical concerns restricting clinical investigation in this population, particularly given the suggested risk of teratogenicity associated with a number of common withdrawal management medications in animal studies. 9 A 2009 Cochrane review of pharmacotherapies found no randomized or quasi-randomized studies of pharmacologic interventions for pregnant participants enrolled in alcohol treatment programs and concluded that considerably more research was needed to assess the safety of available treatments in this population. 86 As reviewed below, the limited research on the safety of pharmacological options for withdrawal management during pregnancy has been focused almost exclusively on benzodiazepines. However, in response to emerging evidence in support of gabapentin for this indication, this supplement also provides a brief overview of the safety and efficacy of this medication. Considered as an aggregate, the literature summarized in this section suggests that the harms of acute alcohol withdrawal surpass the potential risks associated with its pharmacological treatment with these agents. See Table 5 below for a comparative overview of the clinically relevant characteristics of benzodiazepines and gabapentin. Appendix 3.C provides general prescribing information and sample dosing protocols for the medications reviewed in this section.
Refer to the Guideline for a comprehensive review of evidence concerning all evidence-based pharmacotherapies for alcohol withdrawal in the general population.
# Benzodiazepines
Benzodiazepines have the most substantial history and supportive evidence in alcohol withdrawal management for pregnant and non-pregnant populations. 4,87 Numerous systematic reviews have established the superior efficacy of this class of medications in suppressing alcohol withdrawal symptoms and preventing withdrawal seizures and delirium tremens. 4,[88][89][90] Early case-control studies on the use of benzodiazepines in pregnancy suggested that these medications may be associated with increased risk of fetal malformations. 3,80 However, a number of more recent cohort studies found no increased risk of congenital malformations, cardiac defects, or neurobehavioural problems among children born to people who used benzodiazepines during pregnancy in comparison to the general population. 3,91,92 A 2011 systematic review and meta-analysis including nine case-control and cohort studies also examined the correlation between maternal benzodiazepine use and major fetal malformation. 93 The authors also concluded that, in sum, benzodiazepines did not appear to increase teratogenic risk (OR, 1.07 [95% CI 0.91 to 1.25]), although the case-control studies demonstrated an increased risk of cleft lip. 93 Currently, the use of benzodiazepines during pregnancy holds a category D designation by the US Food and Drug Administration (FDA), which denotes evidence of risk to human fetuses with prolonged use. 9 This categorization is attributed to evidence suggesting an increased risk of cleft lip.9 However, it is important to note that the duration of alcohol withdrawal management is typically 5-7 days, which does not constitute prolonged use. Additionally, the majority of studies concerning the fetal safety of benzodiazepine treatment in pregnancy do not account for the purpose, duration, and dose of maternal benzodiazepine use. 3 One case-control study examining the fetal outcomes of short-term (generally 3 weeks) diazepam treatment during pregnancy found that short-term exposure to this medication presented no detectable teratogenic risk to the fetus. 94 Additional considerations for benzodiazepine use during the final trimester of pregnancy include "floppy infant syndrome" and neonatal benzodiazepine withdrawal. Floppy infant syndrome is characterized by a constellation of treatable symptoms such as mild sedation, hypotonia, reluctance to suck, apneic spells, and cyanosis that can persist for hours to months after birth.3 Neonatal benzodiazepine withdrawal symptoms may include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, diarrhea, and vomiting. 3,95 While there is no conclusive data regarding the specific type of benzodiazepine that would prevent the development of these symptoms, some reports suggest that short acting benzodiazepines (e.g., lorazepam) may be preferable in the third trimester for minimizing the duration and severity of neonatal benzodiazepine withdrawal. 80,95 Overall, considering the well-established risks of untreated withdrawal, the literature suggests that potential benefits of benzodiazepine use for the treatment of acute alcohol withdrawal outweigh its risks, particularly in the case of severe AUD where the prevention of seizures and delirium tremens is a key consideration. In reference to these findings, the 2014 World Health Organization guidelines recommend management with a benzodiazepine, titrated to the severity of withdrawal. 4
# Gabapentin
The effectiveness of gabapentin for alcohol withdrawal management in non-pregnant patients at low risk of developing seizures and delirium tremens is demonstrated by a growing evidence base. To date, results from two RCTs (n=126) indicate that gabapentin (at total doses of 1200mg/day) is as effective as benzodiazepines for the outpatient management of mild to moderate alcohol withdrawal symptoms, and may yield additional benefits in terms of improved daytime alertness, sleep quality, anxiety, and mood. 96,97 With respect to safety for use during pregnancy, gabapentin is listed as a category C drug by the FDA; there is no evidence suggesting that this medication is teratogenic in humans, though some dose-dependent adverse effects to the fetus have been observed in animal studies. 9,98 Recent evidence suggests that the use of this medication for withdrawal management during pregnancy is safe. 9,45 Clinicians should be mindful that this medication is not suitable for preventing severe complications of withdrawal (i.e., seizures and delirium tremens). Therefore, it is recommended to assess the patient's risk of severe complications of withdrawal using the PAWSS tool prior to selecting between benzodiazepines and gabapentin.
# Caution regarding other agents
Alternative options for the management of alcohol withdrawal in the non-pregnant population include other anticonvulsants (i.e., carbamazepine, valproic acid) and alpha-adrenergic agonists including clonidine (See Guideline Chapter 4). However, due to the lack of sufficient supporting evidence, and reported risk of teratogenicity, these agents should not be considered for pregnant patients unless acute withdrawal constitutes a life-threatening emergency and the use of recommended options is contraindicated. 9 Safety for use during pregnancy 9 FDA category D:
• Evidence of cleft lip and "floppy infant syndrome" in human studies
• Potential benefits may outweigh risks FDA category C:
• No adequate human studies
• Possible risk extrapolated from animal models include preterm birth, low birth weight, and neonatal withdrawal symptoms
• Potential benefits may outweigh risks
# Efficacy
Superior efficacy for suppression of withdrawal symptoms compared to placebo and other active treatments. 90 Superior efficacy for prevention of seizures compared to placebo and active treatments. [88][89][90] Emerging data (2 RCTs) showing equal efficacy to benzodiazepines in suppressing mild to moderate withdrawal.
May be superior for treatment of insomnia and anxiety symptoms. 96,97 Insufficient evidence for prevention of seizures or delirium tremens. Less common side effects include changes in skin colour, nausea, headache, blurred vision, tremors, hypotension, GI disturbances. Memory loss may also occur.
Higher doses may cause ataxia, slurred speech and drowsiness.
Favourable side effect profile in comparison to other anticonvulsants.
# Safety for breastfeeding
Sedation and poor weight gain in infants have been rarely reported. Short acting agents (e.g., lorazepam, oxazepam) may be preferable. Overall, deemed compatible with breastfeeding by WHO and ACGC. 4,101 Small number of case reports reported no adverse neonatal effects. Infants should be monitored for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. 102 Other considerations
Potential for non-medical use, diversion, and dependence.
Potential for drug-drug interactions leading to excess sedation, impaired psychomotor and cognitive functioning.
Potential for non-medical use, diversion, and dependence.
Toxicity profile parallels that of alcohol.
Easy to transition from withdrawal management to long-term relapse prevention.
* Note: This information is directly adapted from the product monographs of these medications. The fact that benzodiazepines are excreted into human milk was cited as a reason for caution during breastfeeding. See Section 7.2.2 for a summary of evidence supporting the compatibility of these medications with breastfeeding.
5 Continuing Care
# Pharmacotherapy
There are no clinical trials evaluating the possible options for the pharmacological management of AUD during pregnancy. The meagre existing literature on this topic is extrapolated from animal studies and evidence pertaining to non-pregnant populations. A recent practice guideline by the American Psychiatric Association recommends against pharmacotherapeutic interventions for AUD during pregnancy, except for the management of alcohol withdrawal. 9,45 This is due to the risk of teratogenicity associated with many evidencebased AUD medications. In line with available guidelines, all patients with AUD should be offered evidencebased psychosocial treatment interventions and supports for AUD. However, the risks of pharmacotherapy to the fetus should be weighed against risk of relapse to alcohol use in the case of pregnant patients with moderate to severe AUD.
Naltrexone and acamprosate are considered first-line AUD treatment agents for non-pregnant patients. This section provides an overview of the safety and efficacy of these treatments for pregnant individuals in reference to available literature. Gabapentin is also reviewed as a potential alternative option for this population. Overall, it is suggested that the benefits of preventing relapse outweigh the risk of possible effects of these agents on the fetus. 9 See Table 6 below for a comparative summary of the characteristics of these medications. Sample dosing protocols and PharmaCare coverage information are provided in Appendix 4. Additionally, please refer to the Guideline for a comprehensive review of all evidence-based AUD pharmacotherapies for the general population.
# Naltrexone
Naltrexone is a mu-opioid receptor antagonist shown to block euphoria associated with alcohol consumption. 103 It is hypothesized to work by diminishing the rewarding effect of alcohol in the brain following its consumption, as well as reducing cravings for alcohol in some individuals. 103 This blunting effect on neural reward pathways is consistent with research findings that naltrexone is particularly effective in preventing a return to heavy or ongoing drinking. 104 Naltrexone has a well-established evidence base for safety and efficacy in the treatment of AUD among non-pregnant populations. 105 Notably, a 2010 meta-analysis including 50 RCTs (n=7793 participants) reported that 17% fewer participants treated with naltrexone engaged in heavy drinking, and had 4% fewer drinking days per month when compared to the placebo group. 104 Participants treated with naltrexone also showed a greater reduction in heavy drinking days (-3.25%) and the amount of alcohol consumed (-10.83g) compared to the placebo group. 104 The FDA has classified naltrexone as a category C medication for use during pregnancy, meaning that there are no adequate human studies on the effects of naltrexone on the fetus, while animal studies have demonstrated mild adverse effects on the fetus. 3,9 Animal studies on in utero exposure to naltrexone have found that this medication crossed the placenta and was associated with reduced sensitivity of the offspring to morphine, and possibly with early fetal loss and increased birth weight. 9 However, limited evidence pertaining to the use of naltrexone for the treatment of opioid use disorder has demonstrated no adverse effects on pregnancy outcomes, although the long-term developmental effects of in utero exposure to this medication are not known. 106,107
# Acamprosate
Acamprosate is believed to restore the balance between glutamate-mediated excitation and GABA-mediated inhibition of neural activity, and reduce general neuronal hyperexcitability. 103 Together, these modify responses to alcohol-related cognitive cues. 103 Acamprosate has been used for the treatment of AUD for several decades in Europe prior to its approval in North America, and has an established evidence base for safety and efficacy in non-pregnant populations. [109][110][111][112][113] A 2010 meta-analysis including 24 RCTs (n=6915) reported that acamprosate reduced the risk of return to any drinking by 14% and increased the cumulative duration of abstinence by 11 days compared to placebo. 111 In addition, the authors found that the treatment effects of acamprosate persisted at 3-12 months after treatment discontinuation. 111 Acamprosate is classified as a category C medication. Until recently, human data on the impact of in utero exposure to acamprosate was limited to one observational personal communication reporting one case of cleft lip among 18 pregnancies, while animal studies show dose-related defects in offspring including retinal dysplasia, iris malformation, hydronephrosis, and increased rate of stillbirth. 9,114 However, more comprehensive supportive evidence was presented by a 2019 population-based retroactive cohort study from New South Wales, Australia, comparing maternal and neonatal health outcomes of acamprosate-exposed pregnancies (n=54) to those of untreated alcohol-exposed (alcohol comparison group; n=162) and non-exposed (community comparison group; n=162) pregnancies. 115 Authors reported that rates of hospital admissions during pregnancy and 42 days post-partum in acamprosate-treated individuals were not significantly different from the community comparison group (adjusted rate ratio [RR] = 0.85, 95% CI = 0.65-1.11), but were significantly lower compared with the alcohol comparison group (adjusted RR = 1.26, 95% CI = 1.00-1.60).115 Acamprosateexposed neonates were not significantly different from the alcohol comparison group or the community comparison group in terms of birth weight, proportion of small-for-gestational-age neonates, or incidence of congenital abnormalities (including FASD). 115 It should also be noted that this study only included individuals who were exposed to acamprosate for more than 30 days during pregnancy in the case group, so that the results would be applicable to patients receiving pharmacotherapy for continuing AUD care. Available data suggests that the benefits associated with the use of this medication during pregnancy may outweigh the risks of continued alcohol consumption during this period. 9,114,115
# Gabapentin
Emerging evidence for the efficacy of gabapentin in preventing relapse in non-pregnant populations is derived primarily from three placebo-controlled clinical trials. Two RCTs comparing 7-day gabapentin treatment to placebo found that gabapentin was more effective in reducing alcohol craving, the number of drinks per day, and percentage of heavy drinking days, and increasing the number of days abstinent. 116,117 Most recently, a 12-week trial of 150 participants in an outpatient setting demonstrated that gabapentin significantly improved rates of cumulative abstinence (estimated number needed to treat [NNT] of 8) and heavy drinking (estimated NNT of 5), with no difference in adverse events compared to placebo. 118 A distinctive advantage of gabapentin is that it has been found effective for outpatient withdrawal management in patients at low risk of developing severe complications of withdrawal (PAWSS<4), and patients who complete withdrawal using this medication may have the option to continue its use beyond the acute withdrawal period as part of a long-term treatment strategy without the risk of disruption to care. 119 In terms of safety for use during pregnancy, gabapentin is a category C medication which indicates evidence of risk to the fetus in animal studies. Available animal models reveal a higher risk of embryotoxicity during organogenesis, but this is purported to occur at supratherapeutic doses that would not typically be seen in humans. 120 In a limited 2013 prospective cohort study with pregnant participants, no fetal malformations were observed, but the authors reported a possible association with preterm birth and low birth weight. 121 Clinicians considering gabapentin for pregnant patients should be mindful of the risk of non-medical use and dependence associated with this medication. [122][123][124][125] It is also important to note that concurrent use of alcohol, opioids, or other CNS depressants with higher doses of gabapentin increases the risk of respiratory depression, profound sedation, syncope, and death. 100 While available evidence suggests that these risks are significantly lower than those associated with untreated AUD, [126][127][128][129] clinicians should arrange frequent follow-ups and monitor patients for non-medical use, dependence, diversion, and concurrent alcohol or opioid use. Particular attention is advisable in the case of patients who are prescribed multiple medications for concurrent conditions. 123 Gabapentin withdrawal has also been reported in a number of infants born to patients who used gabapentin; this condition is treatable, though it may require admission to the neonatal intensive care unit. 9,130
# Caution regarding other agents
The use of other AUD medications, such as topiramate and disulfiram, during pregnancy is not recommended.
A preliminary report on 203 prospectively followed pregnancies exposed to topiramate found a high rate of major congenital malformations among neonates. 131 Similarly, sparse evidence associates maternal disulfiram use with fetal limb reduction. 132 There is no evidence-based guidance regarding patients who are stable on one of these medications prior to becoming pregnant. In these cases, clinicians should carefully consider the risks and benefits of transitioning patients to alternative treatment options in communication with an addiction specialist and the patient. 45 Where possible, transitioning the patient to safer pharmacotherapies (i.e., naltrexone, acamprosate, or gabapentin) or psychosocial treatment interventions and supports may be appropriate. Additionally, patients of childbearing capacity who are prescribed one of these medications should be informed of possible risks in the event of pregnancy and advised of the importance of contraception in the course of treatment. Higher doses may cause ataxia, slurred speech, or drowsiness.
Favourable side effect profile in comparison to other anticonvulsants.
# Concurrent alcohol use
Safe to start while patients are using alcohol, but may be more effective and side effects minimized if started following completion of withdrawal.
Safe to start while patients are using alcohol, but may be more effective if started following completion of withdrawal management.
Higher than therapeutic dose and use concurrent with alcohol increases the risk of respiratory depression, profound sedation, syncope, and death.
# Breastfeeding
Minimally excreted into breast milk. Limited case studies show no adverse neonatal effects. 135,136 Not a barrier to breastfeeding.
No adequate human studies.
Deemed "probably safe" in pharmacokinetic investigations. 45,137 Small number of case reports reported no adverse neonatal effects.
Infants should be monitored for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. 102 * This information is directly adapted from the product monographs of these medications, where lack of sufficient data pertaining to pregnancy and lactation was cited as cause for caution. Section 7.2.3 for a review of available information on the safety of AUD pharmacotherapy for breastfeeding.
# Psychosocial treatment interventions
Validated psychosocial treatment interventions for AUD in pregnancy do not differ from those offered to the general population. There is modest RCT evidence supporting the effectiveness of cognitive behavioural therapy (CBT), motivational interviewing (MI), and contingency management during pregnancy. 3 A 2009 Cochrane review of psychological and educational interventions for reducing alcohol use in pregnancy (4 RCTs, n=715) concluded that there was insufficient data on the effectiveness of these interventions for reducing alcohol consumption or supporting abstinence. 57 However, the authors cited inconsistent results, small sample sizes, high risk of bias, and heterogeneity in intervention types and outcomes assessed across trials as confounding factors hindering evidence synthesis. The authors also acknowledged that the existing literature supports the usefulness of these psychosocial interventions in increasing abstinence from alcohol use and reducing alcohol consumption among pregnant individuals. 57 Accordingly, most clinical practice guidelines recommend that all pregnant individuals with AUD be offered psychosocial treatment interventions to support abstinence or reduced alcohol consumption. 138 It is important to note that MI, CBT, and CM are well-studied in the context of substance use disorders among the general populations, and have a significant track record of use in a wide range of settings and patient populations. 139,140 For a comprehensive review of evidence on the efficacy of these interventions, see the corresponding sections of the Guideline. See Appendix 5 for an instructive overview of MI.
# Considerations for Bed-Based Treatment Facilities
Although the evidence supporting the efficacy of bed-based treatment facilities e for substance use disorder is relatively limited, guidelines pertaining to pregnant individuals cite residential settings as potentially beneficial for patients who require more intensive medical care and support to improve health and pregnancy outcomes. 120,141 These facilities may also be appropriate for patients with comorbidities and complex medical and psychosocial needs, as well as those who have unstable housing and social circumstances. Decisions regarding the selection of this treatment setting should be made in collaboration with, and with the consent of, the patient.
The following factors should be considered when selecting a treatment facility for pregnant patients:
• Capacity to provide pharmacological treatment for AUD as directed by the patient's prescriber
• Capacity to provide wraparound medical and psychosocial support for concurrent conditions as well as AUD
• Access to comprehensive specialist pregnancy and prenatal care
• If applicable, access to post-partum and neonatal care, as well as onsite accommodation or visitation provision for patient's child(ren) and family. 142 Keeping parents and children together should be among primary considerations when selecting a treatment setting for this population.
Effective discharge planning is also crucial to ensure positive long-term bed-based treatment outcomes. 143,144 The treatment facility should communicate with outpatient care providers and relevant community-based services to ensure the continuation of care and support after discharge. It may be necessary to intensify support and monitoring during transition between settings as patients are particularly vulnerable to relapse to alcohol use in these periods. Every effort should be made to ensure patient's access to safe and stable housing prior to discharge. 142 Several systematic reviews have concluded that there is insufficient research evidence to recommend an optimal screening/rescreening interval for alcohol use in adults and youth. 127 In the absence of robust evidence, most public health agencies, including the Canadian Task Force on Preventive Health Care 139 and the Canadian Paediatric Society, 140,141 recommend screening adults and youth on an annual basis. This is for reasons of convenience -alcohol screening can be combined with other components of a routine medical exam or preventive health screening -and to detect changes, as an individual's alcohol use can shift from low-to high-risk over a one-year period. In line with this, a U.S. study found that use of annual substance use screening intervals identifies a modest number of incident cases of high-risk use in adult primary care patients. 142 Of 1014 patients who initially screened negative for high-risk alcohol or drug use, 34 (3.4%) screened positive for high-risk use when screened again one year later, with the majority (23/34) meeting criteria for high-risk alcohol use. 142
e Also referred to as "residential treatment" or "inpatient treatment" facilities in the literature.
7 Post-partum Considerations
# Rooming-in and skin-to-skin contact
Rooming-in and skin-to-skin contact during the immediate post-partum period is associated with healthy parent-infant bonding leading to improved long-term developmental outcomes, higher likelihood of breastfeeding, improved access to integrated care and initial childcare education in a family-centered setting, and reduction of maternal and neonatal distress and alcohol withdrawal symptoms. 4,145,146 Skin-to-skin contact and gentle rocking of the infant in a quiet environment are also widely recommended interventions for management of neonatal withdrawal symptoms. 4,136 Thus, in line with standards of care pertaining to the general populations, healthcare facilities providing obstetric care should have a rooming-in protocol in place whereby the monitoring and treatment of patients with AUD and their infants can take place without interrupting nursing and parent-infant contact.
# Breastfeeding
Breastfeeding f is consistently recommended in guidelines pertaining to neonatal care, including care for infants born to parents in treatment for substance use disorders. 4 This is in view of a robust evidence base demonstrating that breastfeeding is the ideal means of supporting the healthy growth and development of a child while promoting parent-infant bonding and reducing maternal stress. 4 In the case of nursing parents who use alcohol or are receiving pharmacotherapy for AUD, the risks and benefits of breastfeeding should be considered on an individual basis. This section provides a brief overview of the pharmacokinetics of alcohol and AUD pharmacotherapies (i.e., naltrexone, acamprosate, and gabapentin) during lactation and discusses neonatal and developmental safety concerns associated with the maternal use of these agents while breastfeeding.
# Alcohol and lactation
Available research on the effects of maternal alcohol use during lactation on the neonate is limited and contradictory. While there is some evidence suggesting that occasional drinking while breastfeeding does not have significant adverse effects on nursing infants, there is insufficient investigation and lack of consensus regarding the long-term consequences of heavy maternal alcohol use during breastfeeding. Alcohol is transferred into breast milk; the alcohol concentration in breast milk is known to resemble that in maternal blood, and the amount of alcohol transferred to nursing infants during feeding is approximately 5 to 6% of the weight-adjusted dose consumed by the nursing parent. 147,148 Thus, some studies have suggested that, even in the case of binge drinking, the infants may not be subjected to clinically relevant amounts of alcohol 148,149 while others associate heavy maternal alcohol use during lactation with decreased rate of infant growth and psychomotor development. 149,150 A systematic review of 11 studies (n=36) investigating alcohol's effect on nursing neonates found that infants breastfed by mothers who had consumed alcohol prior to feeding temporarily ingested 20% less milk, arguably as a result of reduced milk ejection reflex. 148 Temporary sedation and changes in sleeping patterns in the neonate have also been documented. 4,148 In view of these effects and the lack of conclusive evidence on the possibility of long-term developmental risk, most guidelines strongly recommend that breastfeeding mothers refrain from consuming alcohol during lactation. 4,147 However, many guidelines also emphasise that alcohol use is not necessarily a contraindication to breastfeeding. For example, the World Health Organization lists alcohol use among maternal conditions during which breastfeeding may still continue based on a case-by-case analysis of benefits and risks. 151 Breastfeeding patients who continue consuming alcohol should be strongly advised to reduce drinking and provided with education to schedule breastfeeding and alcohol use to ensure alcohol is eliminated from breastmilk at the time of feeding or storage of breastmilk. In the case of moderate drinking (i.e., 1-2 standard drinks in a day), guidelines generally recommend waiting 2-2.5 hours after drinking to store breastmilk or breastfeed. 4 However, the time required for the elimination of alcohol is dependent on the amount of alcohol consumed; alcohol appears to be eliminated from breastmilk more slowly in the case of daily heavy alcohol use (i.e., more than two standard drinks per day), and there is a decrease in the length of time that mothers can breastfeed their infants, resulting in significant risk. 152 Therefore, the risk of breastfeeding may outweigh its benefits in the case of chronic heavy maternal alcohol use.
See Appendix 6 for a sample patient information handout of alcohol use and safer nursing practices.
# Alcohol withdrawal pharmacotherapy and lactation
Benzodiazepines: All major classes of benzodiazepines are known to be excreted into human milk in varying but generally low concentrations. 95 Limited evidence characterises possible adverse effects of neonatal exposure to benzodiazepines through human milk as lethargy, sedation, and reduced sucking ability which may lead to poor weight gain. 95,[153][154][155] However, available literature suggests that these adverse effects are rare and mild. [150][151][152] For example, in a 2012 retrospective cohort study (n=124) examining the neonatal impact of maternal benzodiazepine use during lactation, adverse outcomes-namely sedation-were observed in two (1.6%) infants, both of whom were breastfed by participants who used benzodiazepines in conjunction with other CNS depressants. 154 Similarly, a 2014 review of 16 studies on the impact of neonatal benzodiazepine exposure found rare reports of sedation, predominantly associated with longer-acting benzodiazepines (e.g., diazepam, clonazepam). 155 The authors emphasize the absence of serious negative effects among infants exposed to relatively short acting drugs and suggest that lorazepam and oxazepam may be among preferable agents for breastfeeding patients.
There findings are in line with guidelines by the WHO and the American College of Obstetricians and Gynecologists which deem benzodiazepines compatible with breastfeeding unless the infant's ability to metabolize the medication is impaired. 4,101 Gabapentin: The safety of gabapentin for breastfeeding has been investigated by a small number of case reports involving a range of doses and durations of treatment, and no significant adverse effects were reported. 102,156 Limited information indicates that maternal doses of gabapentin up to 2.1g daily produce relatively low levels in infant serum. 102 Accordingly, an expert consensus guideline indicates that gabapentin is an acceptable medication during lactation. 102 However, the authors advise to monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. 102
# AUD pharmacotherapy and lactation
There are no controlled studies and limited human data on the safety of maternal use of naltrexone, acamprosate, and gabapentin during breastfeeding. On account of this lack of evidence, careful assessment of benefits and risks, fully informed patient consent, and close monitoring of the infant is advised when considering these medications for nursing parents.
Naltrexone: Limited data indicate that naltrexone is minimally excreted into human milk. A case study cited by the Drugs and Lactation Database involves two 1.5-month-old infants breastfed by individuals who were receiving 50mg of oral naltrexone daily during pregnancy and lactation. 135,136 The authors reported no naltrexone-related adverse effects in the infants. Accordingly, while the Health Canada-approved product monograph for naltrexone recommends caution with regards to the use of this medication by nursing parents, 133 the benefits of breastfeeding may outweigh potential risks of neonatal exposure to naltrexone.
Acamprosate: Acamprosate's effect on human breastmilk has not been studied. In animal studies, this medication was excreted in the milk of lactating rats. In reference to this lack of evidence, the product monograph of acamprosate lists pregnancy and breastfeeding among contraindications to the use of this medication. 134 However, available guidance on the neonatal risks of pharmacotherapies during lactation suggests that the use of this medication during breastfeeding is "probably safe" for neonates. 45,137 Gabapentin: Please Section 7.2.2, Alcohol withdrawal pharmacotherapy and lactation for a summary of evidence supporting the compatibility of gabapentin with breastfeeding.
# Child Protection
The prenatal period:
Clinicians in Canada do not have a legal obligation to report prenatal substance use or substance use during the course of pregnancy. Any antenatal referrals or reports should be made with the informed consent of the patient.
Integrated care programs and collaborative long-term support planning in the course of pregnancy may foster family stability and enable new parents to play an active role in their child's care with the help of resources available in her family and community. 157,158 The involvement of expecting parents, supportive family members, public health and community-based resources, and services provided by the BC Ministry of Children and Family Development (MCFD) prior to childbirth can help improve pregnancy outcomes. However, the involvement of these services should be considered on a case-by-case basis with the collaboration and consent of the pregnant patient.
# The neonate (and other children in the custody of patient):
Maternal substance use alone is not grounds for the apprehension of an infant or referral to MCFD. However, the health care team is legally obligated under Section 14 of the Child and Family and Community Service Act (CFCSA) to report child protection concerns to the MCFD. Prior to making a report, clinicians should refer to Section 13 of the CFCSA for a comprehensive outline of circumstances under which notifying MCFD is warranted. The decision to report should be made on a case-by-case basis in consultation with the full health care team. It should be noted that the apprehension of infants is associated with a range of negative long-term social and health outcomes for the mother and child. [159][160][161] If a child is temporarily apprehended during the immediate post-partum period, mothers should be offered appropriate supports to ensure that the outcomes they experience after the loss of their child do not become barriers to reunification. 159
# Appendices Preface
The following appendices have been provided to support clinical practice and were developed through discussion and consensus of the guideline committee. The practice guidance herein was informed by review of existing national and international evidence-based clinical practice guidelines issued by recognized addiction medicine organizations and authorities. Where appropriate, Health Canada-approved drug product monographs were consulted to ensure compliance with provincial and national safety regulations and standards for practice.
Recommendations adhere to the CPSBC Professional Standards and Guidelines for Safe Prescribing of Drugs with the Potential for Misuse/Diversion (www.cpsbc.ca/files/pdf/PSG-Safe-Prescribing.pdf).
# Appendix 1 Alcohol Use Screening
In line with available guidelines, this document emphasises the key role of universal and regular substance use screening in health promotion, and specifically recommends screening pregnant patients for alcohol use in the first prenatal assessment (or at the first available opportunity) and re-screening routinely throughout pregnancy and post-partum and as clinically relevant. This appendix provides an instructive overview of the screening process in three steps: Step 1-Starting the Conversation using the Low-Risk Alcohol Drinking Guidelines, Step 2-Screening for High-Risk Alcohol Use, and Step 3 -Assessment and Diagnosis of an AUD.
# Step 1 Starting the Conversation
Introducing the topic of alcohol use to patients in a non-judgmental, conversational, and clear manner can foster a candid conversation and improve the accuracy of self-reported alcohol use. The following strategies are recommended to establish comfort and trust prior to beginning screening questions.
# Use Canada's Low-Risk Alcohol Drinking Guidelines as a Communication Tool
Briefly reviewing Canada's Low-Risk Alcohol Drinking Guidelines (LRADG) handout can help guide conversations toward alcohol use screening. Clinicians may use the LRADG handouts to provide patients with general information regarding the risks of alcohol use to the patient and fetus while clarifying concepts that would enhance the accuracy of alcohol screening, such as what is meant by "alcoholic beverages" and standard drink sizes.
# Sample Script:
" Have you heard about Canada's Low-Risk Alcohol Drinking Guidelines? I talk to all of my patients about these guidelines. They contain important information about safer alcohol use that everyone needs to know. "
# Secure consent and assure the patient of the confidentiality of the conversation
Patients' reluctance to share information about their alcohol use can be a barrier to obtaining accurate screening results and establishing an effective therapeutic relationship for next steps. It is important to::
• Ask the patient's permission before screening • Assure the patient of the confidentiality of the information they share • Emphasize that you ask all your patients about alcohol use
# Sample Script:
" I regularly ask my patients about alcohol and other substance use. Would it be alright for us to talk about this now?"
" Now that we've talked about some of the effects of alcohol, would you mind if I ask you some questions about your alcohol use?"
Step 2 Screening for High-Risk Alcohol Use
In consideration of the time constraints reported by clinicians providing prenatal care, this guideline has recommended a simplified and stepped screening method using a single alcohol screening question (SASQ) to identify alcohol use in pregnant individuals. In addition to a brief sample script for this abbreviated screening process, this appendix presents alternative screening methods validated for pregnant patients. Clinicians are encouraged to select a screening approach based on their clinical experience and judgement.
# SASQ sample script
" Do you sometimes drink beer, wine, or other alcoholic beverages?"
No: Screening is complete.
• Offer encouragement.
• Review the LRADG, emphasising that abstinence is recommended during pregnancy.
• If patient reports not drinking, ask about their alcohol use history:
• Offer encouragement to patients with a personal or family history of AUD who have stopped drinking since they have become pregnant; ask if they have encountered challenges in the process, and offer encouragement and support as needed.
• Rescreen annually frequently depending on personal and family history.
# Yes:
Positive result for high-risk drinking.
• Ask about the patient's average weekly alcohol consumption in standard drinks over the past three months to assess risk and determine whether a diagnostic test is needed (record amounts for follow-up sessions):
• Ask patient: "On average, how many days a week do you drink alcohol?"
• Ask patient: "On a typical drinking day, how many drinks do you have?"
• (Drinking days x number of drinks per drinking day = weekly average).
• If deemed useful, clinicians may choose to use an additional pregnancy-validated screening tool (e.g., AUDIT, AUDIT-C, T-ACE, TWEAK) to assess risk prior conducting the diagnostic test (See below for a review of additional screening tools).
• If patient's self-reported drinking is above low-risk limits for non-pregnant female adults, or if their responses are vague or inconsistent with the clinician's observations, proceed to diagnosis and assessment for AUD (Step 3).
• All patients screening positive for alcohol use should receive brief intervention (Appendix 2).
# Additional screening tools AUDIT and AUDIT-C
The Alcohol Use Disorders Identification Test (AUDIT) was developed by the World Health Organization (WHO) to assist in the early identification of "hazardous" g or "harmful" h alcohol consumption. The AUDIT is a well-studied and commonly used alcohol screening tool which has been validated for a wide range of settings and populations, including pregnant individuals. This tool consists of 10 questions that may enable the administrator to obtain relatively comprehensive information about a patient's alcohol consumption patterns at present and over the past year. 5 Each question is assigned a score between 0-4 that corresponds to frequency of occurrence, resulting in a total score ranging from 0 to 40 points. For adult patients, a score of 8 or higher is associated with "problem drinking, " while 13 or more indicates alcohol dependence. This AUDIT questionnaire takes approximately 3-4 minutes to complete and score.
The condensed AUDIT-Consumption (AUDIT-C) tool, which consists of three questions focusing on frequency and quantity of alcohol use, uses sex-specific cut-off points: in adult patients who were assigned female at birth, a score of 3 or higher indicates hazardous or harmful drinking. This condensed questionnaire takes approximately one minute to complete and score.
The WHO and the US Preventive Health Services Task Force recommend use of the AUDIT or AUDIT-C for detection of hazardous or harmful drinking in all adult primary care patient populations. 61,162,163 Similarly, a recent article examining the potential of adequate alcohol screening and harmonized data collection for the prevention of FASD has found that the AUDIT-C contains the required elements for clinicians to ascertain pregnant patients' pattern of alcohol use in a relatively compact format. 164 However, provider-level barriers, including lack of experience and time constraints (which are of particular concern in the context of pregnancy), have been cited as barriers to more widespread uptake and use of these tools in primary care. 11,48,[165][166][167] As an alternative, self-administered print and electronic versions of these questionnaires are available and can be provided to patients to complete in advance of scheduled clinical appointments or while they are waiting to be seen. Self-administered versions of the AUDIT and AUDIT-C appear to be as effective as clinician-administered screening for the identification of hazardous or harmful alcohol use. 168 Another potential limitation of the AUDIT and AUDIT-C is that the low-risk limits and standard drink sizes used in these instruments are slightly different from those indicated in Canada's Low-Risk Alcohol Drinking Guidelines. The US Centers for Disease Control and Prevention have made adaptations in the standard drink size and cut-off points for use in the United States of America; a similar adjustment in accordance to the LRADG would significantly enhance the utility of AUDIT-C as a validated compact tool for alcohol screening during pregnancy. 164 The AUDIT and AUDIT-C questionnaires are provided in Boxes 1 and 2 below.
g Hazardous use: A pattern of alcohol use that increases the risk of harmful physical and/or mental health consequences as well as social consequences for the individual. Hazardous use occurs in the absence of addiction or alcohol use disorder. h Harmful use: A pattern of alcohol use associated with health consequences and/or that causes damage to health. Damage may be physical or mental.
Harmful use commonly, but not invariably, has adverse social consequences, but social consequences alone are not sufficient to justify a diagnosis of harmful use. Harmful use occurs in the absence of addiction or alcohol use disorder. (ICD-10 code, previously known as "non-dependent use" in .
# Box 1 The Alcohol Use Disorders Identification Test ( AUDIT ) 169
Read questions as written. Record answers carefully. Begin the AUDIT by saying "Now I am going to ask you some questions about your use of alcoholic beverages during this past year." Explain what is meant by "alcoholic beverages" by using local examples of beer, wine, vodka, etc. Code answers in terms of "standard drinks". Place the correct answer number in the box at the right.
1. How often do you have a drink containing alcohol? In female patients, a score of 3 or more is considered positive for hazardous drinking.
If score is positive, proceed to diagnosis and assessment for AUD.
Total score:
# T-ACE
The Tolerance, Annoyed, Cut down, Eye opener (T-ACE) is the first screening tool validated for pregnant patients, and is currently recommended by the American College of Obstetrics and Gynecology and the National Institute of Alcohol Abuse and Alcoholism. 60 This tool is regularly used as a part of primary care for this population due to its brevity, clarity, and ease of administration. 60 The T-ACE was developed through a substantial simplification of the 25-question Michigan Alcohol Screening Test (MAST) into a 4-item questionnaire which has a similar structure to the CAGE tool. 171 The T-ACE takes approximately one minute to conduct and score. The T-ACE questionnaire is provided in Box 3.
# Box 3 The T-ACE Tool T-ACE
# Questions Points
Tolerance How many drinks does it take to make you feel the first effect (before pregnancy)? 3 or more = 2 points
# Annoyed
Have people ever annoyed you by criticizing you about your drinking?
Yes = 1 point
# Cut down
Do you sometimes feel the need to cut down your drinking? Yes = 1 point Eye Opener Do you sometimes take a drink in the morning when you first get up?
Yes = 1 point Patients who score 2 or higher on the T-ACE should be referred for further assessment for alcohol use disorder.
# TWEAK
Tolerance, Worry, Eye-opener, Amnesia, Cut down (TWEAK) is a 5-question screening tool developed specifically for pregnant patients. As a slight variation of the T-ACE, TWEAK combines features from CAGE and MAST. This method is suitable for use in primary care settings and takes less than 2 minutes to administer and score. The result is calculated on a 7-point scale, and a score of 2 or higher indicates high risk drinking.5,54
The TWEAK questionnaire is provided in Box 4.
# Worried
Have close friends or relatives worried or complained about your drinking in the past year?
Yes = 2 points Eye Opener Do you sometimes take a drink in the morning when you first get up?
Yes = 1 point Amnesia (stands for blackouts)
Has a friend or family member ever told you about things you said or did while you were drinking that you could not remember?
Yes = 1 point Eye Opener Do you sometimes feel the need to cut down on your drinking?
Yes = 1 point
Step 3 Assessment and Diagnosis of an Alcohol Use Disorder
Any continued alcohol use in the course of pregnancy constitutes high-risk drinking and indicates the need for further assessment, and, if appropriate, a structured interview using the DSM-5 criteria to confirm the diagnosis and severity of AUD (see Box 5 below).
Patients who are drinking above low-risk limits but do not have an AUD should receive a brief counselling intervention and be encouraged to discontinue alcohol consumption during pregnancy(see Appendix 2).
Brief intervention alone is not an effective intervention for individuals with an AUD.172 Patients who are diagnosed with an AUD should be offered treatment and care options for withdrawal management and continuing care. Baseline assessment and other withdrawal management considerations, including sample dosing schedules, are outlined in Appendix 3. Appendix 4 offers an instructive overview of continuing AUD pharmacotherapies while Appendix 5 outlines the key principles and considerations for motivational interviewing, a recommended evidence-based psychosocial intervention for AUD.
# Box 5 DSM-5 Diagnostic Criteria for Alcohol Use Disorder 173
A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period, indicates presence of an AUD.
# Sample Clinical Interview Questions 174
In the past year (12 months), have you...
# 1
Alcohol is often taken in larger amounts or over a longer period than was intended Had times when you ended up drinking more, or longer, than you intended?
2
There is a persistent desire or unsuccessful efforts to cut down or control alcohol use More than once wanted to cut down or stop drinking, or tried to, but couldn't?
# 9
Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol Continued to drink even though it was making you feel depressed or anxious, or adding to another health problem? Or, continued drinking after having a memory blackout?
# 10
Tolerance, as defined by either of the following: a) A need for markedly increased amounts of alcohol to achieve intoxication or desired effect b) A markedly diminished effect with continued use of the same amount of alcohol Had to drink much more than you once did to get the effect you want? Or found that your usual number of drinks had much less effect than before?
# 11
Withdrawal, as manifested by either of the following: a) The characteristic withdrawal syndrome for alcohol b) Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms
Found that when the effects of alcohol were wearing off, you had withdrawal symptoms, such as trouble sleeping, shakiness, restlessness, nausea, sweating, a racing heart, or a seizure? Or sensed things that were not there?
Severity: MILD: presence of 2-3 symptoms, MODERATE: presence of 4-5 symptoms, SEVERE: presence of 6 or more symptoms.
Modifiers for the diagnosis include:
• Early remission: After full criteria for AUD were previously met, none of the criteria for AUD have been met (with the exception of craving) for at least 3 months but less than 12 months. • Sustained remission: After full criteria for AUD were previously met, none of the criteria for AUD have been met
(with the exception of craving) during a period of 12 months or longer. • Controlled environment: If the individual is in an environment where access to alcohol is restricted.
# 1.
Ask Be mindful of the impact our behaviors can have on people with a history of trauma:
• Utilize universal precautions for creating a calm and welcoming environment. This includes minimizing noise, decreasing clutter, maintaining a comfortable temperature
• Be aware of internal emotions and thoughts and focus on those that bolster support for the patient • Be aware of your tone of voice and physical space as you introduce yourself and your role and explain the collaborative process planned (Practical note: ensure that you do not physically block the patent's pathway to the door)
• Respond and communicate respectfully (e.g., ask what name they would like to be called, their gender, their partner's gender, and what pronouns they prefer. Validate patient's gender identity, sexual orientation, and preferences for how they wish to be addressed)
• Listen intently to understand responses and their context
• Commit to setting aside your own judgements and thoughts about screening results
• Maintain awareness of your language and tone of voice when responding.
• Screen patient for alcohol use. See Appendix 1 for detailed guidance on screening
• Express appreciation for answering sensitive screening questions
# Advise
• Clearly describe the screening result and its implications on the health of the patient and fetus
• Provide direct personalized recommendations
• Where possible, relay relevant health risks in reference to patient's concerns, including risks to the fetus:
"You are drinking more than is medically safe, and this is putting your health (and the health of the fetus) at risk…."
"I recommend that you cut down or stop drinking."
# Assess
• Engage patient in a brief conversation to assess and encourage motivation, ability to reduce or discontinue their alcohol use at this time • Identifying strengths rather than deficits will enhance change talk; use this approach when discussing how to achieve a higher number if that's their goal
• Recognize that anything the patient is willing to do to address the issue is a step in the right direction
• Connect the patient to others who may be able to meet any needs that are outside your scope of practice
• Reinforce that you are here to help and that this is an ongoing discussion. Ideally, you want patients to always feel comfortable to discuss these issues with you during visits
• Document the agreed upon plan so you can engage in informed follow-up during the next appointment
# Arrange
If patient has met, or made progress towards, planned intervention goal:
• Congratulate, reinforce, and support continued change
• Coordinate care with referral partners if the patient has accessed additional support. Communicate with external/community agencies on patient's progress
• Assess and address any co-occurring medical conditions and mental health symptoms (e.g., insomnia, depression, anxiety) noting that these may improve with reduction in alcohol use
• With the patient's consent, assist with identifying new goals according to patient's intentions, and schedule follow-up appointments
If patient has been unable to meet planned intervention goal:
• Acknowledge that change is difficult • Encourage the patient to consider possible connections between their drinking and other health/social problems they may be experiencing. This exercise may reveal opportunities for change
• If the following measures are not already being taken, consider:
• Referring patient to external or community-based resources (e.g., peer support groups)
• Recommending the involvement of family (if appropriate)
• Offering pharmacotherapy to patients with AUD If the answer to either is YES, proceed to next questions.
# PART B: BASED ON PATIENT INTERVIEW -1 point each 1
Have you been recently intoxicated/drunk, within the last 30 days?
2
Have you ever undergone alcohol use disorder rehabilitation treatment or treatment for alcoholism? (i.e., in-patient or out-patient treatment programs or AA attendance)
3
Have you ever experienced any previous episodes of alcohol withdrawal, regardless of severity?
4
Have you ever experienced blackouts?
# 5
Have you ever experienced alcohol withdrawal seizures?
# 6
Have you ever experienced delirium tremens or DTs?
7
Have you combined alcohol with other "downers" like benzodiazepines or barbiturates, during the last 90 days? 10
Is there any evidence of increased autonomic activity? e.g., heart rate >120 bpm, tremor, agitation, sweating, nausea * Due to the common absence of a BAL the committee has added this modification. Please see next page.
# Interpretation
Maximum score = 10. This instrument is intended as a SCREENING TOOL. The greater the number of positive findings, the higher the risk for the development of alcohol withdrawal syndrome (AWS).
A score of ≥ 4 suggests HIGH RISK for moderate to severe (complicated) AWS; prophylaxis and/or inpatient treatment are indicated.
An online version of the original (unmodified) PAWSS can be found at: https://www.mdcalc.com/predictionalcohol-withdrawal-severity-scale.
# Remarks and Cautions
The PAWSS has not been validated for pregnant patients or outpatient care settings. While this guideline endorses the usefulness of the PAWSS for risk assessment in all settings and populations, it emphasizes that this tool should be used in conjunction with best clinical judgment based on a comprehensive assessment of a patient's medical history and current circumstances, needs, and preferences.
# Modifications
# Question 9 -Blood Alcohol Level (BAL):
The vast majority of outpatient care settings will not be equipped to assess BAL at the point-of-care. As an alternative, the committee recommends that the PAWSS administrator ask patients:
• Have you consumed any alcohol in the past 24 hours?
Based on rates of alcohol metabolism and elimination in humans, 183 it is very unlikely that a patient who has not consumed alcohol in the past 24 hours would have a BAL greater than 200mg/dL. While any alcohol consumption in the past 24 hours is a conservative measure of BAL>200mg/dL (i.e., this low threshold may over-identify those at risk), it is the consensus of the committee that the benefits of identifying individuals at risk of severe complications outweigh the risk of false negatives for this questionnaire item.
Alternatively, if a portable breath alcohol concentration device (i.e., a "breathalyzer") is available, breath alcohol concentration can be used in place of BAL. Research indicates that breath alcohol concentration is strongly correlated with and an accurate proxy measure of BAL. 184,185
# Qualifiers
The following questionnaire items should be clearly understood by the PAWSS administrator and defined for the patient to maximize the accuracy of results.
# Question 4 -Blackouts:
Blackouts are transient episodes of retrograde amnesia typically without loss of consciousness that accompany various degrees of alcohol intoxication.75 Blackouts can be an indicator of severe intoxication or long-term alcohol use, as a considerable degree of alcohol tolerance is required to ingest the amount of alcohol that could trigger a subsequent episode of amnesia without loss of consciousness. 75 The PAWSS administrator should clearly distinguish between alcohol-related blackouts and loss of consciousness (i.e., "passing out") as they pose the question to the patient.
# Question 5 -Withdrawal Seizures:
Withdrawal seizures are typically generalized and brief tonic-clonic seizures that occur 6-48 hours after reduction or discontinuation of alcohol use. 186 To prevent patients from mistaking other experiences, such as tremor, for a seizure, clinicians should define what is meant by a withdrawal seizure and differentiate this experience from other withdrawal symptoms. Additionally, ppatients with AUD are at increased risk of idiopathic epilepsy or seizure for other reasons, 187,188 so the PAWSS administrator should clearly define withdrawal seizures as seizures that occur within 1-2 days of discontinuation or significant reduction of alcohol use.
# Question 6 -Delirium Tremens (DTs):
Delirium tremens is a severe consequence of alcohol withdrawal that requires immediate hospitalization and management; if left untreated, the risk of death is approximately 3-5%. 189 Symptoms of delirium tremens include profound disorientation, confusion, and agitation accompanied by severe autonomic hyperactivity. 189 In colloquial language, delirium tremens or "DTs" has come to loosely represent general symptoms of alcohol withdrawal. The PAWSS administrator should clearly distinguish delirium tremens from other withdrawal symptoms to avoid false positive results.
# Notes
• Training is required to administer this tool accurately; a regular audit and feedback process is recommended to ensure intra-and inter-rater variability is within an acceptable range. 190,191 • This tool should be used in conjunction with best clinical judgment when making decisions on appropriate medication protocols, schedules, and dosages.
• Due to the need for a clinical interview, the CIWA-Ar is not appropriate where there is a language barrier or if the patient is cognitively impaired, delirious, or displaying a decreased level of consciousness. 192 C. Prescribing guidance for withdrawal management pharmacotherapy
# Baseline assessment and preparation
• Confirm DSM-5 diagnosis of AUD • Note: Section 230 of the Motor Vehicle Act (MVA) requires that physicians and nurse practitioners file a report with RoadSafetyBC if any patient who has a medical condition that makes it dangerous for them to drive continues to do so against medical advice. For more information, please refer to: https:// www2.gov.bc.ca/assets/gov/driving-and-transportation/driving/publications/reporting-a-conditionfact-sheet-for-doctors.pdf
• Patients undergoing withdrawal management should be advised not to drive or operate machinery until treatment is complete and symptoms are resolved
# Laboratory Investigations
The following may be ordered to assess general health, alcohol-related comorbidities, and other conditions that could impact pharmacotherapy selection:
• CBC, serum electrolytes, glucose, liver function and renal function panels
• HCG test for patients of childbearing capacity
• ECG for patients with cardiac disease or a history of arrhythmia or syncope
• Chest x-ray for patients with chronic respiratory problems or respiratory symptoms Note: Treatment should be initiated immediately whenever possible, and should not be delayed by waiting for laboratory test results unless patient safety would be compromised.
# Pharmacotherapy options
This guideline endorses the use of benzodiazepines, which is well-studied and endorsed for withdrawal management in this population, or gabapentin, which may be an appropriate alternative for pregnant patients at low risk of developing severe complications of withdrawal (PAWSS <4). To facilitate medication selection for patients who meet the criteria for outpatient withdrawal management, this appendix provides information on the contraindications and cautions pertaining to each alcohol withdrawal medication along with sample dosing protocols. Both medications are eligible for full coverage through PharmaCare drug benefits Plan C, Plan W, and Fair PharmaCare. Neither is covered by Plan G for treatment of alcohol withdrawal.
Prescribers and allied healthcare providers are encouraged to connect with an addiction medicine specialist for advice and guidance on complex cases. The Rapid Access to Consultative Expertise (RACE) line connects physicians and nurse practitioners with a perinatal addiction specialist. The 24/7 Addiction Medicine Clinician Support Line provides telephone consultation to physicians, nurse practitioners, nurses, and pharmacists who are involved in addiction and substance use care and treatment in BC, and is available 24 hours a day, 7 days a week, 52 weeks a year to provide rapid response for time sensitive clinical inquiries. The contact information of these provincial consultation resources are as follows:
RACE -Shared Care Telephone Advice Line -Vancouver, British Columbia • Chronic respiratory diseases: Cautious dosing is recommended due to the risk of respiratory depression
# Safety considerations:
• Benzodiazepines potentiate the effects of alcohol; concurrent alcohol use can result in serious safety risks including over-sedation, falls, delirium, respiratory depression (e.g., non-fatal or fatal overdose), and need for prolonged hospitalization
• If benzodiazepines are selected for outpatient withdrawal management, consider a fixed dosing schedule to limit risks. Benzodiazepines should be discontinued after withdrawal symptoms have resolved (typically 5-7 days)
• All patients and families should be aware of the risk of dependence and tolerance, and receive education on safe use, the signs of an overdose, and emergency contact information
• Where appropriate, consider the following strategies to reduce risk: daily dispensing from a pharmacy, involving family members or caregivers to administer medication and monitor patient response, frequent follow-up visits, or daily check-ins by phone
• Prescribers should review benzodiazepines' drug-drug interactions when considering this class of medications for alcohol withdrawal management Side Effects:
• The most common side effects of benzodiazepines are drowsiness and dizziness
• Less common side effects include changes in skin colour, nausea, headache, blurred vision, tremors, hypotension, GI disturbances, and memory loss Sample Dosing Protocol: Gabapentin 196 Common Contraindications:
• Hypersensitivity to gabapentin Cautions:
• Renal impairment: Gabapentin is eliminated solely by renal excretion. Dosage adjustments are recommended for patients with renal impairment (including elderly patients with declining renal function) and patients undergoing hemodialysis.
# Safety considerations:
• Patients with compromised respiratory function, respiratory or neurological disease, renal impairment and the elderly are at higher risk of experiencing severe adverse CNS effects including sedation, somnolence, loss of consciousness as well as serious respiratory depression.
• Gabapentin is eliminated primarily by renal excretion; dosage adjustment may be required in elderly patients and patients with renal impairment.
• A higher-than-therapeutic dose and concurrent alcohol or opioid use increases the risk of respiratory depression, profound sedation, syncope, and death. Patients who continue the use of alcohol or other CNS depressants should be observed closely for signs and symptoms of CNS depression, and the dose of gabapentin may need to be adjusted accordingly.
• Prescribers should review gabapentin's drug-drug interactions when considering this medication for alcohol withdrawal management.
# Side Effects:
• The most common side effects are ataxia, slurred speech, and drowsiness.
# Sample Dosing Protocol 197 :
• Start with 300mg TID + additional 300mg PRN + 600mg to 1200mg HS
• Titrate quickly to 600mg TID + 600mg to 1200mg HS as tolerated (i.e., even after first dose) + additional 300mg TID PRN if symptoms persist + 600mg to1200mg HS PRN
• On resolution of acute withdrawal symptoms, taper to 600mg TID + 600mg to 900mg HS
• Taper to zero over next 3-5 days, decreasing dose by 600mg daily
# • Do not exceed daily dose of 3600mg
Notes:
• This protocol applies to immediate-release (IR) tablets.
# Affirmations:
The MI counsellor should express active interest in interactions with the patient by acknowledging and amplifying actions, thoughts, and values that are noteworthy or merit credit. Such affirmations can be as simple as acknowledging that the patient made the effort to come to the appointment or recognizing the patient's willingness to persist in seeking healthy change. Provide Summaries: Summaries are a specific form reflective listening that punctuate the session and recognize key concerns in the conversation. These are particularly useful in transition points -after the patient has spoken about a particular topic, has recounted a personal experience, or when the session is nearing an end. Summaries can provide a stepping-stone towards change by distilling the productive aspects of the conversation. Like reflections, summaries are concise and strategically constructed to recognize problems, concerns, and desire to change. End summaries with an invitation to correct or complete a thought:
"Did I miss anything? "Is that accurate? Anything you want to add or correct?" Task 2 Eliciting Change Talk 199,200 Active listening may enable the patient to recognize and voice their own desire and potential for change. Through reflective and evocative questions, the MI counsellor can elicit and support productive thinking that reflects statements the patient makes about the need, willingness, or ability to make healthy behavioural changes.
Methods for Evoking Change Talk 200 :
• Using the "importance ruler": "How important would you say it is for you to…?
• " On a scale of zero to ten, where zero is not at all important and ten is extremely important, where would you say you are?" This scale can also be used to gauge confidence to change. A patient's change talk generally falls into two categories: talk in preparation of change and talk about change that is already happening.
# Preparation
• Desire to change: "I want to get better, "; "I wish I were more comfortable around people. "
• Ability to change: "I've been able to stop at times in the past, "; "I can do this. "
• Reasons for change: "I would sleep better, "; "I will feel healthier."
• Need to change: "I can't stand living like this anymore, "; "This is worse than I thought. "
# Active Change
• Commitment: "I am going to get help for this problem, "; • Actions: "I have talked to my boss about needing time off to get help, "; and • Taking steps: "I have started cutting back on my alcohol use to make it easier later to stop. "
# What should you do if you plan to drink?
• Keep the number of drinks below the Low Risk Drinking Guidelines (no more than two drinks in a day, no more that 10 drinks per week)
• Breastfeed your baby immediately before you drink. This allows time for the alcohol you drink to leave your breast milk before the next feeding (alternatively you may pump and store your milk before drinking)
• Eat and hydrate before and while drinking alcohol
• After a drinking session, wait at least 2 hours per drink before nursing. While you wait, you may "pump and dump" your breast milk to ensure your comfort (remember that pumping and dumping does not reduce the amount of alcohol in your breast milk)
4. What should you do if you drink more than planned?
• Get someone unaffected by alcohol to take care of the baby
• Anyone affected by alcohol should not sleep with the baby Talk to your healthcare provider if you need more information or support.
# Acknowledgements
The Guideline Supplement Committee gratefully acknowledges Emily Wagner and Josey Ross for their supervisory support and editorial contribution. The committee would also like to thank the following BCCSU staff members for their contribution to this work: Maya Bird, Jessica Bright, Trish Emerson, Yuko Endo, Kevin Hollett, Grace Nie, Warren O'Briain, and Kelsey Van Pelt. This work was undertaken, in part, thanks to funding from the Province of British Columbia. Additional funding support was provided by the Canadian Institutes of Health Research through the Canadian Research Initiative in Substance Misuse (SMN-139148).
# Appendix 2 Brief intervention for alcohol use during pregnancy
The 5As model is widely used in primary care and other clinical settings to support behavioural change, including dietary changes, exercise plans, smoking cessation, and substance use. 61,175 Guidance for adapting the 5As approach as a brief alcohol intervention is provided below. [176][177][178][179][180] Box 6 Script and instructions for trauma-informed brief intervention delivery
# Brief Intervention Component
Trauma-Informed Care Considerations Appendix 3 Patient criteria and considerations for outpatient alcohol withdrawal management during pregnancy
# A. Criteria for outpatient withdrawal management during pregnancy
In order to minimize the risk of adverse obstetric effects associated with alcohol withdrawal symptoms and withdrawal management interventions, it is recommended that pregnant patients with AUD undergo withdrawal management in inpatient settings where possible, so that patients can receive symptom-triggered treatment with close monitoring of withdrawal symptoms and fetal health. 3,4,9 It should also be noted that available studies on withdrawal management for this specific population have been conducted in inpatient settings. However, if inpatient withdrawal management is not an option due to patient preference or lack of timely access to available beds, outpatient treatment with close monitoring may be offered to pregnant patients who otherwise meet the criteria for this setting. • PAWSS score <4
• Absence of contraindications including, but not limited to:
• Severe or uncontrolled comorbid medical conditions (e.g., diabetes, COPD, heart disease, decompensated cirrhosis)
• Acute confusion or cognitive impairment • Acute illness or infection requiring medical intervention • Co-occurring serious psychiatric symptoms or disorders (e.g., suicidal ideation, psychosis)
• Chronic or complex pain disorders • Co-occurring severe substance use disorders (excluding tobacco)
• Pregnancy complications
• Ability to attend daily medical visits for first 3-5 days, and alternating day visits thereafter
• For patients and practices in rural or remote areas where daily in-person visits are not feasible, remote follow-up options such as telemedicine, or secure phone or video calls, are acceptable alternatives (but see notes below)
• Ability to take oral medications
• Has a reliable family member or community-based contact who can monitor symptoms during acute withdrawal period (i.e., 3-5 days) and support adherence to medications
• Any other medical or social condition that, in the treating clinician's best judgment, would present serious risks to patient safety if alcohol withdrawal was managed on an outpatient basis Additional Considerations:
• Patients who do not have support from family or community should not be denied treatment; inpatient treatment should be considered as an alternative. If inpatient care is not an option due to patient preference, scarcity of beds, or rural and remote location, patients with insufficient social supports should be accommodated and treated through alternative strategies such as supplementary follow-up visits and connection to local pharmacist.
• In communities where medically-supervised home withdrawal management programs are available, primary care follow-ups can be supplemented by home visits as appropriate.
• Intensive outpatient withdrawal management programs (e.g., "DayTox") may also be an option in some communities.
• A patient's track record of adherence to clinical recommendations should be considered as a factor in this decision.
# Appendix 4 AUD pharmacotherapy
This appendix provides an overview of practical considerations and dosing instructions to support medication selection and administration for AUD treatment during pregnancy and lactation. In reference to available evidence reviewed in this document and published guidelines pertaining to non-pregnant populations, the medications listed below include naltrexone and acamprosate, which are considered first-line options, and gabapentin which is regarded as an alternative treatment.
As comparative safety and efficacy of AUD pharmacotherapies have not been comprehensively established for pregnant patients, the decision to prescribe these medications for this patient population should be informed by a careful assessment of risks, benefits, drug-drug interactions, and contraindications.
Prescribers and allied healthcare providers are encouraged to connect with an addiction medicine specialist for advice and guidance on complex cases. The Rapid Access to Consultative Expertise (RACE) line connects physicians and nurse practitioners with a perinatal addiction specialist. The 24/7 Addiction Medicine Clinician Support Line provides telephone consultation to physicians, nurse practitioners, nurses, and pharmacists who are involved in addiction and substance use care and treatment in BC, and is available 24 hours a day, 7 days a week, 52 weeks a year to provide rapid response for time sensitive clinical inquiries. The contact information of these provincial consultation resources are as follows::
RACE -Shared Care Telephone Advice Line -Vancouver, British Columbia • No adequate human studies.
• Deemed "probably safe" in pharmacokinetic investigations. 45,137 • Small number of case reports reported no adverse neonatal effects.
• Infants should be monitored for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. 102 Sample dosing** • Start at 12.5 mg once daily.
• Titrate up as tolerated to 50mg once daily over 2 weeks.
• Two 333 mg tablets three times per day.
• Start 100mg to 300mg TID. If symptoms persist, TID doses can be increased up to a suggested maximum daily dose of1800mg.
# Appendix 5 Motivational interviewing
It is strongly recommended that providers complete Motivational Interviewing (MI) training to maximize the effectiveness of this intervention. This appendix provides a brief overview of MI principles and guidance on using this intervention with patients who have AUD. MI training programs and continuing education courses are listed in the Resources section.
Principles 198,199 MI is a conversational person-centered counseling method that seeks to empower patients to examine and address feelings of ambivalence that may impact their motivation to change. This intervention is based on the recognition that when clinicians issue directives or otherwise exert pressure (whether real or perceived) on patients to change their behaviour, this often results in pushback or resistance. By following the overarching principles of MI listed below, clinicians can empower patients to define and pursue well-being in their own way.
• Partnership: The MI counsellor i joins the patient as a collaborator, not an authority, to understand the patient's individual obstacles to change and to work together to overcome them.
• Acceptance: In conversation, the MI counsellor consistently acknowledges and affirms the patient's inherent worth, potential, and autonomy. This allows the MI counsellor to approach the patient with "accurate empathy" -an active, non-judgmental interest in the patient perspective, which is the key to collaborative progress towards well-being.
• Compassion: The MI counsellor's ultimate concern is the patient's safety and wellbeing, and understanding what that means from the patient's perspective.
• Evocation: Rather than imposing a set of goals and values on the patient, the MI counsellor evokes from the patient what their goals are and how they prefer to receive help and support.
# Task 1 Active Listening 199
The following actions are components of active listening in MI. These strategies help build a productive partnership with the patient. The strategies of active listening are often referred to by the mnemonic "OARS", which stands for Open questions, Affirmations, Reflective listening, and providing Summaries.
Open questions: The goal of asking open questions is to support the patient to say more. The MI counsellor's goal is for the patient to speak for at least half of the total session time. Open questions invite the patient to explore their feelings about, motivations for, and barriers to change.
# Task 3 Collaborative planning 199
Once the MI counsellor establishes through OARS that they have understood the patient's concerns and current "state of change" (i.e. through noting signifiers of preparation for change or active change), they may offer feedback and share information based on MI counsellor's experience and expertise as requested by the patient. 592 Offering advice is always preceded by asking the patient's permission, as well as inviting them to give their ideas and thoughts first.
In the course of MI, increased change talk and signs of increased motivation signal an opportunity to bridge towards planning for change. Strategic questions may prompt the patient to ask for advice; unsolicited advice should never be imposed on the patient.
The core principles of active listening (OARS) apply to the all the stages of MI, including planning. The MI counsellor should move at the patient's pace and "roll with resistance". In response to the patient's increased motivation for change, the MI counsellor can pose more specific and goal-oriented open questions, providing reflections and affirmation to acknowledge and mobilize motivation into planned action.
Resources
# Appendix 6 Information handout for new parents on alcohol and safer breastfeeding J
Breastfeeding is the ideal means of supporting the healthy growth and development of a child while promoting parent-infant bonding and reducing maternal stress. 4 This fact sheet provides important information for patients about eliminating or reducing the negative effects of alcohol while continuing to support nursing.
# Key Facts
• Breastfeeding is beneficial for you and your baby.
• Unless your doctor advises against breastfeeding, breast milk is the only food your baby needs for the first six months of life.
• If you drink alcoholic beverages, alcohol passes freely from your blood stream into breast milk.
• It is safest to avoid alcohol for the first three months of your baby's life. This gives your baby's liver time to develop. 148,201 • When your baby is older than three months, follow Canada's Low Risk Alcohol Drinking Guidelines if you choose to drink alcohol.
• Breastfeed just before you drink alcohol.
• Do not breastfeed for at least 2 hours per drink after a drinking occasion.
• Anyone affected by alcohol should not sleep with the baby.
1. Why is it safest to avoid drinking alcohol for the first three months of your baby's life?
• Alcohol passes from your blood stream into your breast milk.
• Alcohol has a greater effect on babies younger than three months of age because their livers are less developed.
• Higher amounts of alcohol (more than one drink) can have negative effects on your baby: it can reduce milk production, interfere with your baby's sleep patterns, and affect your baby's early development.
• Young babies breastfeed often and without any pattern. This makes it difficult to time your drinking to be sure there is no alcohol in your breast milk when your baby wants to feed.
# How long does alcohol stay in breast milk?
• Alcohol shows up in breast milk.
• It takes two hours on average for an average body to get rid of the alcohol from one drink. It takes four hours for two drinks, six hours for three drinks, and so on. | None | None |
9567c8c0d664f06d689225215b239aa40c563335 | cma | None | This document is intended for use by experienced clinicians, including prescribers and pharmacists. The information is not intended to replace sound professional judgment in individual situations, and should be used in conjunction with other reliable sources of information. Clinicians should always consider the risk/benefit profile for their individual patient, discuss these risks with the patient or caregiver before initiating therapy, and closely monitor for treatment benefit and adverse effects.#
For questions about the reproduction, adaptation, translation, or other uses of this material, contact: [email protected]
# Financial contribution from:
It can be challenging to manage drug interactions between COVID-19 treatments and DOACs. Vaccination can reduce the risk of needing treatment for COVID-19.
People who take a DOAC should stay up to date with their COVID-19 vaccines, including boosters. | This document is intended for use by experienced clinicians, including prescribers and pharmacists. The information is not intended to replace sound professional judgment in individual situations, and should be used in conjunction with other reliable sources of information. Clinicians should always consider the risk/benefit profile for their individual patient, discuss these risks with the patient or caregiver before initiating therapy, and closely monitor for treatment benefit and adverse effects.#
For questions about the reproduction, adaptation, translation, or other uses of this material, contact: [email protected]
# Financial contribution from:
It can be challenging to manage drug interactions between COVID-19 treatments and DOACs. Vaccination can reduce the risk of needing treatment for COVID-19.
People who take a DOAC should stay up to date with their COVID-19 vaccines, including boosters. | None | None |
818fb3cdcd947b7ffb12b6444fa781f787ccf7cf | cma | None | # Introduction
Globally, the prevalence of urolithiasis is steadily increasing, and though some regional variability exists, contemporary estimates report up to 10-12% of men and 7-8% of women now suffer from nephrolithiasis. Renal colic is one of the most frequent and expensive emergency department (ED) presentations. 1,2 A study comparing renal colic management patterns in two Canadian cities identified widely varying trends in care, with admission rates as high as 60%, and surgical intervention rates over 50%. Though early intervention has been purported to allow patients to return back to normal life sooner, it appears early intervention led to increased subsequent ED visits, re-admissions, and secondary procedures. 4 Another study looking at costs associated with management of acute renal colic found that an initial trial of non-surgical management was associated with lower indirect costs. 5 The aim of this Canadian Urological Association (CUA) guideline document is to provide evidence-based consensus recommendations on various aspects relevant to the management of ureteral stones; the major topic areas included were conservative management, medical expulsive therapy, shockwave lithotripsy (SWL), ureteroscopy (URS), and special clinical scenarios (e.g., pregnancy, pediatrics).
# Methods
Separate reviews of the literature were performed for each of the major topic areas. English-language publications were identified from PubMed/Medline, with a focus on recent publications since our last CUA guideline document on ureteral stones published in 2015. 6 The 2011 University of Oxford Centre for Evidence-Based Medicine Levels of Evidence grading system was used to evaluate the level of evidence of recommendations included in the document. 7 All recommendations were based on expert review of the literature and represent the consensus of all authors of this guideline document.
# I. Conservative management of ureteral stones
Non-operative management remains a reasonable first-line approach for most patients presenting with ureteral stones. A 2010 meta-analysis of 37 studies demonstrated that 38-71% of symptomatic ureteral stones <4 mm would pass spontaneously. 8 As well, looking at the placebo control arms of several large randomized controlled trials (RCTs) evaluating the efficacy of medical expulsive therapy (MET), spontaneous passage rates range from 40-80% for stones <10 mm. Clearly, an initial course of conservative management seems reasonable for many.
The urologist is often called upon in the setting of a suspected "septic stone" -conservative management is not Guideline: Ureteral calculi an option in this setting. With a sufficient index of suspicion, early goal-directed therapy, including blood and urine cultures, broad-spectrum intravenous antibiotics, resuscitation, and source control is paramount. Decompression of an obstructed pyelonephritis reduces mortality 12 and avoiding delays can prevent prolonged hospital admissions. 13 The method of drainage should be tailored to the patient's clinical scenario and stone characteristics, as well as to the available resources at each center. 14,15 In the only prospective, randomized trial, patients presenting with a fever >38°C, leukocytosis, and obstructing stone <15 mm were randomized to either a ureteric stent or a nephrostomy tube (NT). 16 There were no differences in any clinical outcome evaluated, including time to defervescence, duration of hospital stay, and resolution of obstruction. Other studies have also found that timely decompression is paramount, regardless of method. It is generally agreed that definitive treatment should not be undertaken until the obstructed system has been decompressed and the infection adequately treated. Although, there is no strong evidence as to how long to wait after initial treatment, one study recommends a minimum of seven days before definitive treatment. 20 While patients with true urosepsis (life-threatening organ dysfunction caused by a dysregulated response to a genitourinary infection) 21 are more easily identified, accurately diagnosing pre-septic patients with a concomitant urinary tract infection (UTI) and an obstructing stone may not be as clear. Irritative lower urinary tract symptoms, hematuria, and pro-inflammatory urine/blood markers have led to inconsistent interpretation about the presence of infection and ultimately antibiotic use. 22 Many patients are inappropriately given antibiotics and there is an opportunity to improve clinical practice and antibiotic stewardship with some continued medical education initiatives.
Acute kidney injury (AKI) is present in approximately 6% of patients presenting with renal colic. 23 When significant renal impairment accompanies ureteral stones, early decompression or definitive therapy may mitigate further deterioration. Early intervention may also be indicated if the patient with a ureteral stone presents with intractable symptoms (pain, nausea, etc.) or significant frailty/comorbidities.
There is limited data supporting early surgical intervention rather than a period of initial conservative therapy, with one RCT demonstrating that early ureteroscopic management (<12 hours after ED admission) led to similar stone-free and complication rates but lower rates of postoperative stenting. 24 Two RCTs looking at early SWL (<48 hours) vs. delayed SWL (2-7 days) demonstrated earlier time to stone-free status, fewer required treatments, and perhaps lower complications in the early SWL arms. 25,26 Importantly, these studies had a high risk of bias, highlighted by the fact that spontaneous stone passage rates in the delayed intervention arms of these RCTs was only 0-5.4%.
Recommendation: Many patients with ureteral stones can initially be managed non-operatively, as spontaneous passage rates are high, particularly for smaller stones (<5 mm). Close followup is necessary for those being managed conservatively, to ensure spontaneous stone passage or to decide upon the need for timely intervention (level 2, strong recommendation). Obstructive pyelonephritis requires early goal-directed therapy, including timely decompression in an antegrade or retrograde fashion, whichever method is most expedient (level 2, strong recommendation).
# Imaging
Use of computed tomography (CT) scans have increased by over 10-fold in recent years, 27 being performed in 90% of those diagnosed with urolithiasis in the acute setting, whereas ultrasonography (US) is used in less than 7% of these patients. 28 There is evidence to suggest patient gender may impact initial imaging modality selected. 29,30 A large, randomized trial comparing initial imaging modalities for renal colic presentations in the ED found most clinical outcomes were equivalent between US and non-contrast CT (NCCT) imaging, recommending initial US given the lack of radiation exposure. 28 In this RCT, USs performed by radiologists, compared to point-of-care US (POCUS) were less likely to result in followup CT scans, but did increase visit times within the ED. 31 While POCUS is convenient, it is more operator-dependent and consulting teams often have no images or formal report to review. Details founds on a NCCT are often, but not always, required for definitive stone management and followup, particular for complex scenarios.
Supplementing US with kidney-ureter-bladder (KUB) X-rays can enhance the sensitivity of detecting a ureteral stone. Studies demonstrate that combining these modalities results in sensitivity ranging from 79-100% and specificity up to 100%. 32 One study also demonstrated that the addition of a formal KUB X-ray, even when CT scout images were available, improved followup diagnostic accuracy. 33 Obtaining a KUB X-ray at the time of a diagnostic imaging in the ED is useful for not only determining stone composition, but also to track the progress of stone passage in followup.
Reduced-dose NCCT scans have been shown to maintain sensitivities and specificities from 90-97%, while preserving enough detail to identify alternate diagnoses. When assessing for stones specifically, body mass index (BMI) has been shown to be less of a concern, with >95% diagnostic accuracy and radiation doses <3.7 mGy regardless of BMI. 34 Though dual-energy CT scans have shown utility in identifying uric acid stone composition, 35 there is little additional benefit in the acute setting, as obstructing stones are not typically treated with dissolution therapy.
Overall, while adhering to as-low-as-reasonably-achievable (ALARA) radiation exposure principles, the patient's Lee et al age, pregnancy status, stone history, and preceding exposure to ionizing radiation should be considered whenever ordering imaging for non-life-threatening indications. An overreliance on CT imaging has been identified and should be addressed in our practice patterns. Recommendation: Ultrasonography with KUB X-ray should be considered the initial modality of choice for acute ureteral stones. Judicious use of CT scans, preferably low-dose, provides valuable information for management decisions (level 1, strong recommendation). While often omitted, the utility of a KUB X-ray at the time of presentation is very important for future followup and decision-making regarding definitive treatment options (level 4, expert opinion).
# Discharge planning
# Medical expulsive therapy (MET)
Recently, several large RCTs 11,36,37 failed to show improved stone passage rates or reduced analgesic requirements when using alpha-blockers for MET. However, several published meta-analyses suggest overall benefit of MET for ureteral stones. Subgroup analysis data suggests this benefit may be mainly for larger (5-10 mm), distal ureteral stones. 36,37, A Cochrane review of 67 studies analyzed all studies, specifically looking at lower-and higher-quality studies. The higher-quality, placebo-controlled studies showed a benefit with MET (relative risk 1.16, 95% confidence interval 1.07-1.25), a decrease in hospitalizations (RR 0.51, 95% CI 0.34-0.77), and no significant changes in the need for intervention. 43
# Analgesia
Moving away from a reliance on opioids in acute care patients with renal colic is important and these patients have been found to do well with non-opiate analgesia. 44 In one study, 1500 adult acute care patients were randomized to intramuscular diclofenac, intravenous morphine, or intravenous paracetamol. At 30 minutes, non-steroidal anti-inflammatories (NSAIDs) were more effective in reducing pain by 50% compared to morphine, with no adverse events. 45 Another randomized trial showed protocoled nonopioid analgesia could reduce opioid requirements during initial presentation if first-and second-line interventions included NSAIDS and intravenous lidocaine. However, opioid-sparing approaches were associated with higher rates of repeat visits to the ED. 46 Discharge prescriptions can vary significantly based on the patient population and comorbidities. Accounting for important patient characteristics (e.g., post-traumatic stress disorder, anxiety/depression, chronic pain syndromes) when prescribing analgesia for acute renal colic is also important. 47,48
# Forced hydration
While there is clear utility in re-hydrating hypovolemic patients with significant nausea and vomiting, or in those with a suspected pre-renal AKI, intravenous (IV) hydration for the sole purpose of forced stone passage is not supported by the literature and should be avoided. 49 Recommendation: The role of MET in promoting spontaneous passage is controversial, but the current literature suggests if there is any benefit, it is for larger (5-10 mm) ureteral (distal) stones. The advantages and disadvantages of MET should be discussed with the patient in a shared decision-making process (level 1, strong recommendation). The use of opioid-sparing analgesic regimens has been shown to be efficacious and opioids for management of renal colic should be minimized; patient education is paramount (level 1, strong recommendation). Forced IV hydration for the purposes of stone expulsion is not recommended (level 1, moderate recommendation).
# Renal colic followup
Unfortunately, neither resolution of symptoms nor patient reports of successful passage of obstructing ureteral stones is always confirmatory. One study demonstrated that 6.2% of patients reporting passage of a symptomatic ureteral stone had persistent obstruction on followup CT scan imaging. 50 Another study demonstrated that resolution of pain was only 79.7% sensitive and 55.8% specific for successful passage of a ureteral stone, based on followup US and KUB X-ray imaging. 51 As such, followup imaging to ensure passage of an obstructing ureteral stone is suggested. The ideal imaging modality of choice remains uncertain, but one study found that 38% of patients with a persistent ureteral stone, confirmed on ultra-low-dose CT, had neither hydronephrosis on CT nor a visible stone on the CT scout image. 52 Data suggests the majority of patients that will pass ureteral stones spontaneously will do so within approximately one month of presentation. 11, Examining the literature on long-term renal damage and ureteral obstruction, it is difficult to elucidate an objectively safe or unsafe duration of observation for a ureteral stone where no imperative indication for treatment exists; the data is mainly from animal studies and usually involves a complete obstruction model. While degree and duration of obstruction are clearly important, other factors unique to each patient also need to be considered: poor baseline renal function, older age, male gender, and presence of certain comorbidities (e.g., diabetes) have been associated with increased risk of chronic kidney disease. 53,54 Recommendation: Resolution of symptoms and patientreported stone passage after a bout of renal colic do not always confirm passage of an obstructing ureteral stone.
# Guideline: Ureteral calculi
Followup imaging is recommended to confirm stone passage (level 3, strong recommendation). The recommended duration of conservative management is unique to each patient, with multiple factors to be considered. Surgical intervention should likely be considered if a patient has not passed an obstructing ureteral stone after 4-6 weeks (level 5, moderate recommendation).
# II. Shockwave lithotripsy
Despite the advances in ureteroscopes and laser technologies, SWL remains a first-line treatment option for ureteral calculi. SWL outcomes can be directly influenced by case selection, surgeon technique, and modifiable parameters to enhance safety and maximize successful outcomes. Much of the data for SWL outcomes is derived from patients with renal calculi, but these findings should be generalizable to ureteric stones, particularly for those in the upper ureter, where renal parenchyma is included in the shockwave path.
# Clinical factors affecting SWL treatment success
# Composition
The majority of stones are composed of calcium oxalate and most will fragment well with SWL treatment. There are certain stone compositions, such as cystine, pure calcium oxalate monohydrate, and brushite, that are more resistant to SWL and may be better served by ureteroscopic management. 55 Uric acid stones, while fragile in the face of SWL, require either the use of ultrasound or pyelography (intravenous or retrograde) for targeting during SWL.
# Stone density
Stone density, as measured on NCCT scan in Hounsfield units (HU), has been shown to predict successful SWL outcomes. A crude surrogate for composition, a linear relationship exists between increased stone density and poor stone fragmentation with a threshold of 1000 HU, above which stones are less likely to be successfully fragmented. The variation coefficient of stone density (VCSD), which is a measurement of stone heterogeneity on CT scan and reflects the crystal architecture of the stone, has been reported as a novel predictor of SWL success and may outperform HU as a predictor of success; however, further study in this measurement would be useful. 61
# Skin-to-stone distance (SSD)
A longer SSD has been associated with reduced treatment success for SWL for renal and ureteral stones, 65 with SSD greater than 10 cm often associated with decreased stone-free rates (SFRs).
# Optimizing treatment outcomes
# Dose escalation/pause
Gradually increasing SWL energy up to optimal dose allows for better patient accommodation to the sensation of treatment and, for upper ureteral stones, reduces renal injury by inducing renal vasoconstriction. An alternative strategy is to pre-treat with a series of low-energy shocks, then pause treatment for a short period of time before resuming at higher-energy levels. 68
# Number of treatments
If SWL is not successful, it can be repeated, but the incremental benefit of more than two treatments for the same ureteric stone is small. 73,74 The optimal time interval between SWL treatments is unclear but can be short (2-3 days) for mid and distal ureteral stones.
# Treatment rate
Several randomized trials have indicated that a lower shock rate can improve stone fragmentation, particularly for stones larger than 1 cm. The optimal treatment rate is not clear, however, studies suggest that SWL at 60-90 shocks/minute leads to better fragmentation than 120 shocks/minute, particularly for larger stones. Most studies were performed with renal calculi, however, improved outcomes have been demonstrated for upper ureteric stones as well. 76
# Number of shocks
The optimal number of shocks has not been definitively established but requires balancing treatment efficacy with adverse effects, particularly renal damage. For upper ureteral stones, the recommended shock rate range is 2000-3500, but manufacturer's guidelines should be closely considered. 74 For mid to distal ureteric stones, where the renal parenchyma is not affected by SWL energy, treatment can safely be carried out up to 4000 or more shocks. 74 Some studies have assessed the efficacy and safety of increasing the number of shockwaves per session to >4000. 84,85 Recommendation: Patients with upper ureteric stones should initially receive low-energy shocks, with gradual voltage escalation up to maximum energy (level 2, strong recommendation). If unsuccessful, repeat SWL can be considered but more than two treatments to the same ureteric stone has little incremental benefit and URS should then be considered (level 4, moderate recommendation). Patients with upper ureteric stones >1 cm or those selected for retreatment after initial failed SWL, should be treated at a rate <120 shocks/minute for optimal fragmentation (level 1, strong recommendation). An adequate number of shocks (2000-4000 for most lithotripters) should be administered to ensure adequate treatment of ureteric stones (level 4, weak recommendation). A higher number of shocks may result in improved SFRs, but data is limited to make this a recommendation for routine practice.
# Alpha-blockers
Alpha-blockers (most commonly tamsulosin) have been studied to assess their impact on SWL outcomes in multiple RCTs and meta-analyses. Meta-analyses have shown improved SWL success rates, 89, time to stone passage, risk of steinstrasse, and need for auxiliary procedures. 93 A recently published Cochrane systematic review demon strated routine alpha-blocker therapy may result in improved stone clearance, less need for auxiliary treatments, fewer major adverse events, and a reduced stone clearance time. 97 Additional benefits with respect to pain and analgesic use are also of interest.
# Stenting
Routine pre-SWL stenting is not necessary and does not improve the success rate or passage of fragments. In fact, having a stent may impede the passage of fragments following SWL and does not appear to decrease the risk of steinstrasse or infection, with the possible exception of steinstrasse risk for stones >2 cm. 100 Stents may be beneficial for obstructing stones, if relief of obstruction is warranted prior to treatment (e.g., obstruction with infection, renal failure, intolerable pain), and prior to SWL for stones in a solitary kidney. 105 Recommendation: Alpha-blockers (e.g., tamsulosin) should be prescribed after SWL for ureteral stones to improve treatment success rates (level 1, moderate recommendation). Ureteral stents do not improve SFRs after SWL and do not reduce the risk of steinstrasse or infection following SWL for most patients (i.e., stones <2 cm) (level 1, moderate recommendation).
# III. Ureteroscopy
Modern URS is a mainstay in the surgical treatment of ureteral stones worldwide. As a result of advancements in technology in recent decades, URS can be safely performed with high SFR and relatively low complications.
# Preoperative alpha-blockers
The use of alpha-blockers prior to URS appears to improve intraoperative outcomes and patient SFR. A recent systematic review and meta-analysis comprising of 12 RCTs and 1352 patients evaluated alpha-blocker use before planned URS for the management of ureteral calculi. 106 With a median preoperative use of one week, a 61% risk reduction in need for ureteral dilatation was observed. Furthermore, the use of preoperative alpha-blockers significantly improved SFR (RR 1.18, 95% CI 1.11-1.24, p<0.00001), reduced operative time by an average of six minutes (p=0.004), and decreased patient hospital stay (p=0.001). Whether one week of use is optimal or simply convenient for patients was not defined. Larger, more appropriately powered RCTs may provide further direction regarding the efficacy of preoperative alphablockers for URS of ureteral stones.
Recommendation: Preoperative alpha-blockers may improve intraoperative and postoperative outcomes for patients undergoing URS. However, the optimal duration of preoperative alpha-blocker therapy is still uncertain (level 1, moderate recommendation).
# Postoperative imaging
The goal o f postoperative imaging is to assess for residual stone burden and screen for ongoing obstruction. Residual stone fragments may lead to additional stone-related episodes and surgical intervention. 107,108 Some authors have concluded that in the setting of uncomplicated URS, routine postoperative upper tract imaging is not necessary. 109 Instead, they have recommended postoperative imaging indications include chronic stone impaction, significant ureteral trauma, prior renal impairment, endoscopic evidence of stricture, and postoperative pain or fever. However, silent obstruction, described as asymptomatic, persistent, postoperative obstructive hydronephrosis, has been shown to occur at a rate of 1.9-10% following URS, highlighting the importance of routine postoperative imaging. The mean interval from URS to possible development of ureteral stricture is estimated to be 13 months. 112 While NCCT is the best modality for identifying both residual fragments and postoperative obstruction, the effective dosage of radiation and the cost of this modality have prevented its routine use post-URS. Rather, a combination of US and KUB X-ray are typically used to detect obstruction and stone-free status.
Recommendation: An US ± KUB X-ray is recommended following URS for ureteral stones (level 4, strong recommendation). In complicated cases, further imaging with NCCT can be performed.
# Guideline: Ureteral calculi
# Ureteral access sheaths
Ureteral access sheaths (UAS) can offer numerous advantages during URS. They allow for rapid and multiple reentries into the upper tract, potentially reducing damage to the ureteroscope. UAS can also enhance visibility, decrease intrarenal pressure, and allow for drainage and elimination of dust and stone fragments. 113 The proper selection of UAS size is crucial to balancing URS outcomes. Excessive force should never be applied when using UAS. Most of the literature on UAS use during URS is related to renal stones.
In a prospective cohort analysis of 2239 patients, no significant difference in SFR was seen whether a UAS was or was not used during flexible URS (75.3% vs. 50.4%, p=0.604). 114 However, in a subgroup analysis of stones ≥10 mm, SFRs were significantly higher in the UAS group (84.9% vs. 81.5%, p<0.01). One systematic review revealed no significant difference in operative times, SFRs, or intraoperative complications with UAS use. 115 A critical drawback of these systematic reviews is that a substantial number of studies did not use NCCT to determine true SFR and as a result, the impact of UAS use on SFR after URS remains unclear.
In a study of 2239 patients treated with flexible URS, no significant difference in ureteral injuries was reported in patients treated with UAS in comparison to those without UAS. 114 Grades of ureteral injuries related to UAS were reported as low-grade injuries involving the mucosa in almost half of patients and high-grade lesions involved smooth muscle layer in 15% of patients. 116 Importantly, endoscopically detected high-grade ureteral lesions following UAS insertion do not appear to result in an increased rate of stricture. 117
# Recommendation: Current evidence suggests UAS use for ureteral stones has no significant impact on SFR nor on intraoperative complications (level 2, moderate recommendation), but may improve visualization, reduce intra-renal pressures, and facilitate fragment removal (level 4, strong recommendation).
# Stenting
Ureteral stent placement prior to elective URS can facilitate UAS and ureteroscope insertion. In a recent prospective study of rigid and flexible ureteroscopes, the ureter was inaccessible in 8% of cases, necessitating the placement of a ureteral stent and delayed definitive treatment. 118 Some studies have demonstrated no clear advantage in SFR nor complication rate with routine preoperative stenting, 119,120 while others have shown routine pre-URS stenting was associated with a higher SFR for larger stones. The impact of post-URS stenting on SFR is not clear and meta-analyses have shown conflicting results. One recent meta-analysis found that stenting did not improve SFR nor reduce late postoperative complications after routine URS. 124 Conversely, in another meta-analysis of 22 RCTs, the SFR was significantly better in the stented group (95% CI 0.34-0.89; p=0.01). 101 In terms of the impact on stricture rate, a meta-analysis of 14 trials and 1652 patients demonstrated that post-URS stenting likely does not reduce stricture rates at 90 days (RR 0.58, CI 0.23-1.47). 125 Conversely, use of a stent has been shown to reduce unplanned medical visits post-URS. Following UAS use, routine ureteral stenting seems to be beneficial in reducing pain and unplanned medical visits. 128,129 Nonetheless, there are scenarios where routine post-URS stent placement is advisable: suspected ureteric injury or stricture, solitary kidney, and patient with renal impairment.
The evidence is not clear on whether use of a stent post-URS impacts opioid use, 125,130 but urinary symptoms have been demonstrated to be significantly worse with stent use. 101,124,126,131 Studies have demonstrated beneficial effects of various medications (e.g., alpha-blockers, anticholinergics, B-agonists) to ameliorate stent-related urinary symptoms. 132,133 There is no consensus regarding the optimum duration of postoperative stenting. In an animal model, there were no histological ischemic changes in the ureteral wall 72 hours post-UAS insertion, suggesting that three days may be sufficient. 134 On the other hand, Paul et al compared ureteral stent dwell times of three vs. seven days and found that removal at three days was linked to a higher probability of obstruction-related adverse events (23% vs. 3%). 135
# Recommendation: Routine pre-URS stenting is not necessary but may facilitate UAS insertion and improve SFRs in patients with larger stones (level 2, weak recommendation). Routine stenting after uncomplicated URS is likely unnecessary (level 2, strong recommendation) but stent placement after UAS use is warranted (level 3, weak recommendation). Stent-related symptoms following URS may be ameliorated with alpha-blocker and/or anticholinergic medications (level 2, moderate recommendation). If access to the ureteral stone is complicated or impossible, placement of a stent and repeat URS is the safest option (level 5, strong recommendation).
# IV. Comparing treatment outcomes -SWL vs. URS
# Stone-free rate
Previously published literature comparing SWL vs. URS for ureteric calculi, which focused largely on efficacy and safety, guided the development of the 2015 CUA guideline recommendations. Since then, several other studies have been published, including some important data on cost-effectiveness and patient-reported outcomes. Due to the significant variation and heterogeneity of the techniques used to perform SWL and URS, it is difficult to make clear recommendations based on published literature.
For upper ureteric stones, a randomized trial of semirigid URS compared to SWL for stones <2 cm showed similar SFR (86.6% vs. 82.2%) at three months. 136 Those undergoing SWL had significantly higher re-treatment rates but after re-treatment, the need for subsequent auxiliary treatments was similar (21.1% vs. 17.7%, p<0.5). When the groups were substratified by stone size, URS produced a higher SFR for stones 1-2 cm (85.4% vs. 78.4%), though this was not statistically significant. Complication rates were also statistically similar (11.1% vs. 6.6%, p=0.21).
When dealing with distal ureteral stones, URS has traditionally been thought to produce superior results to SWL. However, several studies have demonstrated similar SFR between SWL and URS, with the caveat that SWL often required more than one treatment to achieve that same SFR. A systematic review published in 2017 found that there was a better SFR with URS at four weeks, but this was comparable between groups at three months. 141 There were fewer re-treatments with URS, but higher complication rates. In terms of radiation doses to patients, one study showed equal amounts of radiation used for ureteral stones whether treating with URS or SWL. 142 Costs can vary from region to region for each modality; an American study found that for ureteral stones ≤1.5 cm, the equivalency point for cost efficacy was when the SFR for SWL was 57-76%. 143 For these situations, URS was found to be more cost-effective in an American system. A British cost-efficacy study was undertaken according to their National Institute for Health and Care Excellence (NICE) guidelines 144 and they concluded that for ureteral stones <1 cm, URS would be more costly even if SWL was only 40% efficacious.
# Recommendation: SWL produces similar SFR to URS for ureteral stones, albeit with a higher retreatment rate and lower complication rate (level 1, strong recommendation).
While local/regional cost models need to be considered, SWL may be a more cost-effective option for ureteric stones (level 4, weak recommendation).
# Patient-reported outcomes
Ureteral stones can have a significant impact on the healthrelated quality of life (HRQOL) of patients. Both SWL and URS have been found to have significant impacts on kidney stone patients' quality of life.
Overall, patients with ureteral stones are satisfied with their treatment choice approximately 50% of the time and there is no difference in treatment satisfaction correlated to the selected modality (SWL vs. URS). However, in one study specifically examining distal ureteric calculi, it was determined that more patients were satisfied with URS (n=113; 94.2%) compared to SWL (n=74; 80.4%) (p=0.002). 153 Regarding HRQOL, the main HRQOL outcomes affected by SWL and URS are the physical functioning, social functioning, and pain domains on the 36-item Short Form Health Survey (SF-36). 154,155 A study comparing the HRQOL between patients who received SWL to those who received URS using the SF-36, found that patients who received URS scored worse than those who received SWL due in part to the higher analgesic requirements and longer hospital stay after URS compared to SWL, which was mainly attributed to the use of a ureteral stent. 156 Interestingly, the improved HRQOL for SWL over URS extended beyond the short-term and persisted at six months of followup, despite the higher SFR with URS. In contrast, a study compared the impact of URS vs. SWL on the HRQOL of patients with proximal ureteral stones and found that although there was no difference in change in HRQOL for patients with stones 10 mm scored significantly lower on their SF-36. 157 Finally, a systematic review examined how ureteric calculi influence HRQOL and patient treatment preference. 158 A number of studies were reviewed, however, overall URS and SWL were both found to significantly impact SF-36 results similarly.
Recommendation: Overall, there is similar patient satisfaction between SWL and URS for the treatment of ureteric calculi, but SWL has been found to have slightly better HRQOL outcomes, due primarily to the avoidance of a ureteral stent (level 2, moderate recommendation).
# V. Special clinical considerations
# Anticoagulation
Some studies have shown up to a 20-to 40-fold increased risk of peri-renal hematomas and hemorrhagic complications among patients with uncorrected coagulopathies undergoing SWL when compared with patients with a normal bleeding profile. As such, in consultation with a hematologist or a cardiologist, bleeding coagulopathies need to be corrected and anticoagulation therapy appropriately withheld around the time of SWL. 163 Patients with an increased risk of thromboembolic disease should be managed by bridging therapy while oral anticoagulation is held. 164 A retrospective study of 434 patients on acetylsalicylic acid (ASA) or low-molecular-weight heparin (LMWH) undergoing SWL for renal and proximal ureteric stones demonstrated that the continued use of ASA and a therapeutic (but Guideline: Ureteral calculi not prophylactic) dose of LMWH were independent predictors of renal hematoma, as determined by ultrasound one day post-SWL. 165 A systematic review performed in 2014 found sparse and poor-quality evidence with respect to the safety of SWL while on antiplatelet or anticoagulant medications, but one of the authors' conclusions included careful consideration of SWL among patients on low-dose ASA. 166 Recent advances in URS technology have made it possible for patients with coagulopathies to safely undergo URS and laser lithotripsy while anticoagulated. 160, However, this is associated with lower SFRs and increased risk of postoperative gross hematuria necessitating admission and bladder irrigation. 161,171 Therefore, risks and benefits of withholding anticoagulation or proceeding with URS while anticoagulated should be discussed with the patient and his/her cardiologist or hematologist.
In terms of using a UAS during URS for patients on anticoagulants, studies have demonstrated no increased risk of hemorrhagic complications. 116,169 Recommendations: SWL and antegrade URS are contraindicated in patients with uncorrected coagulopathies. When the risk of holding antiplatelet or anticoagulants outweigh the benefits, proceeding with URS while a patient is anticoagulated is an acceptable option (level 2, moderate recommendation).
# Antegrade management of ureteral stones
Antegrade URS can be considered a treatment option in the following situations: 1) patients with a urinary diversion in whom SWL or retrograde access is not feasible; 2) in select cases with a large, impacted proximal ureteral stones; 3) when performed in conjunction with renal stone removal; 4) in select cases following failure of a retrograde URS attempt for a large, impacted proximal ureteral stone; 172 and 5) when the ureteral stone is in a transplant kidney. 173 Dealing with stones in patients with urinary diversions represents a challenge to most urologists. The established anatomical changes in these patients necessitate accurate preoperative assessment by NCCT. 174 If SWL is not an option or the patient's stone doesn't respond to SWL, one of the most important factors to consider is whether retrograde access to the ureter is possible. If the ureter is accessible through a retrograde approach (e.g., through an ileal conduit), flexible retrograde URS may be a good option, as antegrade URS in these patients is associated with higher rates of postoperative fever or sepsis (8% vs. 0%, p15 mm), impacted, proximal ureteral stones, the SFR with antegrade URS ranges from 98.5-100%, with a low risk for complications. 172, However, as would be expected, the antegrade approach is associated with longer fluoroscopy time, longer procedural time, and longer hospital stay. 181 Recommendations: Percutaneous antegrade URS should be considered in the treatment of stones in patients with urinary diversion and select large, impacted, proximal ureteral stones, especially when prior retrograde URS has failed (level 4, strong recommendation).
# Ureteral stones in children
Pediatric urolithiasis has become increasingly common in the last two decades, with the incidence increasing approximately 4-10% annually. 182,183
# Diagnostic imaging
Due to concerns regarding radiation exposure in children, US is used more commonly than in adults as the first-line diagnostic modality when renal colic is suspected. However, similar to adults, there are sensitivity issues with US, in particular for mid-ureteral calculi. 187 The addition of conventional radiography (KUB X-ray) can improve diagnostic accuracy, 188,189 but as in adults, NCCT has the highest sensitivity and specificity. 185,186,190 The use of ultra-low-dose NCCT can mitigate radiation exposure to levels similar to KUB X-ray, while maintaining diagnostic performance. 191,192
# Management
The optimal management of ureteral stones in children is dependent on patient and stone factors, similar to adults, but the anatomic spectrum of pediatric patients, and the subsequent management, varies much more widely. 193 Unless there is an indication to intervene acutely, a trial of passage of at least two weeks is the first-line management in children with urolithiasis <5 mm. 105,185, If urinary drainage is urgently required, ureteral stent insertion is preferred in children due to decreased complications compared to percutaneous decompression. Evidence suggests MET in children may be effective and safe. 193,194,197 There is a paucity of high-level evidence in the literature regarding the optimal management algorithm for pediatric patients requiring surgical intervention for ureteric stones. 193,198 In children with mid to distal urolithiasis, URS has been consistently shown to be superior to SWL and thus is recommended as first-line management. 105,185, For children with proximal ureteral stones, the overall SFRs between SWL and URS have been shown to be similar, 198 so both SWL and URS may be considered first-line options. The usual considerations regarding the suitability of SWL must be considered. In children with large stone burdens, repeated procedures may be required or discussions involving more invasive options (percutaneous ante-
# Lee et al
grade URS or open/laparoscopic/robotic procedures) may be undertaken. 105,185 Retrograde access for children who have undergone a Cohen cross-trigonal ureteral re-implantation can be uniquely challenging but is not a contraindication for URS. 202
# Complications
The complication and re-treatment rates for pediatric SWL are similar to those of adults. 198,199 However, unlike the adult population, the complication rates for pediatric URS varies widely (3.7-20.5%). 188,198,203,204 In particular, overall reported rates of ureteral injury (2.1-2.8%), ureteric stricture (0.2-1.0%), and ureteral avulsion (0.4%) are higher among the pediatric population. 200,203 The complications associated with pediatric URS are more strongly linked with age/size of the child and equipment size. 203,205 To minimize ureteric complications, it is recommended that ureteroscopes <8 French be used on pediatric patients, 199,200,204,205 and that mini 4.5 French ureteroscopes be used for children <3 years old. 203
# Stenting
Data does not support routine pre-stenting prior to URS in children. 105 However, failed retrograde access is more common in children (30-70%) than adults. 196,206 In these situations, pre-stenting and repeat URS after passive dilation may be preferable to active dilation with catheters, balloon dilators, and sheaths due to risk of significant ureteric trauma. This is especially true in younger children. 188 Postoperative stenting should be performed at the discretion of the attending physician, with similar indications as in adults. 185,205
# Followup
There are no clear differences between pediatric and adult followup post-surgical intervention for urolithiasis. In most series, postoperative ureteral stents are removed within 1-2 weeks under a second general anesthesia. Alternative options include magnetic and tethered stents.
Postoperatively, children should be followed with an US and KUB X-ray 4-6 weeks after the procedure. 200,205,207,208 After their first episode of urolithiasis, the overall recurrence rates in the pediatric population ranges from 19-50 % over a followup of 2-3 years. 195,209,210 However, there is currently no high-level evidence dictating a specific surveillance schedule. As such, it is recommended that this mirror that of the adult population.
Recommendation: Ultrasound is the first-line diagnostic modality used in children with suspected ureteral stones. This may be coupled with a KUB X-ray to increase accuracy.
# Low-dose NCCT may be used in certain situations (level 3, strong recommendation). A trial of passage with/without
MET is recommended for children with smaller (<5 mm) stones (level 2, strong recommendation). SWL is a safe and effective option for ureteral stones in children (level 2, strong recommendation). If ureteral dilation is required, passive dilation is preferred (level 4, moderate recommendation). It is recommended that ureteroscopes <8 French be used for URS in children (level 4, moderate recommendation).
# Pregnancy
No level 1 evidence exists regarding the treatment of ureteral stones during pregnancy. Retrospective case series provide some guidance on how to manage this situation.
# Diagnostic imaging
The first diagnostic test in suspected nephrolithiasis during pregnancy should be US (abdominal ± transvaginal) due to the lack of radiation. However, if US is non-diagnostic, magnetic resonance imaging (MRI) can be considered in the first trimester. 211,212 If available, a protocol involving magnetic resonance urography (MRU) with a T2-weighted half Fourier single-shot turbo spin-echo (HASTE) is preferred due to improved accuracy. 213 Ultra-low/low-dose NCCT may be considered as additional options in the second and third trimesters. 186,214,215
# Management
Most ureteral stones will pass spontaneously and the first option in management is conservative therapy, including hydration and analgesia. 216 NSAIDs should be avoided in pregnancy due to known fetal risks. 217 Data suggests MET with alpha-blockers is relatively safe in this patient population, however, efficacy is currently not well-established. 218,219 It should be noted that these medications are category B-rated and should be used with caution, as an off-label adjunct. 105 Immediate causes for intervention are the same as those in non-pregnant situations, but also include induction of premature labor (contractions, fetal distress). 220 The immediate methods of intervention in these situations are NT or ureteral stent insertion. Although safe, the evidence for NT placement are comprised of small, low-level studies. In pregnancy, ureteral stents and NTs are at risk for accelerated encrustation, thereby requiring changes every 4-6 weeks. 224,225 Failing conservative management, URS using laser lithotripsy has been shown to be feasible and safe. 226 In fact, if ultrasound imaging is non-diagnostic and low-dose NCCT or MRI is unavailable, URS can also be used for both diagnostic and therapeutic purposes. 227,228 A number of studies have demonstrated that URS is a viable technique to treat stones in pregnancy. 227, Postoperative stenting following URS in this situation is recommended in an attempt to reduce postoperative complications. 227,234 With respect to safety of Guideline: Ureteral calculi the pregnancy, traditional teaching was that URS should be undertaken during the second trimester, 220,235 but more recent literature suggests there is no evidence to support a "safest" trimester. 221 With regards to intraoperative imaging, if URS or ureteral stent insertion is undertaken, then a lead apron or shield should be put between the X-ray fluoroscopy source and the fetus to shield it from radiation. 236 Alternatively, URS or ureteral stent insertion can be performed under US guidance alone, avoiding radiation exposure. Continuous fetal monitoring has been advocated during these interventions, 212,220 although may not always be necessary.
Pregnancy is a contraindication to SWL, and although there have been reports of the inadvertent treatment of pregnant patients with SWL with no adverse sequelae to the fetus, 237 it should be avoided. Similarly, antegrade URS should likely be delayed until after birth, as the procedure may require prolonged anesthesia and radiation exposure. However, some case series of safe PCNL during pregnancy have been published. 238 Recommendation: First-line diagnostic testing for stones in pregnancy is US, but low-dose NCCT or MRI (without gadolinium in the first trimester) can also be used (level 3, strong recommendation). Obstructing ureteral stones in pregnancy can be managed conservatively in the absence of suspected or confirmed urinary infection (level 3, moderate recommendation). In pregnant patients presenting with signs of sepsis, antibiotics and urinary decompression via a NT or ureteral stent are of primary importance; consultation with the obstetrics team is recommended. URS with laser lithotripsy is safe in pregnancy; however, SWL is contraindicated (level 2, strong recommendation).
Competing interests: Dr. Lee has received a speaker honorarium from Baxter. Dr. Bhojani has reviewed new products for Boston Scientific and participated in WATER 2, an Aquablation multiinstitutional clinical trial supported by Procept. Dr. Chew has been a consultant for Auris Robotics, Bard Medical, Boston Scientific, and Olympus; has been a lecturer for Boston Scientific, Coloplast, Cook Medical, and Olympus; received a study grant from Boston Scientific; received a fellowship salary from Cook Medical; and participated in clinical trials supported by Boston Scientific and Cook Medical. Dr. Elmansy has received payment from Boston Scientific, Clarion Medical Technologies/ AccuTech Medical Technologies, and Janssen; and received speaker honoraria and a travel grant from Lumenis. Dr. Pace has received support for a fellowship and annual lectureship from Cook Urological. The remaining authors report no competing personal or financial interests related to this work. | # Introduction
Globally, the prevalence of urolithiasis is steadily increasing, and though some regional variability exists, contemporary estimates report up to 10-12% of men and 7-8% of women now suffer from nephrolithiasis. [1][2][3] Renal colic is one of the most frequent and expensive emergency department (ED) presentations. 1,2 A study comparing renal colic management patterns in two Canadian cities identified widely varying trends in care, with admission rates as high as 60%, and surgical intervention rates over 50%. Though early intervention has been purported to allow patients to return back to normal life sooner, it appears early intervention led to increased subsequent ED visits, re-admissions, and secondary procedures. 4 Another study looking at costs associated with management of acute renal colic found that an initial trial of non-surgical management was associated with lower indirect costs. 5 The aim of this Canadian Urological Association (CUA) guideline document is to provide evidence-based consensus recommendations on various aspects relevant to the management of ureteral stones; the major topic areas included were conservative management, medical expulsive therapy, shockwave lithotripsy (SWL), ureteroscopy (URS), and special clinical scenarios (e.g., pregnancy, pediatrics).
# Methods
Separate reviews of the literature were performed for each of the major topic areas. English-language publications were identified from PubMed/Medline, with a focus on recent publications since our last CUA guideline document on ureteral stones published in 2015. 6 The 2011 University of Oxford Centre for Evidence-Based Medicine Levels of Evidence grading system was used to evaluate the level of evidence of recommendations included in the document. 7 All recommendations were based on expert review of the literature and represent the consensus of all authors of this guideline document.
# I. Conservative management of ureteral stones
Non-operative management remains a reasonable first-line approach for most patients presenting with ureteral stones. A 2010 meta-analysis of 37 studies demonstrated that 38-71% of symptomatic ureteral stones <4 mm would pass spontaneously. 8 As well, looking at the placebo control arms of several large randomized controlled trials (RCTs) evaluating the efficacy of medical expulsive therapy (MET), spontaneous passage rates range from 40-80% for stones <10 mm. [9][10][11] Clearly, an initial course of conservative management seems reasonable for many.
The urologist is often called upon in the setting of a suspected "septic stone" -conservative management is not Guideline: Ureteral calculi an option in this setting. With a sufficient index of suspicion, early goal-directed therapy, including blood and urine cultures, broad-spectrum intravenous antibiotics, resuscitation, and source control is paramount. Decompression of an obstructed pyelonephritis reduces mortality 12 and avoiding delays can prevent prolonged hospital admissions. 13 The method of drainage should be tailored to the patient's clinical scenario and stone characteristics, as well as to the available resources at each center. 14,15 In the only prospective, randomized trial, patients presenting with a fever >38°C, leukocytosis, and obstructing stone <15 mm were randomized to either a ureteric stent or a nephrostomy tube (NT). 16 There were no differences in any clinical outcome evaluated, including time to defervescence, duration of hospital stay, and resolution of obstruction. Other studies have also found that timely decompression is paramount, regardless of method. [17][18][19] It is generally agreed that definitive treatment should not be undertaken until the obstructed system has been decompressed and the infection adequately treated. Although, there is no strong evidence as to how long to wait after initial treatment, one study recommends a minimum of seven days before definitive treatment. 20 While patients with true urosepsis (life-threatening organ dysfunction caused by a dysregulated response to a genitourinary [GU] infection) 21 are more easily identified, accurately diagnosing pre-septic patients with a concomitant urinary tract infection (UTI) and an obstructing stone may not be as clear. Irritative lower urinary tract symptoms, hematuria, and pro-inflammatory urine/blood markers have led to inconsistent interpretation about the presence of infection and ultimately antibiotic use. 22 Many patients are inappropriately given antibiotics and there is an opportunity to improve clinical practice and antibiotic stewardship with some continued medical education initiatives.
Acute kidney injury (AKI) is present in approximately 6% of patients presenting with renal colic. 23 When significant renal impairment accompanies ureteral stones, early decompression or definitive therapy may mitigate further deterioration. Early intervention may also be indicated if the patient with a ureteral stone presents with intractable symptoms (pain, nausea, etc.) or significant frailty/comorbidities.
There is limited data supporting early surgical intervention rather than a period of initial conservative therapy, with one RCT demonstrating that early ureteroscopic management (<12 hours after ED admission) led to similar stone-free and complication rates but lower rates of postoperative stenting. 24 Two RCTs looking at early SWL (<48 hours) vs. delayed SWL (2-7 days) demonstrated earlier time to stone-free status, fewer required treatments, and perhaps lower complications in the early SWL arms. 25,26 Importantly, these studies had a high risk of bias, highlighted by the fact that spontaneous stone passage rates in the delayed intervention arms of these RCTs was only 0-5.4%.
Recommendation: Many patients with ureteral stones can initially be managed non-operatively, as spontaneous passage rates are high, particularly for smaller stones (<5 mm). Close followup is necessary for those being managed conservatively, to ensure spontaneous stone passage or to decide upon the need for timely intervention (level 2, strong recommendation). Obstructive pyelonephritis requires early goal-directed therapy, including timely decompression in an antegrade or retrograde fashion, whichever method is most expedient (level 2, strong recommendation).
# Imaging
Use of computed tomography (CT) scans have increased by over 10-fold in recent years, 27 being performed in 90% of those diagnosed with urolithiasis in the acute setting, whereas ultrasonography (US) is used in less than 7% of these patients. 28 There is evidence to suggest patient gender may impact initial imaging modality selected. 29,30 A large, randomized trial comparing initial imaging modalities for renal colic presentations in the ED found most clinical outcomes were equivalent between US and non-contrast CT (NCCT) imaging, recommending initial US given the lack of radiation exposure. 28 In this RCT, USs performed by radiologists, compared to point-of-care US (POCUS) were less likely to result in followup CT scans, but did increase visit times within the ED. 31 While POCUS is convenient, it is more operator-dependent and consulting teams often have no images or formal report to review. Details founds on a NCCT are often, but not always, required for definitive stone management and followup, particular for complex scenarios.
Supplementing US with kidney-ureter-bladder (KUB) X-rays can enhance the sensitivity of detecting a ureteral stone. Studies demonstrate that combining these modalities results in sensitivity ranging from 79-100% and specificity up to 100%. 32 One study also demonstrated that the addition of a formal KUB X-ray, even when CT scout images were available, improved followup diagnostic accuracy. 33 Obtaining a KUB X-ray at the time of a diagnostic imaging in the ED is useful for not only determining stone composition, but also to track the progress of stone passage in followup.
Reduced-dose NCCT scans have been shown to maintain sensitivities and specificities from 90-97%, while preserving enough detail to identify alternate diagnoses. When assessing for stones specifically, body mass index (BMI) has been shown to be less of a concern, with >95% diagnostic accuracy and radiation doses <3.7 mGy regardless of BMI. 34 Though dual-energy CT scans have shown utility in identifying uric acid stone composition, 35 there is little additional benefit in the acute setting, as obstructing stones are not typically treated with dissolution therapy.
Overall, while adhering to as-low-as-reasonably-achievable (ALARA) radiation exposure principles, the patient's Lee et al age, pregnancy status, stone history, and preceding exposure to ionizing radiation should be considered whenever ordering imaging for non-life-threatening indications. An overreliance on CT imaging has been identified and should be addressed in our practice patterns. Recommendation: Ultrasonography with KUB X-ray should be considered the initial modality of choice for acute ureteral stones. Judicious use of CT scans, preferably low-dose, provides valuable information for management decisions (level 1, strong recommendation). While often omitted, the utility of a KUB X-ray at the time of presentation is very important for future followup and decision-making regarding definitive treatment options (level 4, expert opinion).
# Discharge planning
# Medical expulsive therapy (MET)
Recently, several large RCTs 11,36,37 failed to show improved stone passage rates or reduced analgesic requirements when using alpha-blockers for MET. However, several published meta-analyses [38][39][40] suggest overall benefit of MET for ureteral stones. Subgroup analysis data suggests this benefit may be mainly for larger (5-10 mm), distal ureteral stones. 36,37,[40][41][42] A Cochrane review of 67 studies analyzed all studies, specifically looking at lower-and higher-quality studies. The higher-quality, placebo-controlled studies showed a benefit with MET (relative risk [RR] 1.16, 95% confidence interval [CI] 1.07-1.25), a decrease in hospitalizations (RR 0.51, 95% CI 0.34-0.77), and no significant changes in the need for intervention. 43
# Analgesia
Moving away from a reliance on opioids in acute care patients with renal colic is important and these patients have been found to do well with non-opiate analgesia. 44 In one study, 1500 adult acute care patients were randomized to intramuscular diclofenac, intravenous morphine, or intravenous paracetamol. At 30 minutes, non-steroidal anti-inflammatories (NSAIDs) were more effective in reducing pain by 50% compared to morphine, with no adverse events. 45 Another randomized trial showed protocoled nonopioid analgesia could reduce opioid requirements during initial presentation if first-and second-line interventions included NSAIDS and intravenous lidocaine. However, opioid-sparing approaches were associated with higher rates of repeat visits to the ED. 46 Discharge prescriptions can vary significantly based on the patient population and comorbidities. Accounting for important patient characteristics (e.g., post-traumatic stress disorder, anxiety/depression, chronic pain syndromes) when prescribing analgesia for acute renal colic is also important. 47,48
# Forced hydration
While there is clear utility in re-hydrating hypovolemic patients with significant nausea and vomiting, or in those with a suspected pre-renal AKI, intravenous (IV) hydration for the sole purpose of forced stone passage is not supported by the literature and should be avoided. 49 Recommendation: The role of MET in promoting spontaneous passage is controversial, but the current literature suggests if there is any benefit, it is for larger (5-10 mm) ureteral (distal) stones. The advantages and disadvantages of MET should be discussed with the patient in a shared decision-making process (level 1, strong recommendation). The use of opioid-sparing analgesic regimens has been shown to be efficacious and opioids for management of renal colic should be minimized; patient education is paramount (level 1, strong recommendation). Forced IV hydration for the purposes of stone expulsion is not recommended (level 1, moderate recommendation).
# Renal colic followup
Unfortunately, neither resolution of symptoms nor patient reports of successful passage of obstructing ureteral stones is always confirmatory. One study demonstrated that 6.2% of patients reporting passage of a symptomatic ureteral stone had persistent obstruction on followup CT scan imaging. 50 Another study demonstrated that resolution of pain was only 79.7% sensitive and 55.8% specific for successful passage of a ureteral stone, based on followup US and KUB X-ray imaging. 51 As such, followup imaging to ensure passage of an obstructing ureteral stone is suggested. The ideal imaging modality of choice remains uncertain, but one study found that 38% of patients with a persistent ureteral stone, confirmed on ultra-low-dose CT, had neither hydronephrosis on CT nor a visible stone on the CT scout image. 52 Data suggests the majority of patients that will pass ureteral stones spontaneously will do so within approximately one month of presentation. 11,[33][34] Examining the literature on long-term renal damage and ureteral obstruction, it is difficult to elucidate an objectively safe or unsafe duration of observation for a ureteral stone where no imperative indication for treatment exists; the data is mainly from animal studies and usually involves a complete obstruction model. While degree and duration of obstruction are clearly important, other factors unique to each patient also need to be considered: poor baseline renal function, older age, male gender, and presence of certain comorbidities (e.g., diabetes) have been associated with increased risk of chronic kidney disease. 53,54 Recommendation: Resolution of symptoms and patientreported stone passage after a bout of renal colic do not always confirm passage of an obstructing ureteral stone.
# Guideline: Ureteral calculi
Followup imaging is recommended to confirm stone passage (level 3, strong recommendation). The recommended duration of conservative management is unique to each patient, with multiple factors to be considered. Surgical intervention should likely be considered if a patient has not passed an obstructing ureteral stone after 4-6 weeks (level 5, moderate recommendation).
# II. Shockwave lithotripsy
Despite the advances in ureteroscopes and laser technologies, SWL remains a first-line treatment option for ureteral calculi. SWL outcomes can be directly influenced by case selection, surgeon technique, and modifiable parameters to enhance safety and maximize successful outcomes. Much of the data for SWL outcomes is derived from patients with renal calculi, but these findings should be generalizable to ureteric stones, particularly for those in the upper ureter, where renal parenchyma is included in the shockwave path.
# Clinical factors affecting SWL treatment success
# Composition
The majority of stones are composed of calcium oxalate and most will fragment well with SWL treatment. There are certain stone compositions, such as cystine, pure calcium oxalate monohydrate, and brushite, that are more resistant to SWL and may be better served by ureteroscopic management. 55 Uric acid stones, while fragile in the face of SWL, require either the use of ultrasound or pyelography (intravenous or retrograde) for targeting during SWL.
# Stone density
Stone density, as measured on NCCT scan in Hounsfield units (HU), has been shown to predict successful SWL outcomes. A crude surrogate for composition, a linear relationship exists between increased stone density and poor stone fragmentation with a threshold of 1000 HU, above which stones are less likely to be successfully fragmented. [56][57][58][59][60] The variation coefficient of stone density (VCSD), which is a measurement of stone heterogeneity on CT scan and reflects the crystal architecture of the stone, has been reported as a novel predictor of SWL success and may outperform HU as a predictor of success; however, further study in this measurement would be useful. 61
# Skin-to-stone distance (SSD)
A longer SSD has been associated with reduced treatment success for SWL for renal [62][63][64][65][66][67] and ureteral stones, 65 with SSD greater than 10 cm often associated with decreased stone-free rates (SFRs).
# Optimizing treatment outcomes
# Dose escalation/pause
Gradually increasing SWL energy up to optimal dose allows for better patient accommodation to the sensation of treatment and, for upper ureteral stones, reduces renal injury by inducing renal vasoconstriction. [68][69][70][71][72] An alternative strategy is to pre-treat with a series of low-energy shocks, then pause treatment for a short period of time before resuming at higher-energy levels. 68
# Number of treatments
If SWL is not successful, it can be repeated, but the incremental benefit of more than two treatments for the same ureteric stone is small. 73,74 The optimal time interval between SWL treatments is unclear but can be short (2-3 days) for mid and distal ureteral stones.
# Treatment rate
Several randomized trials have indicated that a lower shock rate can improve stone fragmentation, particularly for stones larger than 1 cm. The optimal treatment rate is not clear, however, studies suggest that SWL at 60-90 shocks/minute leads to better fragmentation than 120 shocks/minute, particularly for larger stones. [75][76][77][78][79][80][81][82][83] Most studies were performed with renal calculi, however, improved outcomes have been demonstrated for upper ureteric stones as well. 76
# Number of shocks
The optimal number of shocks has not been definitively established but requires balancing treatment efficacy with adverse effects, particularly renal damage. For upper ureteral stones, the recommended shock rate range is 2000-3500, but manufacturer's guidelines should be closely considered. 74 For mid to distal ureteric stones, where the renal parenchyma is not affected by SWL energy, treatment can safely be carried out up to 4000 or more shocks. 74 Some studies have assessed the efficacy and safety of increasing the number of shockwaves per session to >4000. 84,85 Recommendation: Patients with upper ureteric stones should initially receive low-energy shocks, with gradual voltage escalation up to maximum energy (level 2, strong recommendation). If unsuccessful, repeat SWL can be considered but more than two treatments to the same ureteric stone has little incremental benefit and URS should then be considered (level 4, moderate recommendation). Patients with upper ureteric stones >1 cm or those selected for retreatment after initial failed SWL, should be treated at a rate <120 shocks/minute for optimal fragmentation (level 1, strong recommendation). An adequate number of shocks (2000-4000 for most lithotripters) should be administered to ensure adequate treatment of ureteric stones (level 4, weak recommendation). A higher number of shocks may result in improved SFRs, but data is limited to make this a recommendation for routine practice.
# Alpha-blockers
Alpha-blockers (most commonly tamsulosin) have been studied to assess their impact on SWL outcomes in multiple RCTs and meta-analyses. [86][87][88][89][90][91][92][93][94][95] Meta-analyses have shown improved SWL success rates, 89,[94][95][96] time to stone passage, risk of steinstrasse, [93][94][95][96] and need for auxiliary procedures. 93 A recently published Cochrane systematic review demon strated routine alpha-blocker therapy may result in improved stone clearance, less need for auxiliary treatments, fewer major adverse events, and a reduced stone clearance time. 97 Additional benefits with respect to pain and analgesic use are also of interest.
# Stenting
Routine pre-SWL stenting is not necessary and does not improve the success rate or passage of fragments. [98][99][100][101] In fact, having a stent may impede the passage of fragments following SWL and does not appear to decrease the risk of steinstrasse or infection, [100][101][102][103][104] with the possible exception of steinstrasse risk for stones >2 cm. 100 Stents may be beneficial for obstructing stones, if relief of obstruction is warranted prior to treatment (e.g., obstruction with infection, renal failure, intolerable pain), and prior to SWL for stones in a solitary kidney. 105 Recommendation: Alpha-blockers (e.g., tamsulosin) should be prescribed after SWL for ureteral stones to improve treatment success rates (level 1, moderate recommendation). Ureteral stents do not improve SFRs after SWL and do not reduce the risk of steinstrasse or infection following SWL for most patients (i.e., stones <2 cm) (level 1, moderate recommendation).
# III. Ureteroscopy
Modern URS is a mainstay in the surgical treatment of ureteral stones worldwide. As a result of advancements in technology in recent decades, URS can be safely performed with high SFR and relatively low complications.
# Preoperative alpha-blockers
The use of alpha-blockers prior to URS appears to improve intraoperative outcomes and patient SFR. A recent systematic review and meta-analysis comprising of 12 RCTs and 1352 patients evaluated alpha-blocker use before planned URS for the management of ureteral calculi. 106 With a median preoperative use of one week, a 61% risk reduction in need for ureteral dilatation was observed. Furthermore, the use of preoperative alpha-blockers significantly improved SFR (RR 1.18, 95% CI 1.11-1.24, p<0.00001), reduced operative time by an average of six minutes (p=0.004), and decreased patient hospital stay (p=0.001). Whether one week of use is optimal or simply convenient for patients was not defined. Larger, more appropriately powered RCTs may provide further direction regarding the efficacy of preoperative alphablockers for URS of ureteral stones.
Recommendation: Preoperative alpha-blockers may improve intraoperative and postoperative outcomes for patients undergoing URS. However, the optimal duration of preoperative alpha-blocker therapy is still uncertain (level 1, moderate recommendation).
# Postoperative imaging
The goal o f postoperative imaging is to assess for residual stone burden and screen for ongoing obstruction. Residual stone fragments may lead to additional stone-related episodes and surgical intervention. 107,108 Some authors have concluded that in the setting of uncomplicated URS, routine postoperative upper tract imaging is not necessary. 109 Instead, they have recommended postoperative imaging indications include chronic stone impaction, significant ureteral trauma, prior renal impairment, endoscopic evidence of stricture, and postoperative pain or fever. However, silent obstruction, described as asymptomatic, persistent, postoperative obstructive hydronephrosis, has been shown to occur at a rate of 1.9-10% following URS, highlighting the importance of routine postoperative imaging. [109][110][111] The mean interval from URS to possible development of ureteral stricture is estimated to be 13 months. 112 While NCCT is the best modality for identifying both residual fragments and postoperative obstruction, the effective dosage of radiation and the cost of this modality have prevented its routine use post-URS. Rather, a combination of US and KUB X-ray are typically used to detect obstruction and stone-free status.
Recommendation: An US ± KUB X-ray is recommended following URS for ureteral stones (level 4, strong recommendation). In complicated cases, further imaging with NCCT can be performed.
# Guideline: Ureteral calculi
# Ureteral access sheaths
Ureteral access sheaths (UAS) can offer numerous advantages during URS. They allow for rapid and multiple reentries into the upper tract, potentially reducing damage to the ureteroscope. UAS can also enhance visibility, decrease intrarenal pressure, and allow for drainage and elimination of dust and stone fragments. 113 The proper selection of UAS size is crucial to balancing URS outcomes. Excessive force should never be applied when using UAS. Most of the literature on UAS use during URS is related to renal stones.
In a prospective cohort analysis of 2239 patients, no significant difference in SFR was seen whether a UAS was or was not used during flexible URS (75.3% vs. 50.4%, p=0.604). 114 However, in a subgroup analysis of stones ≥10 mm, SFRs were significantly higher in the UAS group (84.9% vs. 81.5%, p<0.01). One systematic review revealed no significant difference in operative times, SFRs, or intraoperative complications with UAS use. 115 A critical drawback of these systematic reviews is that a substantial number of studies did not use NCCT to determine true SFR and as a result, the impact of UAS use on SFR after URS remains unclear.
In a study of 2239 patients treated with flexible URS, no significant difference in ureteral injuries was reported in patients treated with UAS in comparison to those without UAS. 114 Grades of ureteral injuries related to UAS were reported as low-grade injuries involving the mucosa in almost half of patients and high-grade lesions involved smooth muscle layer in 15% of patients. 116 Importantly, endoscopically detected high-grade ureteral lesions following UAS insertion do not appear to result in an increased rate of stricture. 117
# Recommendation: Current evidence suggests UAS use for ureteral stones has no significant impact on SFR nor on intraoperative complications (level 2, moderate recommendation), but may improve visualization, reduce intra-renal pressures, and facilitate fragment removal (level 4, strong recommendation).
# Stenting
Ureteral stent placement prior to elective URS can facilitate UAS and ureteroscope insertion. In a recent prospective study of rigid and flexible ureteroscopes, the ureter was inaccessible in 8% of cases, necessitating the placement of a ureteral stent and delayed definitive treatment. 118 Some studies have demonstrated no clear advantage in SFR nor complication rate with routine preoperative stenting, 119,120 while others have shown routine pre-URS stenting was associated with a higher SFR for larger stones. [121][122][123] The impact of post-URS stenting on SFR is not clear and meta-analyses have shown conflicting results. One recent meta-analysis found that stenting did not improve SFR nor reduce late postoperative complications after routine URS. 124 Conversely, in another meta-analysis of 22 RCTs, the SFR was significantly better in the stented group (95% CI 0.34-0.89; p=0.01). 101 In terms of the impact on stricture rate, a meta-analysis of 14 trials and 1652 patients demonstrated that post-URS stenting likely does not reduce stricture rates at 90 days (RR 0.58, CI 0.23-1.47). 125 Conversely, use of a stent has been shown to reduce unplanned medical visits post-URS. [125][126][127] Following UAS use, routine ureteral stenting seems to be beneficial in reducing pain and unplanned medical visits. 128,129 Nonetheless, there are scenarios where routine post-URS stent placement is advisable: suspected ureteric injury or stricture, solitary kidney, and patient with renal impairment.
The evidence is not clear on whether use of a stent post-URS impacts opioid use, 125,130 but urinary symptoms have been demonstrated to be significantly worse with stent use. 101,124,126,131 Studies have demonstrated beneficial effects of various medications (e.g., alpha-blockers, anticholinergics, B-agonists) to ameliorate stent-related urinary symptoms. 132,133 There is no consensus regarding the optimum duration of postoperative stenting. In an animal model, there were no histological ischemic changes in the ureteral wall 72 hours post-UAS insertion, suggesting that three days may be sufficient. 134 On the other hand, Paul et al compared ureteral stent dwell times of three vs. seven days and found that removal at three days was linked to a higher probability of obstruction-related adverse events (23% vs. 3%). 135
# Recommendation: Routine pre-URS stenting is not necessary but may facilitate UAS insertion and improve SFRs in patients with larger stones (level 2, weak recommendation). Routine stenting after uncomplicated URS is likely unnecessary (level 2, strong recommendation) but stent placement after UAS use is warranted (level 3, weak recommendation). Stent-related symptoms following URS may be ameliorated with alpha-blocker and/or anticholinergic medications (level 2, moderate recommendation). If access to the ureteral stone is complicated or impossible, placement of a stent and repeat URS is the safest option (level 5, strong recommendation).
# IV. Comparing treatment outcomes -SWL vs. URS
# Stone-free rate
Previously published literature comparing SWL vs. URS for ureteric calculi, which focused largely on efficacy and safety, guided the development of the 2015 CUA guideline recommendations. Since then, several other studies have been published, including some important data on cost-effectiveness and patient-reported outcomes. Due to the significant variation and heterogeneity of the techniques used to perform SWL and URS, it is difficult to make clear recommendations based on published literature.
For upper ureteric stones, a randomized trial of semirigid URS compared to SWL for stones <2 cm showed similar SFR (86.6% vs. 82.2%) at three months. 136 Those undergoing SWL had significantly higher re-treatment rates but after re-treatment, the need for subsequent auxiliary treatments was similar (21.1% vs. 17.7%, p<0.5). When the groups were substratified by stone size, URS produced a higher SFR for stones 1-2 cm (85.4% vs. 78.4%), though this was not statistically significant. Complication rates were also statistically similar (11.1% vs. 6.6%, p=0.21).
When dealing with distal ureteral stones, URS has traditionally been thought to produce superior results to SWL. However, several studies have demonstrated similar SFR between SWL and URS, with the caveat that SWL often required more than one treatment to achieve that same SFR. [137][138][139][140] A systematic review published in 2017 found that there was a better SFR with URS at four weeks, but this was comparable between groups at three months. 141 There were fewer re-treatments with URS, but higher complication rates. In terms of radiation doses to patients, one study showed equal amounts of radiation used for ureteral stones whether treating with URS or SWL. 142 Costs can vary from region to region for each modality; an American study found that for ureteral stones ≤1.5 cm, the equivalency point for cost efficacy was when the SFR for SWL was <60-64% or if the chance of URS success was >57-76%. 143 For these situations, URS was found to be more cost-effective in an American system. A British cost-efficacy study was undertaken according to their National Institute for Health and Care Excellence (NICE) guidelines 144 and they concluded that for ureteral stones <1 cm, URS would be more costly even if SWL was only 40% efficacious.
# Recommendation: SWL produces similar SFR to URS for ureteral stones, albeit with a higher retreatment rate and lower complication rate (level 1, strong recommendation).
While local/regional cost models need to be considered, SWL may be a more cost-effective option for ureteric stones (level 4, weak recommendation).
# Patient-reported outcomes
Ureteral stones can have a significant impact on the healthrelated quality of life (HRQOL) of patients. [145][146][147][148][149] Both SWL and URS have been found to have significant impacts on kidney stone patients' quality of life.
Overall, patients with ureteral stones are satisfied with their treatment choice approximately 50% of the time and there is no difference in treatment satisfaction correlated to the selected modality (SWL vs. URS). [150][151][152] However, in one study specifically examining distal ureteric calculi, it was determined that more patients were satisfied with URS (n=113; 94.2%) compared to SWL (n=74; 80.4%) (p=0.002). 153 Regarding HRQOL, the main HRQOL outcomes affected by SWL and URS are the physical functioning, social functioning, and pain domains on the 36-item Short Form Health Survey (SF-36). 154,155 A study comparing the HRQOL between patients who received SWL to those who received URS using the SF-36, found that patients who received URS scored worse than those who received SWL due in part to the higher analgesic requirements and longer hospital stay after URS compared to SWL, which was mainly attributed to the use of a ureteral stent. 156 Interestingly, the improved HRQOL for SWL over URS extended beyond the short-term and persisted at six months of followup, despite the higher SFR with URS. In contrast, a study compared the impact of URS vs. SWL on the HRQOL of patients with proximal ureteral stones and found that although there was no difference in change in HRQOL for patients with stones <10 mm, patients who underwent SWL for proximal ureteral stones >10 mm scored significantly lower on their SF-36. 157 Finally, a systematic review examined how ureteric calculi influence HRQOL and patient treatment preference. 158 A number of studies were reviewed, however, overall URS and SWL were both found to significantly impact SF-36 results similarly.
Recommendation: Overall, there is similar patient satisfaction between SWL and URS for the treatment of ureteric calculi, but SWL has been found to have slightly better HRQOL outcomes, due primarily to the avoidance of a ureteral stent (level 2, moderate recommendation).
# V. Special clinical considerations
# Anticoagulation
Some studies have shown up to a 20-to 40-fold increased risk of peri-renal hematomas and hemorrhagic complications among patients with uncorrected coagulopathies undergoing SWL when compared with patients with a normal bleeding profile. [159][160][161][162] As such, in consultation with a hematologist or a cardiologist, bleeding coagulopathies need to be corrected and anticoagulation therapy appropriately withheld around the time of SWL. 163 Patients with an increased risk of thromboembolic disease should be managed by bridging therapy while oral anticoagulation is held. 164 A retrospective study of 434 patients on acetylsalicylic acid (ASA) or low-molecular-weight heparin (LMWH) undergoing SWL for renal and proximal ureteric stones demonstrated that the continued use of ASA and a therapeutic (but Guideline: Ureteral calculi not prophylactic) dose of LMWH were independent predictors of renal hematoma, as determined by ultrasound one day post-SWL. 165 A systematic review performed in 2014 found sparse and poor-quality evidence with respect to the safety of SWL while on antiplatelet or anticoagulant medications, but one of the authors' conclusions included careful consideration of SWL among patients on low-dose ASA. 166 Recent advances in URS technology have made it possible for patients with coagulopathies to safely undergo URS and laser lithotripsy while anticoagulated. 160,[167][168][169][170] However, this is associated with lower SFRs and increased risk of postoperative gross hematuria necessitating admission and bladder irrigation. 161,171 Therefore, risks and benefits of withholding anticoagulation or proceeding with URS while anticoagulated should be discussed with the patient and his/her cardiologist or hematologist.
In terms of using a UAS during URS for patients on anticoagulants, studies have demonstrated no increased risk of hemorrhagic complications. 116,169 Recommendations: SWL and antegrade URS are contraindicated in patients with uncorrected coagulopathies. When the risk of holding antiplatelet or anticoagulants outweigh the benefits, proceeding with URS while a patient is anticoagulated is an acceptable option (level 2, moderate recommendation).
# Antegrade management of ureteral stones
Antegrade URS can be considered a treatment option in the following situations: 1) patients with a urinary diversion in whom SWL or retrograde access is not feasible; 2) in select cases with a large, impacted proximal ureteral stones; 3) when performed in conjunction with renal stone removal; 4) in select cases following failure of a retrograde URS attempt for a large, impacted proximal ureteral stone; 172 and 5) when the ureteral stone is in a transplant kidney. 173 Dealing with stones in patients with urinary diversions represents a challenge to most urologists. The established anatomical changes in these patients necessitate accurate preoperative assessment by NCCT. 174 If SWL is not an option or the patient's stone doesn't respond to SWL, one of the most important factors to consider is whether retrograde access to the ureter is possible. If the ureter is accessible through a retrograde approach (e.g., through an ileal conduit), flexible retrograde URS may be a good option, as antegrade URS in these patients is associated with higher rates of postoperative fever or sepsis (8% vs. 0%, p<0.05) and higher rates of second-look nephroscopy (36% vs. 16%, p<0.05) compared to those with normal anatomy. 175 For large (>15 mm), impacted, proximal ureteral stones, the SFR with antegrade URS ranges from 98.5-100%, with a low risk for complications. 172,[176][177][178][179][180] However, as would be expected, the antegrade approach is associated with longer fluoroscopy time, longer procedural time, and longer hospital stay. 181 Recommendations: Percutaneous antegrade URS should be considered in the treatment of stones in patients with urinary diversion and select large, impacted, proximal ureteral stones, especially when prior retrograde URS has failed (level 4, strong recommendation).
# Ureteral stones in children
Pediatric urolithiasis has become increasingly common in the last two decades, with the incidence increasing approximately 4-10% annually. 182,183
# Diagnostic imaging
Due to concerns regarding radiation exposure in children, US is used more commonly than in adults as the first-line diagnostic modality when renal colic is suspected. [184][185][186] However, similar to adults, there are sensitivity issues with US, in particular for mid-ureteral calculi. 187 The addition of conventional radiography (KUB X-ray) can improve diagnostic accuracy, 188,189 but as in adults, NCCT has the highest sensitivity and specificity. 185,186,190 The use of ultra-low-dose NCCT can mitigate radiation exposure to levels similar to KUB X-ray, while maintaining diagnostic performance. 191,192
# Management
The optimal management of ureteral stones in children is dependent on patient and stone factors, similar to adults, but the anatomic spectrum of pediatric patients, and the subsequent management, varies much more widely. 193 Unless there is an indication to intervene acutely, a trial of passage of at least two weeks is the first-line management in children with urolithiasis <5 mm. 105,185,[193][194][195][196] If urinary drainage is urgently required, ureteral stent insertion is preferred in children due to decreased complications compared to percutaneous decompression. Evidence suggests MET in children may be effective and safe. 193,194,197 There is a paucity of high-level evidence in the literature regarding the optimal management algorithm for pediatric patients requiring surgical intervention for ureteric stones. 193,198 In children with mid to distal urolithiasis, URS has been consistently shown to be superior to SWL and thus is recommended as first-line management. 105,185,[199][200][201] For children with proximal ureteral stones, the overall SFRs between SWL and URS have been shown to be similar, 198 so both SWL and URS may be considered first-line options. The usual considerations regarding the suitability of SWL must be considered. In children with large stone burdens, repeated procedures may be required or discussions involving more invasive options (percutaneous ante-
# Lee et al
grade URS or open/laparoscopic/robotic procedures) may be undertaken. 105,185 Retrograde access for children who have undergone a Cohen cross-trigonal ureteral re-implantation can be uniquely challenging but is not a contraindication for URS. 202
# Complications
The complication and re-treatment rates for pediatric SWL are similar to those of adults. 198,199 However, unlike the adult population, the complication rates for pediatric URS varies widely (3.7-20.5%). 188,198,203,204 In particular, overall reported rates of ureteral injury (2.1-2.8%), ureteric stricture (0.2-1.0%), and ureteral avulsion (0.4%) are higher among the pediatric population. 200,203 The complications associated with pediatric URS are more strongly linked with age/size of the child and equipment size. 203,205 To minimize ureteric complications, it is recommended that ureteroscopes <8 French be used on pediatric patients, 199,200,204,205 and that mini 4.5 French ureteroscopes be used for children <3 years old. 203
# Stenting
Data does not support routine pre-stenting prior to URS in children. 105 However, failed retrograde access is more common in children (30-70%) than adults. 196,206 In these situations, pre-stenting and repeat URS after passive dilation may be preferable to active dilation with catheters, balloon dilators, and sheaths due to risk of significant ureteric trauma. This is especially true in younger children. 188 Postoperative stenting should be performed at the discretion of the attending physician, with similar indications as in adults. 185,205
# Followup
There are no clear differences between pediatric and adult followup post-surgical intervention for urolithiasis. In most series, postoperative ureteral stents are removed within 1-2 weeks under a second general anesthesia. Alternative options include magnetic and tethered stents.
Postoperatively, children should be followed with an US and KUB X-ray 4-6 weeks after the procedure. 200,205,207,208 After their first episode of urolithiasis, the overall recurrence rates in the pediatric population ranges from 19-50 % over a followup of 2-3 years. 195,209,210 However, there is currently no high-level evidence dictating a specific surveillance schedule. As such, it is recommended that this mirror that of the adult population.
Recommendation: Ultrasound is the first-line diagnostic modality used in children with suspected ureteral stones. This may be coupled with a KUB X-ray to increase accuracy.
# Low-dose NCCT may be used in certain situations (level 3, strong recommendation). A trial of passage with/without
MET is recommended for children with smaller (<5 mm) stones (level 2, strong recommendation). SWL is a safe and effective option for ureteral stones in children (level 2, strong recommendation). If ureteral dilation is required, passive dilation is preferred (level 4, moderate recommendation). It is recommended that ureteroscopes <8 French be used for URS in children (level 4, moderate recommendation).
# Pregnancy
No level 1 evidence exists regarding the treatment of ureteral stones during pregnancy. Retrospective case series provide some guidance on how to manage this situation.
# Diagnostic imaging
The first diagnostic test in suspected nephrolithiasis during pregnancy should be US (abdominal ± transvaginal) due to the lack of radiation. However, if US is non-diagnostic, magnetic resonance imaging (MRI) can be considered in the first trimester. 211,212 If available, a protocol involving magnetic resonance urography (MRU) with a T2-weighted half Fourier single-shot turbo spin-echo (HASTE) is preferred due to improved accuracy. 213 Ultra-low/low-dose NCCT may be considered as additional options in the second and third trimesters. 186,214,215
# Management
Most ureteral stones will pass spontaneously and the first option in management is conservative therapy, including hydration and analgesia. 216 NSAIDs should be avoided in pregnancy due to known fetal risks. 217 Data suggests MET with alpha-blockers is relatively safe in this patient population, however, efficacy is currently not well-established. 218,219 It should be noted that these medications are category B-rated and should be used with caution, as an off-label adjunct. 105 Immediate causes for intervention are the same as those in non-pregnant situations, but also include induction of premature labor (contractions, fetal distress). 220 The immediate methods of intervention in these situations are NT or ureteral stent insertion. Although safe, the evidence for NT placement are comprised of small, low-level studies. [221][222][223] In pregnancy, ureteral stents and NTs are at risk for accelerated encrustation, thereby requiring changes every 4-6 weeks. 224,225 Failing conservative management, URS using laser lithotripsy has been shown to be feasible and safe. 226 In fact, if ultrasound imaging is non-diagnostic and low-dose NCCT or MRI is unavailable, URS can also be used for both diagnostic and therapeutic purposes. 227,228 A number of studies have demonstrated that URS is a viable technique to treat stones in pregnancy. 227,[229][230][231][232][233] Postoperative stenting following URS in this situation is recommended in an attempt to reduce postoperative complications. 227,234 With respect to safety of Guideline: Ureteral calculi the pregnancy, traditional teaching was that URS should be undertaken during the second trimester, 220,235 but more recent literature suggests there is no evidence to support a "safest" trimester. 221 With regards to intraoperative imaging, if URS or ureteral stent insertion is undertaken, then a lead apron or shield should be put between the X-ray fluoroscopy source and the fetus to shield it from radiation. 236 Alternatively, URS or ureteral stent insertion can be performed under US guidance alone, avoiding radiation exposure. Continuous fetal monitoring has been advocated during these interventions, 212,220 although may not always be necessary.
Pregnancy is a contraindication to SWL, and although there have been reports of the inadvertent treatment of pregnant patients with SWL with no adverse sequelae to the fetus, 237 it should be avoided. Similarly, antegrade URS should likely be delayed until after birth, as the procedure may require prolonged anesthesia and radiation exposure. However, some case series of safe PCNL during pregnancy have been published. 238 Recommendation: First-line diagnostic testing for stones in pregnancy is US, but low-dose NCCT or MRI (without gadolinium in the first trimester) can also be used (level 3, strong recommendation). Obstructing ureteral stones in pregnancy can be managed conservatively in the absence of suspected or confirmed urinary infection (level 3, moderate recommendation). In pregnant patients presenting with signs of sepsis, antibiotics and urinary decompression via a NT or ureteral stent are of primary importance; consultation with the obstetrics team is recommended. URS with laser lithotripsy is safe in pregnancy; however, SWL is contraindicated (level 2, strong recommendation).
Competing interests: Dr. Lee has received a speaker honorarium from Baxter. Dr. Bhojani has reviewed new products for Boston Scientific and participated in WATER 2, an Aquablation multiinstitutional clinical trial supported by Procept. Dr. Chew has been a consultant for Auris Robotics, Bard Medical, Boston Scientific, and Olympus; has been a lecturer for Boston Scientific, Coloplast, Cook Medical, and Olympus; received a study grant from Boston Scientific; received a fellowship salary from Cook Medical; and participated in clinical trials supported by Boston Scientific and Cook Medical. Dr. Elmansy has received payment from Boston Scientific, Clarion Medical Technologies/ AccuTech Medical Technologies, and Janssen; and received speaker honoraria and a travel grant from Lumenis. Dr. Pace has received support for a fellowship and annual lectureship from Cook Urological. The remaining authors report no competing personal or financial interests related to this work.
#
Acknowledgement: The authors would like to thank Simon Czajkowski, MSc (Phys), MBE, for his assistance in collating and synthesizing the many references in this document. They would also like to thank Robin Parker, MLIS, PhD(c), for her assistance in conducting the literature search for the section on SWL. | None | None |
298d3f7c3d35a2ba0cad0e2e631efd0f6df6c34e | cma | None | The coronavirus pandemic disease 2019 (COVID-19) has affected over 29 million people globally, with more than 925,000 deaths attributable to SARS-CoV-2 infection. Although there is limited data on the prevalence and the effects of COVID-19 in pregnancy, it has significantly affected obstetrical care and the decisions pregnant women make. The lack of clarity with pandemic protocols (i.e., masking/no-masking, the definition of a person under investigation) and non-evidence-based changes in birth plans (i.e., restriction of visitors and support persons) have been a major stressor for health care providers (HCP), pregnant women and their families.
Since the onset of the pandemic, individuals, some HCP and institutions have recommended that pregnant women, who have planned a trial of labour after cesarean (TOLAC) birth should seriously consider a planned elective repeat cesarean section (ERCS). The main reason for this recommendation is the strain on finite health care personnel and resources, such as shortages of personal protective equipment (PPE) during the COVID-19 pandemic. 1,2 In addition, the added risk of COVID-19 transmission to staff has been postulated as a cause for delayed access to emergency cesarean delivery (CD) in the event of a uterine rupture leading to life threatening consequences for the pregnant woman and fetus. Therefore, ERCS have been promoted by (some) HCP despite the evidence that a successful TOLAC offers numerous benefits to the pregnant woman, including reduced length of hospital stay; reduced recovery time compared to CD and decreased risk of admission to neonatal intensive care unit.
The SOGC recognizes that safety and protection of HCP, provision of adequate PPE and the responsible use of resources are top priorities; however, not at the expense of best practice. Planning for birth in the COVID-19 era should be the same without a risk to the pregnant woman's autonomy. COVID-19 is not an indication for ERCS in the absence of obstetrical indications for repeat CD and HCP should continue to offer TOLAC. The clinical management of TOLAC during the pandemic should be identical to management in the pre-pandemic era. The SOGC remains supportive of TOLAC in eligible pregnant women during the COVID-19 pandemic . Readers are referred to the recent SOGC Clinical Practice Guideline "No. 382: Trial of Labour After Cesarean", which reviews in detail the bodies of evidence about the safety of TOLAC, as well as the recommendations regarding patient selection, conduct of labour and induction and access to emergency delivery. 4 We reinforce the process of shared decision-making as paramount to planning the mode of birth after CD. 8 Pregnant women should be supported in their decision to undergo a TOLAC based on their beliefs and personal preferences. The likelihood for success, as well as the risks and benefits of TOLAC to both the pregnant woman and the fetus, should be reviewed to support an informed choice during the antenatal period. Access to emergency CD is key to optimal outcomes in TOLAC. Pregnant women and their HCP must be aware of the available local resources when offering TOLAC. 3,4 The SOGC recommends that pregnant women who live in areas where local hospitals cannot provide emergency access to CD be transferred to facilities where these services can be provided.
The availability of PPE including gloves, gowns, masks (surgical and N95, where indicated), and eye protection have been a challenge in most hospitals. To conserve PPE, only necessary HCP should be present in the operating room during CD for patients with suspected or confirmed COVID-19 infections. 2 The use of regional anaesthesia is not considered an aerosol generating medical procedure, 9,10 therefore the use of an N95 mask is not required. Epidural anaesthesia is not a contraindication in pregnant women with planned TOLAC. However, pregnant women may require general anaesthesia in labour, 11 which poses an increased risk of aerosolization than does regional anaesthesia and further depletion of PPE. Pregnant women undergoing TOLAC should be identified as at increased risk of requiring emergency access to CD. The obstetrical team should be aware of the women in labour who are planning a TOLAC. A team huddle is recommended to ensure readiness in the event of suspected uterine rupture.
# Key messages
- TOLAC is safe and the risk of uterine rupture is not increased by COVID-19 infection. The risk of vertical transmission of COVID-19 is extremely low. Pregnant women should continue to minimize their exposure to COVID-19 by strictly adhering to preventive measures. Pregnant women should be supported in their choice for TOLAC if there are no known contraindication to labour and vaginal birth. | #
The coronavirus pandemic disease 2019 (COVID-19) has affected over 29 million people globally, with more than 925,000 deaths attributable to SARS-CoV-2 infection. Although there is limited data on the prevalence and the effects of COVID-19 in pregnancy, it has significantly affected obstetrical care and the decisions pregnant women make. The lack of clarity with pandemic protocols (i.e., masking/no-masking, the definition of a person under investigation) and non-evidence-based changes in birth plans (i.e., restriction of visitors and support persons) have been a major stressor for health care providers (HCP), pregnant women and their families.
Since the onset of the pandemic, individuals, some HCP and institutions have recommended that pregnant women, who have planned a trial of labour after cesarean (TOLAC) birth should seriously consider a planned elective repeat cesarean section (ERCS). The main reason for this recommendation is the strain on finite health care personnel and resources, such as shortages of personal protective equipment (PPE) during the COVID-19 pandemic. 1,2 In addition, the added risk of COVID-19 transmission to staff has been postulated as a cause for delayed access to emergency cesarean delivery (CD) in the event of a uterine rupture leading to life threatening consequences for the pregnant woman and fetus. Therefore, ERCS have been promoted by (some) HCP despite the evidence that a successful TOLAC offers numerous benefits to the pregnant woman, including reduced length of hospital stay; reduced recovery time compared to CD and decreased risk of admission to neonatal intensive care unit.
The SOGC recognizes that safety and protection of HCP, provision of adequate PPE and the responsible use of resources are top priorities; however, not at the expense of best practice. Planning for birth in the COVID-19 era should be the same without a risk to the pregnant woman's autonomy. COVID-19 is not an indication for ERCS in the absence of obstetrical indications for repeat CD and HCP should continue to offer TOLAC. The clinical management of TOLAC during the pandemic should be identical to management in the pre-pandemic era. The SOGC remains supportive of TOLAC in eligible pregnant women during the COVID-19 pandemic . [3][4][5][6][7] Readers are referred to the recent SOGC Clinical Practice Guideline "No. 382: Trial of Labour After Cesarean", which reviews in detail the bodies of evidence about the safety of TOLAC, [3][4][5][6][7] as well as the recommendations regarding patient selection, conduct of labour and induction and access to emergency delivery. 4 We reinforce the process of shared decision-making as paramount to planning the mode of birth after CD. 8 Pregnant women should be supported in their decision to undergo a TOLAC based on their beliefs and personal preferences. The likelihood for success, as well as the risks and benefits of TOLAC to both the pregnant woman and the fetus, should be reviewed to support an informed choice during the antenatal period. Access to emergency CD is key to optimal outcomes in TOLAC. Pregnant women and their HCP must be aware of the available local resources when offering TOLAC. 3,4 The SOGC recommends that pregnant women who live in areas where local hospitals cannot provide emergency access to CD be transferred to facilities where these services can be provided.
The availability of PPE including gloves, gowns, masks (surgical and N95, where indicated), and eye protection have been a challenge in most hospitals. To conserve PPE, only necessary HCP should be present in the operating room during CD for patients with suspected or confirmed COVID-19 infections. 2 The use of regional anaesthesia is not considered an aerosol generating medical procedure, 9,10 therefore the use of an N95 mask is not required. Epidural anaesthesia is not a contraindication in pregnant women with planned TOLAC. However, pregnant women may require general anaesthesia in labour, 11 which poses an increased risk of aerosolization than does regional anaesthesia and further depletion of PPE. Pregnant women undergoing TOLAC should be identified as at increased risk of requiring emergency access to CD. The obstetrical team should be aware of the women in labour who are planning a TOLAC. A team huddle is recommended to ensure readiness in the event of suspected uterine rupture.
# Key messages
TOLAC is safe and the risk of uterine rupture is not increased by COVID-19 infection. The risk of vertical transmission of COVID-19 is extremely low. Pregnant women should continue to minimize their exposure to COVID-19 by strictly adhering to preventive measures. Pregnant women should be supported in their choice for TOLAC if there are no known contraindication to labour and vaginal birth. | None | None |
5b53c6466ad1b0e218263b15a4e7db72e67c8bab | cma | None | Longitudinal monitoring of patients with fibrotic interstitial lung disease (ILD) is essential to identifying disease progression and guiding management decisions. There are no evidence-based clinical practice guidelines to inform decision-making for the appropriate components and frequency of monitoring patients with fibrotic ILD. This position statement summarizes the key components of long-term monitoring of fibrotic ILD, including the appropriate frequency of monitoring, specific symptoms and comorbidities to consider, and the objective testing that should be routinely performed. Key messages based on scientific literature review and consensus from a panel of ILD experts are provided to guide clinical practice.La surveillance longitudinale des patients atteints de fibrose pulmonaire interstitielle est essentielle pour d eterminer la progression de la maladie et guider les d ecisions de prise en charge. Il n'existe pas de lignes directrices de pratique clinique fond ees sur des donn ees probantes pour eclairer la prise de d ecision concernant les composantes et la fr equence de la surveillance appropri ees des patients atteints de fibrose pulmonaire interstitielle. Cet enonc e de position r esume les el ements cl es de la surveillance fibrose pulmonaire interstitielle a long terme, y compris la fr equence appropri ee de la surveillance, les symptômes particuliers et les comorbidit es a tenir en compte, ainsi que les tests objectifs qui devraientêtre effectu es en routine. Des messages cl es fond es sur une revue de la litt erature scientifique et le consensus d'un panel d'experts en fibrose pulmonaire interstitielle sont pr esent es pour guider la pratique clinique. Objectives 1. To summarize the current evidence on long-term monitoring of patients with fibrotic ILD. 2. To provide evidence-based or expert consensus recommendations for the long-term monitoring of patients with fibrotic ILD.A working group of respirologists with expertise in the field of ILD was created within the CTS ILD Clinical Assembly.# Introduction
Fibrotic interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can be related to underlying connective tissue disease (CTD), occupational or environmental exposures or an unknown cause. They are characterized by fibrosis of lung interstitium, progressive dyspnea, worsening lung function and poor prognosis. 1 Canadian Thoracic Society (CTS) Position Statements have been recently published on the diagnosis and management of fibrotic ILDs. 2,3 Longitudinal monitoring of patients with fibrotic ILD is essential for identifying disease progression and guiding management decisions. There are no evidence-based clinical practice guidelines to inform decision-making for the appropriate components and frequency of monitoring patients with fibrotic ILD. The aim of this position paper is to provide evidence-based recommendations on the key components of long-term monitoring for the fibrotic ILD patient, and where evidence is lacking, to provide consensus expert opinions.
Two co-chairs (JHF and MK) selected committee members with the intent to represent the diversity of gender, geography, experience and expertise among Canadian ILD respirologists. Areas of expertise represented include general ILD, connective tissue disease, lung transplantation, occupational lung disease, clinical epidemiology and basic science. The primary target audiences for this statement include respirologists, internists, primary care physicians and allied-health care practitioners caring for patients with fibrotic ILD. Secondary target audiences include patients with fibrotic ILD, caregivers and advocates, and those making health policy decisions regarding fibrotic ILD.
# Literature search, evidence appraisal, and recommendations
This document was developed in accordance with the CTS requirements for a position statement (/ guideline-library) and using the AGREE II checklist for guidance. 4 Eight questions regarding the long-term management of fibrotic ILD were selected by consensus using group discussion amongst the above described working group. Topics were chosen based on members' knowledge of the literature and gaps in existing guidance and prioritized according to clinical relevance and the lack of already available evidence-based recommendations. Each question was then formulated in the PICO (problem/population, intervention, comparison, outcome) format, where applicable, by the co-chairs with the final questions approved by all coauthors. Based on expertise, groups of coauthors were assigned to summarize the scientific literature for each PICO question using keyword searches, supplemented by manual search of bibliographies of identified literature. When formulating recommendations, given the lack of available evidence in most areas, committee members were surveyed to obtain expert opinions for some key questions, including the frequency of clinic visits, symptom monitoring and appropriate testing and frequency (Online Supplemental Table 1). Consensus was reached through teleconference and email correspondence and all authors agreed with the key messages presented in the following sections.
# Position statement review
In accordance with the CTS Guideline Production Methodology (), this position statement underwent an external review. External review was conducted by a national and an international ILD expert who were independently invited by the CTS to review this position statement. Each expert provided a detailed review and suggestions, and authors responded to these reviews in detail. Internal review was conducted by 3 members of the CTS Canadian Respiratory Guidelines Committee, who provided further feedback for consideration by authors. Original reviews and responses to reviews are posted along with the position statement and all authors' conflicts of interest at (. ca/guideline-library). The CTS Executive approved the final document for publication.
# Updating this statement
In accordance with the CTS Living Guideline Model (), this document will be regularly reviewed and updated as necessary.
Reviews will occur at a minimum of every 3 years by members of the CTS ILD Clinical Assembly.
# Summary of evidence and key messages
# Monitoring of fibrotic ILD
Q1. How often should patients with fibrotic ILD be assessed in a respirology clinic in order to optimize care?
Most patients with fibrotic ILD should be regularly assessed in a respirology clinic to monitor and manage symptoms, disease progression, treatment side effects and development of comorbidities. Clinic visits facilitate decision-making surrounding initiation, alteration or discontinuation of ILD-targeted medications. Patients should also be assessed regularly to identify the need for lung transplant referral, and end-oflife planning. No literature evidence or clinical practice guidelines were identified in order to inform the appropriate frequency of routine clinic visits, and thus our recommendations are primarily based on expert consensus.
We recommend that patients with fibrotic ILD should typically be assessed at intervals of 3 to 6 months, depending on disease severity and rate of progression. More frequent monitoring may be required around the time of diagnosis and for individuals with disease progression or who are at high risk for progression. Risk factors for disease progression include older age, male sex, lower baseline forced vital capacity (FVC) and diffusing capacity (DLCO) and a usual interstitial pneumonia (UIP) pattern on chest computed tomography (CT). Less frequent monitoring is often appropriate for those patients with a high likelihood of stability, such as those with mild and longstanding disease. Given the variability in disease behavior, the availability of an expedited clinical assessment for fibrotic ILD patients is ideal in the event of worsening symptoms. A shared-care model between ILD centers and local respirologists may provide faster access to appropriate expertise. Routine assessment by a general internist may be required for those patients without access to a respirologist.
Q2. In patients with fibrotic ILD, which symptoms should be routinely monitored in order to optimally assess disease progression, medication side effects, comorbidities and quality of life?
At each visit, the severity of dyspnea and cough, functional capacity, and quality of life should be assessed in Monitoring of fibrotic ILD Q1. How often should patients with fibrotic ILD be assessed in a respirology clinic in order to optimize care? Key Messages:
We suggest that patients with fibrotic ILD should typically be monitored by a respirologist every 3-6 months, with less frequent monitoring appropriate in patients with mild and/or stable disease. We suggest alternating clinic visits with local respirologists or internists for those patients followed in ILD centers in a shared-care model, in order to facilitate timely patient care and efficient use of tertiary and quaternary care resources.
patients with fibrotic ILD. Worsening dyspnea and exercise limitation are key markers of disease progression and important risk factors for mortality. The optimal methods of measuring dyspnea and functional capacity are not known, with practical options including qualitative assessment based on clinical history or simple tools such as the Medical Research Council breathlessness scale. 13 Cough is associated with disease progression and worse quality of life, and may predict time to death or lung transplantation in patients with fibrotic ILD. A qualitative approach to assessing cough severity and frequency is most practical in the clinic setting, with cough questionnaires not commonly used outside of a research environment. Similarly, the use of detailed quality of life questionnaires, such as the St. George's Respiratory Questionnaire or King's Brief Interstitial Lung Disease questionnaire, have not been studied in the routine clinical setting. As a result, we recommend considering dyspnea and cough severity, functional capacity impairment and an individual patient's perceptions on their overall quality of life when making decisions surrounding symptom management, use of ILD-targeted medications, and timing of referral to palliative-care and/or lung transplant. Additional studies are needed to determine whether more detailed patient reported outcome measures have clinical utility. The specific pharmacologic and nonpharmacologic components of fibrotic ILD management are addressed in a separate CTS position paper. 3 In those patients with fibrotic ILD receiving treatment with antifibrotic or immunosuppressive medications, routine symptom monitoring should include assessment of medication tolerability, side effects and complications. The symptoms are therapy-specific but can include nausea, vomiting, diarrhea, fatigue, weight loss, (pirfenidone, nintedanib and some steroid sparing medications, such as, azathioprine, cyclophosphamide and mycophenolate) and complications such as infections (immunosuppressants such as prednisone and steroid sparing medications).
Assessment of additional symptoms should be considered at each clinic visit on an individualized basis. These may include alternative contributors to dyspnea and cough (e.g., infection, coronary artery disease (CAD), pulmonary vascular disease (PVD), heart failure, gastroesophageal reflux disease (GERD)), potential clues to the etiology of ILD (e.g., environmental triggers, CTD symptoms) and features of other common comorbidities. Comorbid conditions such as CAD, GERD, depression and anxiety are common in patients with fibrotic ILD, with as many as 30% of idiopathic pulmonary fibrosis (IPF) patients having 4 or more comorbidities The role of screening for PVD, lung cancer and obstructive sleep apnea (OSA) in patients with fibrotic ILD is discussed later in this document.
Q3. What testing should be performed for routine monitoring of patients with fibrotic ILD in order to detect disease progression?
We recommend routine testing of forced vital capacity (FVC) and diffusing capacity (DLCO) every 3 to 6 months to monitor for disease progression given their strong association with symptoms and mortality, frequent use as clinical trial endpoints, and mandated reporting for reimbursement of some ILD medications. We recommend six-minute walk test (6MWT) or walking oximetry be performed at 6-12-month intervals, although testing frequency will vary depending on availability, disease severity, and rate of progression.
We recommend performing chest computed tomography (CT) periodically in order to monitor for disease progression and assist with decision making surrounding treatment initiation or intensification, usually at intervals of 2 to 3 years in otherwise stable patients with no evidence of symptom or pulmonary function worsening. We do not recommend routine echocardiography for the majority of fibrotic ILD subtypes outside the setting of a suspicion of pulmonary hypertension (PH) and/or suspected cardiac dysfunction. Existing clinical practice guidelines recommend regular screening echocardiography in ILD patients at high risk of developing PH (e.g., annually in systemic sclerosis) and during lung transplant evaluation. Repeat autoimmune serology testing is suggested for patients with previously negative serology in the setting of new features suggestive of CTD. Treatment-specific monitoring is required for many ILD medications. For example, antifibrotic medications require regular testing of hepatic function. Several immunosuppressant medications (e.g., azathioprine, mycophenolate, cyclophosphamide) also require routine laboratory monitoring which often includes complete blood count, renal (creatinine) and hepatic function tests (alanine aminotransferase, alkaline phosphatase, gamma-glutamyl-transferase, bilirubin). In patients with fibrotic ILD, we suggest that clinicians measure 6MWT or walking oximetry regularly, typically every 6 to 12 months, although testing frequency varies depending on local availability, disease severity and rate of progression. In patients with fibrotic ILD, we suggest that clinicians consider follow-up chest computed tomography, every 2 to 3 years to assess for disease progression in otherwise stable patients.
In patients with fibrotic ILD, we do not recommend screening echocardiography except in patients at high risk for pulmonary hypertension or undergoing lung transplant evaluation.
In patients with fibrotic ILD, we do not recommend repeat autoimmune serology once negative, unless there are features suggestive of a connective tissue disease.
In patients with fibrotic ILD on medical therapy, we suggest that clinicians routinely screen for medication side effects and tolerability.
In patients with fibrotic ILD, we suggest that clinicians consider the potential contribution of comorbidities, given the high prevalence of coronary artery disease, pulmonary vascular disease, gastroesophageal reflux disease, depression and anxiety in this population.
Q4. How should disease progression be defined in patients with fibrotic ILD in order to guide management decision making?
Recognizing disease progression in patients with fibrotic ILD is essential to guide management and prognostication. Progression can be identified based on worse symptoms or functional capacity, worsening physiologic testing or chest imaging and/or the occurrence of adverse clinical outcomes such as respiratory hospitalization or death. The majority of data defining disease progression come from studies of patients with IPF which may not be applicable to non-IPF fibrotic ILDs. No single variable performs ideally to define progression, and the most accurate determination of disease progression is achieved from composite outcomes that include symptoms, physiology, imaging, and event-driven endpoints (e.g., hospitalization).
Change in FVC remains the most commonly recommended marker of disease progression, with numerous studies confirming that a relative or absolute 10% decline over 6 to 12 months independently predicts mortality. 10, The minimal important difference (MID) in FVC is estimated at 2-6% in IPF. 31 DLCO can be influenced by multiple factors and is thus not an ideal single measure of ILD progression; 10,25,32 however, DLCO is strongly and independently associated with mortality, suggesting that there is clinical utility to its routine measurement. 10,32 Patients with combined pulmonary fibrosis and emphysema have a relatively preserved FVC that typically declines at a slower pace than in fibrotic ILD patients without emphysema, making FVC a less reliable measure of disease progression in this sub-population. Additional monitoring modalities, such as chest CT are often required to assess disease progression in these patients.
The 6MWT is a simple, reliable, and valid tool for assessing functional capacity in patients with fibrotic ILD, providing valuable information on disease status and clinical deterioration. 37 Baseline 6-minute walk distance (6MWD) and the change over 6 and 12 months are independent predictors of mortality in IPF. 38,39 A > 50 m decline in 6MWD over 24 weeks is associated with a 2-3x increased risk of death. 40,41 A nadir peripheral oxygen saturation 88% during a 6MWT is associated with increased mortality, suggesting that development of exertional hypoxemia is an important indicator of disease progression in fibrotic ILD. 42 The MID of the 6MWD in IPF ranges from 22 to 45 m. 39,40, In patients with CTD-related fibrotic ILD, the utility of the 6MWT may be limited by extrapulmonary issues, such as arthritis and/or myopathy.
Longitudinal radiographic evaluation of patients with fibrotic ILD is less established for detecting disease progression. 47,48 Plain radiography has insufficient sensitivity to demonstrate subtle disease progression. Frequent use of CT is limited by the current radiation dose, but can be done every few years to confirm or exclude the presence of disease progression in patients with otherwise stable metrics.
Recent clinical trials in non-IPF fibrotic ILD have defined progressive disease based on a single parameter or a combination of the following: worsening respiratory symptoms, lung function decline and worsening fibrosis on chest imaging. 49,50 Additional research is needed to evaluate the role of this definition in routine clinical practice.
Data which were derived from large cohorts studied under very standardized research settings can be challenging to apply to an individual in the clinic. An isolated worsening of one feature (e.g., 10% decline in FVC, 15% decline in DLCO, 50 m decline in 6MWD) may herald an important clinical change, but should be repeated and confirmed by a second observation. Smaller changes should similarly be corroborated with other measures or prompt a short-interval ( 3 months) reassessment. In patients with uncertain evidence of progression, alternate etiologies of worsening (e.g., respiratory muscle weakness) should be excluded prior to making major treatment decisions.
# Treatment decisions
Q5. How should disease progression influence the decision to start, stop or change medications in patients with fibrotic ILD?
Pharmacotherapy aimed at stabilizing or slowing the decline in lung function and the evidence supporting those treatments are summarized in the previous CTS position paper on the comprehensive management of ILD. 3 Initiation of anti-fibrotic therapy should be considered in all treatmentnaïve patients with IPF, but may not be appropriate in some situations. In patients who continue to progress despite the use of medication, it can be difficult to establish if patients are "failing" on current therapy or if their observed progression has been attenuated from an even more rapid course that would have occurred without therapy. This poses significant challenges to clinicians who struggle to decide if therapy should be continued, modified or discontinued in the setting of disease progression.
A post-hoc analysis of patients who had a 10% decline in FVC in the pirfenidone and placebo arms of the ASCEND and CAPACITY studies, found continued pirfenidone treatment was associated with a lower risk of FVC decline 10% or death in the subsequent 6 months as compared to placebo (5.9% vs. 27.9%, relative difference 79.8%). 51 These results suggest it may be appropriate to continue therapy in some patients despite evidence of disease progression. In patients requiring discontinuation of their initial anti-fibrotic due to intolerability, many will be able to tolerate the alternative anti-fibrotic agent with subsequent stabilization of their lung function. 52 In patients with IPF who have had progression of their disease despite tolerating
# Monitoring of fibrotic ILD
Q4. How should disease progression be defined in patients with fibrotic ILD in order to guide management decision making? Key Messages:
In order to identify disease progression in patients with fibrotic ILD, we suggest that clinicians integrate multiple parameters, including symptoms, physiological measurements and radiological findings.
In patients with fibrotic ILD, we suggest that clinicians contextualize worsening in a single domain (or measure) with other domains and/or repeat measurements in the short-term ( 3 months) to confirm evidence of disease progression.
moderate-to-high doses of their initial anti-fibrotic therapy for more than 6 months, switching from one medication to the other has never been assessed in a prospective randomized controlled trial, and thus very little is known about the efficacy of this strategy. Decisions about switching antifibrotic agents should be made on a case-by-case basis with a high priority placed on patient preferences regarding side effect profiles.
Trials of add-on (combination) anti-fibrotic therapy have demonstrated that adverse effects are additive, and although these may be acceptable to some patients, these trials were inadequately powered to demonstrate benefit. 53,54 Such studies are needed prior to endorsing the use of combination therapy outside of the clinical trial context. Currently, combination anti-fibrotic therapy is not approved in Canada.
Stopping anti-fibrotic therapy altogether may be appropriate in some cases, especially when patients have significant drug-induced adverse effects in the face of ongoing disease progression. There are rare reports of accelerated progression of IPF following discontinuation of anti-fibrotic medication, 55 although there are limited data on this possible phenomenon and this may be an acceptable risk if the primary goals of care are palliation of symptoms.
Many non-IPF fibrotic ILDs are progressive diseases that lead to worsening lung function, dyspnea, and quality of life. Some patient and disease-related characteristics such as age, sex, severity of lung function impairment, specific auto-antibody profiles and radiological/histopathological pattern can help predict prognosis. 7,56,57 Patients with a high risk of adverse outcome or clear evidence of progressive disease should be considered for early pharmacotherapy. Decisions regarding which therapy to use in which patient is often based on expert opinion rather than high-quality data. In the setting of clear disease progression on one treatment, switching or adding a medication is often considered. A multidisciplinary approach combining rheumatology and respirology specialists for patients with CTD-ILD is essential to ensure that the chosen medication regime is appropriate for both the pulmonary and extra-pulmonary manifestations of disease. 58 Comorbidity screening Q6. Should patients with fibrotic ILD be screened for pulmonary vascular disease in order to improve outcomes and assist with prognostication?
According to data from a large United States medical claims database, patients with IPF are at a 7-and 16-fold increased risk of pulmonary embolism (PE) and PH, respectively, as compared to age and gender matched controls. 23 PE remains an important consideration in patients with an acute or subacute change in their respiratory status. The overall prevalence of PH among patients with advanced IPF primarily assessed in the tertiary care setting varies between 32% and 55% in retrospective cohort data. Recognition of PH may be pertinent for prognostication of patients being considered for lung transplant given its association with increased mortality; however, we do not recommend routine screening echocardiography outside of these select populations. 64 Treatment of PH with targeted pulmonary arterial hypertension (PAH) therapies has not been proven effective or safe for patients with IPF. However, Canadian and international PH clinical practice guidelines recommend that selected patients with moderate-severe PH and/or right-ventricular failure in the setting of only mild-moderate fibrotic lung disease without significant hypoxemia should be referred to specialized PH clinics for further assessment of the cause of PH and potential therapeutic options. 65,66 Patients with certain CTDs, particularly systemic sclerosis, are at increased risk of PAH and annual screening with echocardiography is typically recommended for those with a DLCO <80%. 67 Q7. Should lung cancer screening be routine in patients with fibrotic ILD?
The cumulative incidence of lung cancer amongst patients with IPF is 3.3%, 15.4% and 52.7% after 1, 5 and 10 years follow-up. 68 Patients with IPF independently have a 4-to 5-fold increased risk of developing lung cancer compared to patients with emphysema 69 and matched controls in the general population. 70 Lung cancer risk appears to be highest in patients with combined pulmonary fibrosis and emphysema. 71 Lung cancer rates may also be increased in other fibrotic ILDs, although the evidence is less robust compared to IPF. CTD patients on chronic immunosuppressive medications and recipients of solid organ transplant have a modestly increased In patients with IPF, we suggest that clinicians discuss initiation of an anti-fibrotic medication at the time of diagnosis and place a high priority on individual patient preference regarding risk of future disease progression (worsening) vs. side effect profile when making treatment decisions.
In patients with IPF with disease progression on therapy, it is reasonable to either continue or switch antifibrotic medication. This decision should be made on an individual basis, placing a high priority on patient preferences regarding side effect profile. Add on or combination therapies may become an option in the future but are not yet established.
In patients with IPF with disease progression on therapy, stopping antifibrotic therapy may be appropriate in the setting of significant side effects and/or when the primary goal is palliation of symptoms. Because there is a lack of robust data to guide the timing of initiation and choice of medications to treat non-IPF fibrotic ILD, we suggest that clinicians make pharmacotherapy decisions on an individual basis, considering disease severity and/or risk factors for progressive disease.
In patients with CTD-ILD, we suggest that clinicians pursue a multidisciplinary approach involving rheumatology, when making treatment decisions.
Comorbidity screening Q6. Should patients with fibrotic ILD be screened for pulmonary vascular disease in order to improve outcomes and assist with prognostication? Key messages: Pulmonary embolism and pulmonary hypertension are recognized comorbidities in patients with fibrotic ILD and important considerations in the setting of acute or subacute respiratory deterioration in these patients. We suggest that clinicians refer patients with more than mild pulmonary hypertension and/or right ventricular failure with only mild-moderate fibrotic ILD to pulmonary hypertension clinics, particularly in the setting of CTD or other conditions associated with pulmonary arterial hypertension or chronic thromboembolic disease. Pulmonary hypertension is an important prognostic factor and may be relevant for patients being considered for lung transplant.
risk of malignancy 76,77 compared to the general population, and patients with fibrotic ILD on long term immunosuppressive agents likely have a similarly increased risk. Lung cancer is associated with a particularly poor prognosis in fibrotic ILD. Patients with ILD and lung cancer have decreased survival compared to those with lung cancer alone, after adjusting for various factors, including age, sex, performance status, cancer type and smoking status. 78,79 In addition, the treatment of lung cancer in patients with fibrotic ILD is associated with increased risk of radiation pneumonitis, chemotherapy related toxicity and surgical complications, 72 although select early stage cancers may benefit from surgical management. 80 In theory, screening fibrotic ILD patients for lung cancer could identify earlystage malignancy that has more therapeutic options, such as minimally invasive surgical procedures or stereotactic body radiotherapy, given the challenges in managing these patients. More data are needed to test this possibility and to identify which patients might be most appropriate to screen. International IPF guidelines state the role of lung cancer screening in the setting of IPF remains unknown. 81 Q8. Should obstructive sleep apnea screening be routine in patients with fibrotic ILD?
Small retrospective studies have suggested that OSA is common in patients with ILD, although the majority of data available is for IPF and prevalence estimates have varied widely (from 5.9% to 88%) depending on the population and number of years studied. 23, IPF patients with OSA typically do not endorse excessive daytime sleepiness making widely available screening tools such as the Epworth Sleepiness Scale and STOP-BANG score less helpful in this subgroup. Fibrotic ILD patients experience poor sleep quality with abnormal sleep architecture and nocturnal hypoxemia, 85,91,92 that is associated with fatigue, reduced quality of life, new or worsening PH and increased mortality. 85,90,93 The presence of OSA with nocturnal hypoxia has also been associated with IPF related morbidity and mortality, although the direction of association is unknown and requires further study. 83 Limited evidence in highly selected populations suggests that initiation of continuous positive airway pressure (CPAP) therapy for IPF patients with moderate to severe OSA may improve quality of life, although patients may require additional support to ensure adherence to therapy. 87,94,95 Screening fibrotic ILD patients for OSA would conceivably allow for earlier identification of a potentially treatable comorbidity; however, more data are required to demonstrate any utility of such an approach. Maintaining a high index of suspicion for OSA in this population is reasonable, giving that patients with fibrotic ILD may not report the typical symptoms of excessive daytime sleepiness.
# Conclusions
Longitudinal monitoring of patients with fibrotic ILD is essential for identifying disease progression and guiding management decisions. Key components of monitoring include assessment of symptoms, functional capacity, physiology, radiology and disease-and treatment-related comorbidities. We advocate for a multidisciplinary and collaborative approach to patient care when feasible that may include ILD clinicians, community respirologists or internists, primary care physicians and other relevant subspecialties. Additional studies are needed to generate ILDspecific data that will inform the ideal screening approach for common comorbidities of ILD. | Longitudinal monitoring of patients with fibrotic interstitial lung disease (ILD) is essential to identifying disease progression and guiding management decisions. There are no evidence-based clinical practice guidelines to inform decision-making for the appropriate components and frequency of monitoring patients with fibrotic ILD. This position statement summarizes the key components of long-term monitoring of fibrotic ILD, including the appropriate frequency of monitoring, specific symptoms and comorbidities to consider, and the objective testing that should be routinely performed. Key messages based on scientific literature review and consensus from a panel of ILD experts are provided to guide clinical practice.La surveillance longitudinale des patients atteints de fibrose pulmonaire interstitielle est essentielle pour d eterminer la progression de la maladie et guider les d ecisions de prise en charge. Il n'existe pas de lignes directrices de pratique clinique fond ees sur des donn ees probantes pour eclairer la prise de d ecision concernant les composantes et la fr equence de la surveillance appropri ees des patients atteints de fibrose pulmonaire interstitielle. Cet enonc e de position r esume les el ements cl es de la surveillance fibrose pulmonaire interstitielle a long terme, y compris la fr equence appropri ee de la surveillance, les symptômes particuliers et les comorbidit es a tenir en compte, ainsi que les tests objectifs qui devraientêtre effectu es en routine. Des messages cl es fond es sur une revue de la litt erature scientifique et le consensus d'un panel d'experts en fibrose pulmonaire interstitielle sont pr esent es pour guider la pratique clinique. Objectives 1. To summarize the current evidence on long-term monitoring of patients with fibrotic ILD. 2. To provide evidence-based or expert consensus recommendations for the long-term monitoring of patients with fibrotic ILD.A working group of respirologists with expertise in the field of ILD was created within the CTS ILD Clinical Assembly.# Introduction
Fibrotic interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can be related to underlying connective tissue disease (CTD), occupational or environmental exposures or an unknown cause. They are characterized by fibrosis of lung interstitium, progressive dyspnea, worsening lung function and poor prognosis. 1 Canadian Thoracic Society (CTS) Position Statements have been recently published on the diagnosis and management of fibrotic ILDs. 2,3 Longitudinal monitoring of patients with fibrotic ILD is essential for identifying disease progression and guiding management decisions. There are no evidence-based clinical practice guidelines to inform decision-making for the appropriate components and frequency of monitoring patients with fibrotic ILD. The aim of this position paper is to provide evidence-based recommendations on the key components of long-term monitoring for the fibrotic ILD patient, and where evidence is lacking, to provide consensus expert opinions.
Two co-chairs (JHF and MK) selected committee members with the intent to represent the diversity of gender, geography, experience and expertise among Canadian ILD respirologists. Areas of expertise represented include general ILD, connective tissue disease, lung transplantation, occupational lung disease, clinical epidemiology and basic science. The primary target audiences for this statement include respirologists, internists, primary care physicians and allied-health care practitioners caring for patients with fibrotic ILD. Secondary target audiences include patients with fibrotic ILD, caregivers and advocates, and those making health policy decisions regarding fibrotic ILD.
# Literature search, evidence appraisal, and recommendations
This document was developed in accordance with the CTS requirements for a position statement (https://cts-sct.ca/ guideline-library) and using the AGREE II checklist for guidance. 4 Eight questions regarding the long-term management of fibrotic ILD were selected by consensus using group discussion amongst the above described working group. Topics were chosen based on members' knowledge of the literature and gaps in existing guidance and prioritized according to clinical relevance and the lack of already available evidence-based recommendations. Each question was then formulated in the PICO (problem/population, intervention, comparison, outcome) format, where applicable, by the co-chairs with the final questions approved by all coauthors. Based on expertise, groups of coauthors were assigned to summarize the scientific literature for each PICO question using keyword searches, supplemented by manual search of bibliographies of identified literature. When formulating recommendations, given the lack of available evidence in most areas, committee members were surveyed to obtain expert opinions for some key questions, including the frequency of clinic visits, symptom monitoring and appropriate testing and frequency (Online Supplemental Table 1). Consensus was reached through teleconference and email correspondence and all authors agreed with the key messages presented in the following sections.
# Position statement review
In accordance with the CTS Guideline Production Methodology (https://cts-sct.ca/guideline-library), this position statement underwent an external review. External review was conducted by a national and an international ILD expert who were independently invited by the CTS to review this position statement. Each expert provided a detailed review and suggestions, and authors responded to these reviews in detail. Internal review was conducted by 3 members of the CTS Canadian Respiratory Guidelines Committee, who provided further feedback for consideration by authors. Original reviews and responses to reviews are posted along with the position statement and all authors' conflicts of interest at (https://cts-sct. ca/guideline-library). The CTS Executive approved the final document for publication.
# Updating this statement
In accordance with the CTS Living Guideline Model (https://cts-sct/guideline-library/methodology), this document will be regularly reviewed and updated as necessary.
Reviews will occur at a minimum of every 3 years by members of the CTS ILD Clinical Assembly.
# Summary of evidence and key messages
# Monitoring of fibrotic ILD
Q1. How often should patients with fibrotic ILD be assessed in a respirology clinic in order to optimize care?
Most patients with fibrotic ILD should be regularly assessed in a respirology clinic to monitor and manage symptoms, disease progression, treatment side effects and development of comorbidities. Clinic visits facilitate decision-making surrounding initiation, alteration or discontinuation of ILD-targeted medications. Patients should also be assessed regularly to identify the need for lung transplant referral, and end-oflife planning. No literature evidence or clinical practice guidelines were identified in order to inform the appropriate frequency of routine clinic visits, and thus our recommendations are primarily based on expert consensus.
We recommend that patients with fibrotic ILD should typically be assessed at intervals of 3 to 6 months, depending on disease severity and rate of progression. More frequent monitoring may be required around the time of diagnosis and for individuals with disease progression or who are at high risk for progression. Risk factors for disease progression include older age, male sex, lower baseline forced vital capacity (FVC) and diffusing capacity (DLCO) and a usual interstitial pneumonia (UIP) pattern on chest computed tomography (CT). [5][6][7][8][9] Less frequent monitoring is often appropriate for those patients with a high likelihood of stability, such as those with mild and longstanding disease. Given the variability in disease behavior, the availability of an expedited clinical assessment for fibrotic ILD patients is ideal in the event of worsening symptoms. A shared-care model between ILD centers and local respirologists may provide faster access to appropriate expertise. Routine assessment by a general internist may be required for those patients without access to a respirologist.
Q2. In patients with fibrotic ILD, which symptoms should be routinely monitored in order to optimally assess disease progression, medication side effects, comorbidities and quality of life?
At each visit, the severity of dyspnea and cough, functional capacity, and quality of life should be assessed in Monitoring of fibrotic ILD Q1. How often should patients with fibrotic ILD be assessed in a respirology clinic in order to optimize care? Key Messages:
We suggest that patients with fibrotic ILD should typically be monitored by a respirologist every 3-6 months, with less frequent monitoring appropriate in patients with mild and/or stable disease. We suggest alternating clinic visits with local respirologists or internists for those patients followed in ILD centers in a shared-care model, in order to facilitate timely patient care and efficient use of tertiary and quaternary care resources.
patients with fibrotic ILD. Worsening dyspnea and exercise limitation are key markers of disease progression and important risk factors for mortality. [10][11][12] The optimal methods of measuring dyspnea and functional capacity are not known, with practical options including qualitative assessment based on clinical history or simple tools such as the Medical Research Council breathlessness scale. 13 Cough is associated with disease progression and worse quality of life, and may predict time to death or lung transplantation in patients with fibrotic ILD. [14][15][16] A qualitative approach to assessing cough severity and frequency is most practical in the clinic setting, with cough questionnaires not commonly used outside of a research environment. Similarly, the use of detailed quality of life questionnaires, such as the St. George's Respiratory Questionnaire or King's Brief Interstitial Lung Disease questionnaire, have not been studied in the routine clinical setting. As a result, we recommend considering dyspnea and cough severity, functional capacity impairment and an individual patient's perceptions on their overall quality of life when making decisions surrounding symptom management, use of ILD-targeted medications, and timing of referral to palliative-care and/or lung transplant. Additional studies are needed to determine whether more detailed patient reported outcome measures have clinical utility. [17][18][19] The specific pharmacologic and nonpharmacologic components of fibrotic ILD management are addressed in a separate CTS position paper. 3 In those patients with fibrotic ILD receiving treatment with antifibrotic or immunosuppressive medications, routine symptom monitoring should include assessment of medication tolerability, side effects and complications. The symptoms are therapy-specific but can include nausea, vomiting, diarrhea, fatigue, weight loss, (pirfenidone, nintedanib and some steroid sparing medications, such as, azathioprine, cyclophosphamide and mycophenolate) and complications such as infections (immunosuppressants such as prednisone and steroid sparing medications).
Assessment of additional symptoms should be considered at each clinic visit on an individualized basis. These may include alternative contributors to dyspnea and cough (e.g., infection, coronary artery disease (CAD), pulmonary vascular disease (PVD), heart failure, gastroesophageal reflux disease (GERD)), potential clues to the etiology of ILD (e.g., environmental triggers, CTD symptoms) and features of other common comorbidities. Comorbid conditions such as CAD, GERD, depression and anxiety are common in patients with fibrotic ILD, with as many as 30% of idiopathic pulmonary fibrosis (IPF) patients having 4 or more comorbidities [20][21][22][23][24] The role of screening for PVD, lung cancer and obstructive sleep apnea (OSA) in patients with fibrotic ILD is discussed later in this document.
Q3. What testing should be performed for routine monitoring of patients with fibrotic ILD in order to detect disease progression?
We recommend routine testing of forced vital capacity (FVC) and diffusing capacity (DLCO) every 3 to 6 months to monitor for disease progression given their strong association with symptoms and mortality, frequent use as clinical trial endpoints, and mandated reporting for reimbursement of some ILD medications. We recommend six-minute walk test (6MWT) or walking oximetry be performed at 6-12-month intervals, although testing frequency will vary depending on availability, disease severity, and rate of progression.
We recommend performing chest computed tomography (CT) periodically in order to monitor for disease progression and assist with decision making surrounding treatment initiation or intensification, usually at intervals of 2 to 3 years in otherwise stable patients with no evidence of symptom or pulmonary function worsening. We do not recommend routine echocardiography for the majority of fibrotic ILD subtypes outside the setting of a suspicion of pulmonary hypertension (PH) and/or suspected cardiac dysfunction. Existing clinical practice guidelines recommend regular screening echocardiography in ILD patients at high risk of developing PH (e.g., annually in systemic sclerosis) and during lung transplant evaluation. Repeat autoimmune serology testing is suggested for patients with previously negative serology in the setting of new features suggestive of CTD. Treatment-specific monitoring is required for many ILD medications. For example, antifibrotic medications require regular testing of hepatic function. Several immunosuppressant medications (e.g., azathioprine, mycophenolate, cyclophosphamide) also require routine laboratory monitoring which often includes complete blood count, renal (creatinine) and hepatic function tests (alanine aminotransferase, alkaline phosphatase, gamma-glutamyl-transferase, bilirubin). In patients with fibrotic ILD, we suggest that clinicians measure 6MWT or walking oximetry regularly, typically every 6 to 12 months, although testing frequency varies depending on local availability, disease severity and rate of progression. In patients with fibrotic ILD, we suggest that clinicians consider follow-up chest computed tomography, every 2 to 3 years to assess for disease progression in otherwise stable patients.
In patients with fibrotic ILD, we do not recommend screening echocardiography except in patients at high risk for pulmonary hypertension or undergoing lung transplant evaluation.
In patients with fibrotic ILD, we do not recommend repeat autoimmune serology once negative, unless there are features suggestive of a connective tissue disease.
In patients with fibrotic ILD on medical therapy, we suggest that clinicians routinely screen for medication side effects and tolerability.
In patients with fibrotic ILD, we suggest that clinicians consider the potential contribution of comorbidities, given the high prevalence of coronary artery disease, pulmonary vascular disease, gastroesophageal reflux disease, depression and anxiety in this population.
Q4. How should disease progression be defined in patients with fibrotic ILD in order to guide management decision making?
Recognizing disease progression in patients with fibrotic ILD is essential to guide management and prognostication. Progression can be identified based on worse symptoms or functional capacity, worsening physiologic testing or chest imaging and/or the occurrence of adverse clinical outcomes such as respiratory hospitalization or death. The majority of data defining disease progression come from studies of patients with IPF which may not be applicable to non-IPF fibrotic ILDs. No single variable performs ideally to define progression, and the most accurate determination of disease progression is achieved from composite outcomes that include symptoms, physiology, imaging, and event-driven endpoints (e.g., hospitalization).
Change in FVC remains the most commonly recommended marker of disease progression, with numerous studies confirming that a relative or absolute 10% decline over 6 to 12 months independently predicts mortality. 10,[25][26][27][28][29][30] The minimal important difference (MID) in FVC is estimated at 2-6% in IPF. 31 DLCO can be influenced by multiple factors and is thus not an ideal single measure of ILD progression; 10,25,32 however, DLCO is strongly and independently associated with mortality, suggesting that there is clinical utility to its routine measurement. 10,32 Patients with combined pulmonary fibrosis and emphysema have a relatively preserved FVC that typically declines at a slower pace than in fibrotic ILD patients without emphysema, making FVC a less reliable measure of disease progression in this sub-population. [33][34][35][36] Additional monitoring modalities, such as chest CT are often required to assess disease progression in these patients.
The 6MWT is a simple, reliable, and valid tool for assessing functional capacity in patients with fibrotic ILD, providing valuable information on disease status and clinical deterioration. 37 Baseline 6-minute walk distance (6MWD) and the change over 6 and 12 months are independent predictors of mortality in IPF. 38,39 A > 50 m decline in 6MWD over 24 weeks is associated with a 2-3x increased risk of death. 40,41 A nadir peripheral oxygen saturation 88% during a 6MWT is associated with increased mortality, suggesting that development of exertional hypoxemia is an important indicator of disease progression in fibrotic ILD. 42 The MID of the 6MWD in IPF ranges from 22 to 45 m. 39,40,[43][44][45][46] In patients with CTD-related fibrotic ILD, the utility of the 6MWT may be limited by extrapulmonary issues, such as arthritis and/or myopathy.
Longitudinal radiographic evaluation of patients with fibrotic ILD is less established for detecting disease progression. 47,48 Plain radiography has insufficient sensitivity to demonstrate subtle disease progression. Frequent use of CT is limited by the current radiation dose, but can be done every few years to confirm or exclude the presence of disease progression in patients with otherwise stable metrics.
Recent clinical trials in non-IPF fibrotic ILD have defined progressive disease based on a single parameter or a combination of the following: worsening respiratory symptoms, lung function decline and worsening fibrosis on chest imaging. 49,50 Additional research is needed to evaluate the role of this definition in routine clinical practice.
Data which were derived from large cohorts studied under very standardized research settings can be challenging to apply to an individual in the clinic. An isolated worsening of one feature (e.g., 10% decline in FVC, 15% decline in DLCO, 50 m decline in 6MWD) may herald an important clinical change, but should be repeated and confirmed by a second observation. Smaller changes should similarly be corroborated with other measures or prompt a short-interval ( 3 months) reassessment. In patients with uncertain evidence of progression, alternate etiologies of worsening (e.g., respiratory muscle weakness) should be excluded prior to making major treatment decisions.
# Treatment decisions
Q5. How should disease progression influence the decision to start, stop or change medications in patients with fibrotic ILD?
Pharmacotherapy aimed at stabilizing or slowing the decline in lung function and the evidence supporting those treatments are summarized in the previous CTS position paper on the comprehensive management of ILD. 3 Initiation of anti-fibrotic therapy should be considered in all treatmentnaïve patients with IPF, but may not be appropriate in some situations. In patients who continue to progress despite the use of medication, it can be difficult to establish if patients are "failing" on current therapy or if their observed progression has been attenuated from an even more rapid course that would have occurred without therapy. This poses significant challenges to clinicians who struggle to decide if therapy should be continued, modified or discontinued in the setting of disease progression.
A post-hoc analysis of patients who had a 10% decline in FVC in the pirfenidone and placebo arms of the ASCEND and CAPACITY studies, found continued pirfenidone treatment was associated with a lower risk of FVC decline 10% or death in the subsequent 6 months as compared to placebo (5.9% vs. 27.9%, relative difference 79.8%). 51 These results suggest it may be appropriate to continue therapy in some patients despite evidence of disease progression. In patients requiring discontinuation of their initial anti-fibrotic due to intolerability, many will be able to tolerate the alternative anti-fibrotic agent with subsequent stabilization of their lung function. 52 In patients with IPF who have had progression of their disease despite tolerating
# Monitoring of fibrotic ILD
Q4. How should disease progression be defined in patients with fibrotic ILD in order to guide management decision making? Key Messages:
In order to identify disease progression in patients with fibrotic ILD, we suggest that clinicians integrate multiple parameters, including symptoms, physiological measurements and radiological findings.
In patients with fibrotic ILD, we suggest that clinicians contextualize worsening in a single domain (or measure) with other domains and/or repeat measurements in the short-term ( 3 months) to confirm evidence of disease progression.
moderate-to-high doses of their initial anti-fibrotic therapy for more than 6 months, switching from one medication to the other has never been assessed in a prospective randomized controlled trial, and thus very little is known about the efficacy of this strategy. Decisions about switching antifibrotic agents should be made on a case-by-case basis with a high priority placed on patient preferences regarding side effect profiles.
Trials of add-on (combination) anti-fibrotic therapy have demonstrated that adverse effects are additive, and although these may be acceptable to some patients, these trials were inadequately powered to demonstrate benefit. 53,54 Such studies are needed prior to endorsing the use of combination therapy outside of the clinical trial context. Currently, combination anti-fibrotic therapy is not approved in Canada.
Stopping anti-fibrotic therapy altogether may be appropriate in some cases, especially when patients have significant drug-induced adverse effects in the face of ongoing disease progression. There are rare reports of accelerated progression of IPF following discontinuation of anti-fibrotic medication, 55 although there are limited data on this possible phenomenon and this may be an acceptable risk if the primary goals of care are palliation of symptoms.
Many non-IPF fibrotic ILDs are progressive diseases that lead to worsening lung function, dyspnea, and quality of life. Some patient and disease-related characteristics such as age, sex, severity of lung function impairment, specific auto-antibody profiles and radiological/histopathological pattern can help predict prognosis. 7,56,57 Patients with a high risk of adverse outcome or clear evidence of progressive disease should be considered for early pharmacotherapy. Decisions regarding which therapy to use in which patient is often based on expert opinion rather than high-quality data. In the setting of clear disease progression on one treatment, switching or adding a medication is often considered. A multidisciplinary approach combining rheumatology and respirology specialists for patients with CTD-ILD is essential to ensure that the chosen medication regime is appropriate for both the pulmonary and extra-pulmonary manifestations of disease. 58 Comorbidity screening Q6. Should patients with fibrotic ILD be screened for pulmonary vascular disease in order to improve outcomes and assist with prognostication?
According to data from a large United States medical claims database, patients with IPF are at a 7-and 16-fold increased risk of pulmonary embolism (PE) and PH, respectively, as compared to age and gender matched controls. 23 PE remains an important consideration in patients with an acute or subacute change in their respiratory status. The overall prevalence of PH among patients with advanced IPF primarily assessed in the tertiary care setting varies between 32% and 55% [59][60][61][62][63] in retrospective cohort data. Recognition of PH may be pertinent for prognostication of patients being considered for lung transplant given its association with increased mortality; however, we do not recommend routine screening echocardiography outside of these select populations. 64 Treatment of PH with targeted pulmonary arterial hypertension (PAH) therapies has not been proven effective or safe for patients with IPF. However, Canadian and international PH clinical practice guidelines recommend that selected patients with moderate-severe PH and/or right-ventricular failure in the setting of only mild-moderate fibrotic lung disease without significant hypoxemia should be referred to specialized PH clinics for further assessment of the cause of PH and potential therapeutic options. 65,66 Patients with certain CTDs, particularly systemic sclerosis, are at increased risk of PAH and annual screening with echocardiography is typically recommended for those with a DLCO <80%. 67 Q7. Should lung cancer screening be routine in patients with fibrotic ILD?
The cumulative incidence of lung cancer amongst patients with IPF is 3.3%, 15.4% and 52.7% after 1, 5 and 10 years follow-up. 68 Patients with IPF independently have a 4-to 5-fold increased risk of developing lung cancer compared to patients with emphysema 69 and matched controls in the general population. 70 Lung cancer risk appears to be highest in patients with combined pulmonary fibrosis and emphysema. 71 Lung cancer rates may also be increased in other fibrotic ILDs, although the evidence is less robust compared to IPF. [72][73][74][75] CTD patients on chronic immunosuppressive medications and recipients of solid organ transplant have a modestly increased In patients with IPF, we suggest that clinicians discuss initiation of an anti-fibrotic medication at the time of diagnosis and place a high priority on individual patient preference regarding risk of future disease progression (worsening) vs. side effect profile when making treatment decisions.
In patients with IPF with disease progression on therapy, it is reasonable to either continue or switch antifibrotic medication. This decision should be made on an individual basis, placing a high priority on patient preferences regarding side effect profile. Add on or combination therapies may become an option in the future but are not yet established.
In patients with IPF with disease progression on therapy, stopping antifibrotic therapy may be appropriate in the setting of significant side effects and/or when the primary goal is palliation of symptoms. Because there is a lack of robust data to guide the timing of initiation and choice of medications to treat non-IPF fibrotic ILD, we suggest that clinicians make pharmacotherapy decisions on an individual basis, considering disease severity and/or risk factors for progressive disease.
In patients with CTD-ILD, we suggest that clinicians pursue a multidisciplinary approach involving rheumatology, when making treatment decisions.
Comorbidity screening Q6. Should patients with fibrotic ILD be screened for pulmonary vascular disease in order to improve outcomes and assist with prognostication? Key messages: Pulmonary embolism and pulmonary hypertension are recognized comorbidities in patients with fibrotic ILD and important considerations in the setting of acute or subacute respiratory deterioration in these patients. We suggest that clinicians refer patients with more than mild pulmonary hypertension and/or right ventricular failure with only mild-moderate fibrotic ILD to pulmonary hypertension clinics, particularly in the setting of CTD or other conditions associated with pulmonary arterial hypertension or chronic thromboembolic disease. Pulmonary hypertension is an important prognostic factor and may be relevant for patients being considered for lung transplant.
risk of malignancy 76,77 compared to the general population, and patients with fibrotic ILD on long term immunosuppressive agents likely have a similarly increased risk. Lung cancer is associated with a particularly poor prognosis in fibrotic ILD. Patients with ILD and lung cancer have decreased survival compared to those with lung cancer alone, after adjusting for various factors, including age, sex, performance status, cancer type and smoking status. 78,79 In addition, the treatment of lung cancer in patients with fibrotic ILD is associated with increased risk of radiation pneumonitis, chemotherapy related toxicity and surgical complications, 72 although select early stage cancers may benefit from surgical management. 80 In theory, screening fibrotic ILD patients for lung cancer could identify earlystage malignancy that has more therapeutic options, such as minimally invasive surgical procedures or stereotactic body radiotherapy, given the challenges in managing these patients. More data are needed to test this possibility and to identify which patients might be most appropriate to screen. International IPF guidelines state the role of lung cancer screening in the setting of IPF remains unknown. 81 Q8. Should obstructive sleep apnea screening be routine in patients with fibrotic ILD?
Small retrospective studies have suggested that OSA is common in patients with ILD, although the majority of data available is for IPF and prevalence estimates have varied widely (from 5.9% to 88%) depending on the population and number of years studied. 23,[82][83][84][85][86] IPF patients with OSA typically do not endorse excessive daytime sleepiness making widely available screening tools such as the Epworth Sleepiness Scale and STOP-BANG score less helpful in this subgroup. [87][88][89][90] Fibrotic ILD patients experience poor sleep quality with abnormal sleep architecture and nocturnal hypoxemia, 85,91,92 that is associated with fatigue, reduced quality of life, new or worsening PH and increased mortality. 85,90,93 The presence of OSA with nocturnal hypoxia has also been associated with IPF related morbidity and mortality, although the direction of association is unknown and requires further study. 83 Limited evidence in highly selected populations suggests that initiation of continuous positive airway pressure (CPAP) therapy for IPF patients with moderate to severe OSA may improve quality of life, although patients may require additional support to ensure adherence to therapy. 87,94,95 Screening fibrotic ILD patients for OSA would conceivably allow for earlier identification of a potentially treatable comorbidity; however, more data are required to demonstrate any utility of such an approach. Maintaining a high index of suspicion for OSA in this population is reasonable, giving that patients with fibrotic ILD may not report the typical symptoms of excessive daytime sleepiness.
# Conclusions
Longitudinal monitoring of patients with fibrotic ILD is essential for identifying disease progression and guiding management decisions. Key components of monitoring include assessment of symptoms, functional capacity, physiology, radiology and disease-and treatment-related comorbidities. We advocate for a multidisciplinary and collaborative approach to patient care when feasible that may include ILD clinicians, community respirologists or internists, primary care physicians and other relevant subspecialties. Additional studies are needed to generate ILDspecific data that will inform the ideal screening approach for common comorbidities of ILD.
# Acknowledgments
The authors would like to thank the CTS and the Executive Committee of the Canadian Respiratory Guidelines Committee (CRGC) (Samir Gupta, Christopher Licskai, and Sanjay Mehta) for their thoughtful comments and input. We would also like to acknowledge with deep appreciation our Expert Peer Reviewers who made valuable contributions to the manuscript: Andr e Cantin, MD, Universit e de Sherbrooke, Facult e de M edecine et des Sciences de la Sant e, Sherbrooke, Qu ebec, Canada; and Helen Jo, MD, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
# Editorial independence
The CTS ILD Assembly is accountable to the CTS CRGC and the CTS Board of Directors. The CTS ILD Assembly is functionally and editorially independent from any funding sources of the CTS and does not receive any direct funding from external sources. The CTS receives unrestricted grants that are combined into a central operating account to facilitate the knowledge translation activities of the CTS Assemblies. No funders played a role in the collection, review, analysis or interpretation of the scientific literature or in any decisions regarding the key messages presented in this document.
# Disclosure statement
Members of the CTS ILD Assembly declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy. Individual member conflict of interest statements are posted at https://cts-sct.ca/guideline-library/. | None | None |
1c417751f132c58b723370e32fec84210026fafa | cma | None | Thank you for the opportunity to contribute an expert clinical opinion into your examinations of the safe use of Ulipristal Acetate in the management of uterine fibroids. To address the questions that you posed, we assembled a panel of experts, who are both deeply knowledgeable of the scientific literature, but who also care for substantial numbers of women with uterine fibroids and have that knowledge of the impact on women's health, the options available for treatment as well as the considerations women bring to the discussion of an informed choice. Any consideration of the role of the selective progesterone receptor modulator (SPRM), ulipristal acetate(UPA), in the Canadian clinical armamentarium has to be taken with an understanding of the impact of uterine fibroids on women's health. Uterine fibroids are the most common benign pelvic tumor in women, and are found in up to 68% of women, although not all are symptomatic. The symptoms range from pain and heavy menstrual bleeding to impacts from compression by the mass on bladder bowel and large veins.#
Women with symptomatic fibroids experience diminished quality of life, reduction in the ability of participate in usual activities, loss of time from work, sexual dysfunction and reduced fertility. Uterine fibroids do not impact all women to the same extent. They disproportionately affect the health of black women, with both greater severity and a younger age, leading to a greater impact on the health of women of child-bearing age. In a recent U.S. study 1 nearly one third of women who had undergone a hysterectomy for symptomatic fibroids would have been interested in non-surgical management; in 46% of those it was to have preserved child bearing capability. This is all the more true for the many more women who do not undergo hysterectomy.
The decision to proceed to a hysterectomy for a benign tumor is a decision in which a woman's preference and choices are paramount. It will be determined by her values, as well as by the health impairment she is experiencing, the acceptability of the competing risks and benefits of the options provided, and health goals that she holds. All options carry risks, for every woman the answer will be unique to her.
Because uterine fibroids are benign, it is reasonable to have a very high standard of safety for any therapy, but the reality is that for women with fibroids all options, including taking no action, carry risks. With this context, the panel addressed the questions you posed.
Question 1: a) What would be the impact, in clinical practice, of the removal of the pre-operative treatment indication for ulipristal acetate? Removal of UPA would remove and important tool in the management of women with heavy menstrual bleeding in association with uterine fibroids.
- UPA uses a novel mechanism for effectively managing abnormal uterine bleeding, that addresses the cause of the bleeding, as opposed to managing the symptoms. HMB is one of the most common and problematic issues seen in gynecology clinics, and the associated iron deficiency anemia is increasingly understood to contribute to impaired health. Preoperative anemia (a quality metric) is a very important patient safety issue and up to a quarter of women undergoing GYN surgery (especially those with fibroids) are known to be anemic prep. SPRMs give gynecologists an option to improve hemoglobin and correct preoperative anemiastudies have consistently shown that this medication is effective. Use of UPA reduce need for urgent care, blood transfusions and optimizes blood count. These are benefits in and of themselves, and offer additional benefits in the pre-operative context. Optimizing blood counts pre-operatively surgical risks of transfusion or infection and improves recovery time. Side effects are fewer (and more tolerable) than comparator medication (GnRH agonist) Tablet is preferred to injections by patients b) What would be the impact, in clinical practice, of the removal of the intermittent treatment indication for ulipristal acetate for patients not eligible for surgery/ hysterectomy? One of our first line choices for managing symptomatic uterine fibroids because of its direct effect on fibroid without the side effects seen with other choices (ex. GnRH agonist) Removes a very valuable part of our choices for these patients who are unable to take other options due to other risk factors o Example: patients who have an underlying DVT risk with birth control pill can take UPA; patients who are not able to tolerate progestins due to mood side effects Improves blood count, reduces need for transfusion Medically few true contraindications, few drug reactions o Especially important in patients who are not eligible for surgery since they often have other comorbidities c) What would be the impact, in clinical practice, of the removal of ulipristal acetate from the market? Current challenges with surgery: The wait times for elective gynecologic surgery are very long-they a concern prior to COVID, and are markedly worse now. UPA controls blood loss and offers symptomatic benefit while the patient waits Risk of surgery is real, and the complications are serious (risk of transfusion, injury to the uterus and other organs) Surgical management, particularly of large fibroids, or after prior surgery, or where fibroids and endometriosis co-exist, frequently requires referral to tertiary centers, further prolonging wait times. Women who have not completed child bearing do not want to lose their uterus, nor do they wish to be on medications that induce a chemical menopause. Alternative medical options like GnRH agonists have their own side effects. All side effects are less with UPA than the alternatives available Hypo-estrogenism, with menopausal symptoms and the risks of prolonged hypo estrogenism; Bone loss, with >6 months' use Mood changes Risks of oral contraceptives, particularly with large fibroids that can cause venous stasis.
As gynecologists, our goal is to improve the quality of life of our patients, many of whom are seriously affected with fibroids. SPRMs are effective in improving quality of life, objectively measured. Restricting or removing this option for patients would really limit our ability to help our patients.
Question 2: What is the feasibility, in clinical practice, of defining a patient population that is not eligible for hysterectomy or surgery and for which ulipristal acetate would be the only treatment option for moderate to severe symptoms of uterine fibroids? How would this selection of patients be done in clinical practice?
- It is a straightforward but thorough assessment that balances patient choice, patient concomitant health issues and availability of acceptable options in the patient's region Patient choice is very important in this area of care. Many patients do decline major surgery such as hysterectomy to manage their symptomatic uterine fibroids. Women know options, and exercise their right of informed choice and consent The exclusion of surgery as an option is frequently patient, not provider driven.
Question 3: a) How do the experts see the benefits of ulipristal acetate 5 mg beyond symptom relief, i.e. avoiding surgery/hysterectomy in the longer term? Avoiding surgery is a very important benefit since surgery for uterine preservation procedures is associated with a high recurrence risk (30%) and where the second surgery is more difficult than the first Other complications of surgery like hysterectomy long term are a real burden on our society o Ex. incontinence, uterine prolapse, bowel adhesion, chronic pain b) In your clinical experience, does pre-operative treatment with ulipristal acetate facilitate a less extensive surgical procedure such as hysteroscopic myomectomy, and if so, to which extent? Improves preoperative hemoglobin to allow for better surgical recovery o Rapid bleeding response o Convenience of oral agent (comparator GnRH agonist is an injection by a HCP o Non-anemic patients have decreased complications up to 30 days postoperatively. UPA helps to shrink fibroids in some cases and that further helps with surgical approach to a less invasive approach Question 4: How do experts see the risks associated with ulipristal acetate 5 mg compared to the risks associated with hysterectomy/surgery procedure and how could these be best communicated to the patient? The risks are very personalized and should be assessed case by case The risks of surgery are well documented and are higher that the risks attached to UPA. In certain patients, the risk is much higher for surgery (example injury in those with multiple previous surgeries and scarring is significant, risk of those who are medically compromised) Communication of risks in general, and very rare risks in particular, is complex. We do not perceive risks uniformly. We tend to perceive risks as greater if we are anxious, compared to when we are calm. We will be influenced in risk perception by recent experience. We tend to attribute greater relevance to new risks, to new medications, compared to a familiar one, e.g. acetaminophen or the oral contraceptive. We are more aware of risks if they have received media or social media attention, and we are more intolerant of risks if they are for a condition that we may regard as not a serious. Fibroids and heavy menstrual bleeding may be seen as inconveniences, rather than the medical problems that they are. These problems are compounded when dealing with rare of very rate risks. According to the WHO, a frequency of < 1: 10,000 is very rare. A risk of < than 1:100,000 is very hard for us to comprehend. To communicate these risks, it is important to use relevant comparators, or graphic illustrations to help make the risks tangible. The infographic below 2, is an example of a risk communication tool. Check lists for providers and patients can also help guide a risk discussion.
- Risk discussions should be informed by evidence based guidelines, such as the SOGC Clinical Practice Guidelines, and can be augmented by evidence based patient information in written or web based formats. A well informed decision takes sufficient time to digest information that can at first seem over whelming.
Women who choose treatment with UPA, must agree that they have a responsibility to undertake regular liver function testing, and to report any symptoms that are suggestive of hepatic involvement. Any facilitation of adherence to testing should improve safety.
The experts convened for this opinion were unanimous in their opinion that UPA does offer an important and safe tool for the management of symptomatic fibroids, and that it can be given safely, informing women of all relevant risks, and respecting choice and autonomy. | Thank you for the opportunity to contribute an expert clinical opinion into your examinations of the safe use of Ulipristal Acetate in the management of uterine fibroids. To address the questions that you posed, we assembled a panel of experts, who are both deeply knowledgeable of the scientific literature, but who also care for substantial numbers of women with uterine fibroids and have that knowledge of the impact on women's health, the options available for treatment as well as the considerations women bring to the discussion of an informed choice. Any consideration of the role of the selective progesterone receptor modulator (SPRM), ulipristal acetate(UPA), in the Canadian clinical armamentarium has to be taken with an understanding of the impact of uterine fibroids on women's health. Uterine fibroids are the most common benign pelvic tumor in women, and are found in up to 68% of women, although not all are symptomatic. The symptoms range from pain and heavy menstrual bleeding to impacts from compression by the mass on bladder bowel and large veins.#
Women with symptomatic fibroids experience diminished quality of life, reduction in the ability of participate in usual activities, loss of time from work, sexual dysfunction and reduced fertility. Uterine fibroids do not impact all women to the same extent. They disproportionately affect the health of black women, with both greater severity and a younger age, leading to a greater impact on the health of women of child-bearing age. In a recent U.S. study 1 nearly one third of women who had undergone a hysterectomy for symptomatic fibroids would have been interested in non-surgical management; in 46% of those it was to have preserved child bearing capability. This is all the more true for the many more women who do not undergo hysterectomy.
The decision to proceed to a hysterectomy for a benign tumor is a decision in which a woman's preference and choices are paramount. It will be determined by her values, as well as by the health impairment she is experiencing, the acceptability of the competing risks and benefits of the options provided, and health goals that she holds. All options carry risks, for every woman the answer will be unique to her.
Because uterine fibroids are benign, it is reasonable to have a very high standard of safety for any therapy, but the reality is that for women with fibroids all options, including taking no action, carry risks. With this context, the panel addressed the questions you posed.
Question 1: a) What would be the impact, in clinical practice, of the removal of the pre-operative treatment indication for ulipristal acetate? Removal of UPA would remove and important tool in the management of women with heavy menstrual bleeding in association with uterine fibroids.
UPA uses a novel mechanism for effectively managing abnormal uterine bleeding, that addresses the cause of the bleeding, as opposed to managing the symptoms. HMB is one of the most common and problematic issues seen in gynecology clinics, and the associated iron deficiency anemia is increasingly understood to contribute to impaired health. Preoperative anemia (a quality metric) is a very important patient safety issue and up to a quarter of women undergoing GYN surgery (especially those with fibroids) are known to be anemic prep. SPRMs give gynecologists an option to improve hemoglobin and correct preoperative anemiastudies have consistently shown that this medication is effective. Use of UPA reduce need for urgent care, blood transfusions and optimizes blood count. These are benefits in and of themselves, and offer additional benefits in the pre-operative context. Optimizing blood counts pre-operatively surgical risks of transfusion or infection and improves recovery time. Side effects are fewer (and more tolerable) than comparator medication (GnRH agonist) Tablet is preferred to injections by patients b) What would be the impact, in clinical practice, of the removal of the intermittent treatment indication for ulipristal acetate for patients not eligible for surgery/ hysterectomy? One of our first line choices for managing symptomatic uterine fibroids because of its direct effect on fibroid without the side effects seen with other choices (ex. GnRH agonist) Removes a very valuable part of our choices for these patients who are unable to take other options due to other risk factors o Example: patients who have an underlying DVT risk with birth control pill can take UPA; patients who are not able to tolerate progestins due to mood side effects Improves blood count, reduces need for transfusion Medically few true contraindications, few drug reactions o Especially important in patients who are not eligible for surgery since they often have other comorbidities c) What would be the impact, in clinical practice, of the removal of ulipristal acetate from the market? Current challenges with surgery: The wait times for elective gynecologic surgery are very long-they a concern prior to COVID, and are markedly worse now. UPA controls blood loss and offers symptomatic benefit while the patient waits Risk of surgery is real, and the complications are serious (risk of transfusion, injury to the uterus and other organs) Surgical management, particularly of large fibroids, or after prior surgery, or where fibroids and endometriosis co-exist, frequently requires referral to tertiary centers, further prolonging wait times. Women who have not completed child bearing do not want to lose their uterus, nor do they wish to be on medications that induce a chemical menopause. Alternative medical options like GnRH agonists have their own side effects. All side effects are less with UPA than the alternatives available Hypo-estrogenism, with menopausal symptoms and the risks of prolonged hypo estrogenism; Bone loss, with >6 months' use Mood changes Risks of oral contraceptives, particularly with large fibroids that can cause venous stasis.
As gynecologists, our goal is to improve the quality of life of our patients, many of whom are seriously affected with fibroids. SPRMs are effective in improving quality of life, objectively measured. Restricting or removing this option for patients would really limit our ability to help our patients.
Question 2: What is the feasibility, in clinical practice, of defining a patient population that is not eligible for hysterectomy or surgery and for which ulipristal acetate would be the only treatment option for moderate to severe symptoms of uterine fibroids? How would this selection of patients be done in clinical practice?
It is a straightforward but thorough assessment that balances patient choice, patient concomitant health issues and availability of acceptable options in the patient's region Patient choice is very important in this area of care. Many patients do decline major surgery such as hysterectomy to manage their symptomatic uterine fibroids. Women know options, and exercise their right of informed choice and consent The exclusion of surgery as an option is frequently patient, not provider driven.
Question 3: a) How do the experts see the benefits of ulipristal acetate 5 mg beyond symptom relief, i.e. avoiding surgery/hysterectomy in the longer term? Avoiding surgery is a very important benefit since surgery for uterine preservation procedures is associated with a high recurrence risk (30%) and where the second surgery is more difficult than the first Other complications of surgery like hysterectomy long term are a real burden on our society o Ex. incontinence, uterine prolapse, bowel adhesion, chronic pain b) In your clinical experience, does pre-operative treatment with ulipristal acetate facilitate a less extensive surgical procedure such as hysteroscopic myomectomy, and if so, to which extent? Improves preoperative hemoglobin to allow for better surgical recovery o Rapid bleeding response o Convenience of oral agent (comparator GnRH agonist is an injection by a HCP o Non-anemic patients have decreased complications up to 30 days postoperatively. UPA helps to shrink fibroids in some cases and that further helps with surgical approach to a less invasive approach Question 4: How do experts see the risks associated with ulipristal acetate 5 mg compared to the risks associated with hysterectomy/surgery procedure and how could these be best communicated to the patient? The risks are very personalized and should be assessed case by case The risks of surgery are well documented and are higher that the risks attached to UPA. In certain patients, the risk is much higher for surgery (example injury in those with multiple previous surgeries and scarring is significant, risk of those who are medically compromised) Communication of risks in general, and very rare risks in particular, is complex. We do not perceive risks uniformly. We tend to perceive risks as greater if we are anxious, compared to when we are calm. We will be influenced in risk perception by recent experience. We tend to attribute greater relevance to new risks, to new medications, compared to a familiar one, e.g. acetaminophen or the oral contraceptive. We are more aware of risks if they have received media or social media attention, and we are more intolerant of risks if they are for a condition that we may regard as not a serious. Fibroids and heavy menstrual bleeding may be seen as inconveniences, rather than the medical problems that they are. These problems are compounded when dealing with rare of very rate risks. According to the WHO, a frequency of < 1: 10,000 is very rare. A risk of < than 1:100,000 is very hard for us to comprehend. To communicate these risks, it is important to use relevant comparators, or graphic illustrations to help make the risks tangible. The infographic below 2, is an example of a risk communication tool. Check lists for providers and patients can also help guide a risk discussion.
Risk discussions should be informed by evidence based guidelines, such as the SOGC Clinical Practice Guidelines, and can be augmented by evidence based patient information in written or web based formats. A well informed decision takes sufficient time to digest information that can at first seem over whelming.
Women who choose treatment with UPA, must agree that they have a responsibility to undertake regular liver function testing, and to report any symptoms that are suggestive of hepatic involvement. Any facilitation of adherence to testing should improve safety.
The experts convened for this opinion were unanimous in their opinion that UPA does offer an important and safe tool for the management of symptomatic fibroids, and that it can be given safely, informing women of all relevant risks, and respecting choice and autonomy. | None | None |
8a24c4f874519172ef1bfe075f5d7671a1594c75 | cma | None | COVID-19 a novel corona virus, of which there are now seven known strains that affect humans. It was first diagnosed in Wuhan province, China in December of 2019 and subsequently spread. As of March 11, 2020, 88 countries worldwide were involved, infecting over 126,000 individuals (44,067 outside China). The case mortality rate is estimated at 2 -4%.# Preparing to Manage Patients with Known or Suspected COVID-19
All anesthesiologists who may anticipate caring for patients with COVID-19 should ensure that their health care facility has appropriate equipment to manage airborne precautions including appropriate N95 masks, full length gowns, face shields, gloves and surgical hats.
# In addition, team members should be properly N95 mask fit tested to ensure proper N95 mask selection and fitting. It is crucial this testing be completed well in advance of patient care.
A designated area for the management of selected COVID-19 patients should be discussed and decided prior to treating any of these patients. The proper donning and doffing of Personal Protective Equipment (PPE) should be practised prior to the treatment of any patients. Simulation of a COVID-19 patient in acute respiratory distress and requiring intubation may be warranted in either a high fidelity or low fidelity simulator.
# Prior to Intubation
➢ The goal is to ensure that emergency intubation is avoided, that equipment and supplies for intubation, including Personal Protective Equipment (PPE) are accessible, and that the patient is in an appropriate room for intubation (avoid open areas, hallways etc.) including, if available, an Airborne Infection Isolation Room (AIIR), or a negative pressure room. Nasal cannula at 5l per minute or less maybe used to provide supplemental oxygen to the COVID-19 patient in respiratory distress. There may be a risk of aerosolization using High flow nasal cannula (HFNC) or non-invasive positive pressure ventilation (NIV), but the risk posed by these devices is unclear5l oxygen by nasal cannula ➢ Appropriate room to intubate (isolation room, or isolated area) ➢ No Non-invasive ventilation, HFNC
# Intubation
The goal is to minimize the time aerosolized virus can enter the room by minimizing/eliminating bag mask ventilation, and the time prior to securing the airway. Ensure PPE equipment is properly worn so any particles in the room do not contact health care workers directly.
- Wash hands-use an alcohol-based hand cleaner (over 60% alcohol) or soap and water if hands are visibly soiled. - Place appropriate PPE including 1) Hat 2) Gown 3) N95 Mask 4) Face shield 5) Double gloves 6)
Neck covering before entering the room -consider having a spotter to guide you during the donning and doffing procedure. The principal is to have no skin exposed during the intubation procedure and ensure when donning, consideration be given to ease of doffing to minimize the risk of contamination. A ANSI/AAMI level 3 or higher gown is suggested.
() - Ensure a minimal number of people are present.
- The person performing the intubation should be the most skilled available.
- Perform airway assessment with PPE on.
- Anticipate that visualization of the glottis may be impaired by the glare created by room lights on the face shield. - Pre-oxygenate for 5 minutes on 100% oxygen when possible with patient spontaneously breathing (flows <5l minute, 100% oxygen) - Avoid bag mask ventilation if possible, if not, use small tidal volumes and hold the mask with a two-handed technique. The principle is to minimize the leak around the mask which may aerosolize virus. o A quantitative CO2 monitor should be available to indicate adequate bag seal. - Plan for modified rapid sequence induction (RSI) even in fasted patients o Rocuronium should be used to prevent coughing or bucking if a second look is necessary, using dosing appropriate for RSI (1.2mg/kg). o Consider induction with ketamine, or have vassopressors in the room (anticipate hemodynamic instability and limit movement into and out of the room during intubation) o Some guidelines suggest anti-emetics to reduce the risk of vomiting during airway manipulation. o Have suction available. o Plan for NO bag mask ventilation prior to intubation if possible, small tidal volume breaths if patient desaturates.
# - Consider video laryngoscope for first attempt as it allows for an increase in distance between operator and patient. - If difficult airway suspected have adjuvants available.
- Having an LMA or other supraglottic device available may be warranted as a supra glottic device is inferior to intubation but may be superior to bag mask for patients in the can't intubate can ventilate or can't intubate can't ventilate category. - Have an end tidal CO2 monitor available (quantitative preferable) to ensure appropriate placement of ET tube. - Use of hydrophobic/HEPA filter between the ET tube and ventilator/Laerdal bag.
- Consider taping the filter to the ET tube to reduce the risk of accidental disconnection.
- Immediate inflation of the cuff following ETT placement.
- When switching between methods of ventilation (when transferring to transport ventilator) consider clamping the ETT to limit aerosolization of respiratory secretions. - Using one outer glove on one hand (for double glove technique only) cover the blade of the intubating device to limit aerosolization of the secretions.
# Following intubation
- Dispose of any consumables in appropriate bins.
- Remove PPE as described below. Remember these items are now heavily contaminated and care must be taken not to transfer the contaminated surfaces to your skin, hands or face. We recommend washing hands at least twice as outlined below, and any time the hands are thought to be soiled. - Always wash hands following the final removal of all PPE items, using alcohol-based cleaners, unless the hands are visibly soiled -soap and water should then be used. Ensure you do not touch your clothes skin or face with your hands prior to the final hand washing.
# Uncertainties
As with any developing disease for which little information is available, approaches and guidelines/ recommendations may differ between groups. Several differences in recommendations are apparent as follows:
- The use of an AIIRS or negative pressure room to perform intubations. This is recommended by the CDC and suggested by the WHO and PHAC. People with PPE equipment should be protected with or without negative pressure. The airflow out of a room, however, should determine the time required to reduce the risk from air contact precaution to droplet precaution. For positive pressure operating rooms the time to clear aerosol is unclear and ranges from 2-3 hours to 30 minutes depending on the number of air exchanges per hour. Thus, use of N95 masks in a patient room may still be warranted immediately after intubation and for a period after until it is felt that the risk of airborne particles is gone. #tableb1.
# The Anesthesia
# Proper Donning and Doffing of PPE
Public Health Ontario suggests that when using a surgical hat, placing and removing the hat would occur with Step 4) Face mask/eye protection | COVID-19 a novel corona virus, of which there are now seven known strains that affect humans. It was first diagnosed in Wuhan province, China in December of 2019 and subsequently spread. As of March 11, 2020, 88 countries worldwide were involved, infecting over 126,000 individuals (44,067 outside China). The case mortality rate is estimated at 2 -4%.# Preparing to Manage Patients with Known or Suspected COVID-19
All anesthesiologists who may anticipate caring for patients with COVID-19 should ensure that their health care facility has appropriate equipment to manage airborne precautions including appropriate N95 masks, full length gowns, face shields, gloves and surgical hats.
# In addition, team members should be properly N95 mask fit tested to ensure proper N95 mask selection and fitting. It is crucial this testing be completed well in advance of patient care.
A designated area for the management of selected COVID-19 patients should be discussed and decided prior to treating any of these patients. The proper donning and doffing of Personal Protective Equipment (PPE) should be practised prior to the treatment of any patients. Simulation of a COVID-19 patient in acute respiratory distress and requiring intubation may be warranted in either a high fidelity or low fidelity simulator.
# Prior to Intubation
➢ The goal is to ensure that emergency intubation is avoided, that equipment and supplies for intubation, including Personal Protective Equipment (PPE) are accessible, and that the patient is in an appropriate room for intubation (avoid open areas, hallways etc.) including, if available, an Airborne Infection Isolation Room (AIIR), or a negative pressure room. Nasal cannula at 5l per minute or less maybe used to provide supplemental oxygen to the COVID-19 patient in respiratory distress. There may be a risk of aerosolization using High flow nasal cannula (HFNC) or non-invasive positive pressure ventilation (NIV), but the risk posed by these devices is unclear5l oxygen by nasal cannula ➢ Appropriate room to intubate (isolation room, or isolated area) ➢ No Non-invasive ventilation, HFNC
# Intubation
The goal is to minimize the time aerosolized virus can enter the room by minimizing/eliminating bag mask ventilation, and the time prior to securing the airway. Ensure PPE equipment is properly worn so any particles in the room do not contact health care workers directly.
• Wash hands-use an alcohol-based hand cleaner (over 60% alcohol) or soap and water if hands are visibly soiled. • Place appropriate PPE including 1) Hat 2) Gown 3) N95 Mask 4) Face shield 5) Double gloves 6)
Neck covering before entering the room -consider having a spotter to guide you during the donning and doffing procedure. The principal is to have no skin exposed during the intubation procedure and ensure when donning, consideration be given to ease of doffing to minimize the risk of contamination. A ANSI/AAMI level 3 or higher gown is suggested.
(https://www.fda.gov/medical-devices/personal-protective-equipment-infectioncontrol/medical-gowns) • Ensure a minimal number of people are present.
• The person performing the intubation should be the most skilled available.
• Perform airway assessment with PPE on.
• Anticipate that visualization of the glottis may be impaired by the glare created by room lights on the face shield. • Pre-oxygenate for 5 minutes on 100% oxygen when possible with patient spontaneously breathing (flows <5l minute, 100% oxygen) • Avoid bag mask ventilation if possible, if not, use small tidal volumes and hold the mask with a two-handed technique. The principle is to minimize the leak around the mask which may aerosolize virus. o A quantitative CO2 monitor should be available to indicate adequate bag seal. • Plan for modified rapid sequence induction (RSI) even in fasted patients o Rocuronium should be used to prevent coughing or bucking if a second look is necessary, using dosing appropriate for RSI (1.2mg/kg). o Consider induction with ketamine, or have vassopressors in the room (anticipate hemodynamic instability and limit movement into and out of the room during intubation) o Some guidelines suggest anti-emetics to reduce the risk of vomiting during airway manipulation. o Have suction available. o Plan for NO bag mask ventilation prior to intubation if possible, small tidal volume breaths if patient desaturates.
# • Consider video laryngoscope for first attempt as it allows for an increase in distance between operator and patient. • If difficult airway suspected have adjuvants available.
o Having an LMA or other supraglottic device available may be warranted as a supra glottic device is inferior to intubation but may be superior to bag mask for patients in the can't intubate can ventilate or can't intubate can't ventilate category. • Have an end tidal CO2 monitor available (quantitative preferable) to ensure appropriate placement of ET tube. • Use of hydrophobic/HEPA filter between the ET tube and ventilator/Laerdal bag.
• Consider taping the filter to the ET tube to reduce the risk of accidental disconnection.
• Immediate inflation of the cuff following ETT placement.
• When switching between methods of ventilation (when transferring to transport ventilator) consider clamping the ETT to limit aerosolization of respiratory secretions. • Using one outer glove on one hand (for double glove technique only) cover the blade of the intubating device to limit aerosolization of the secretions.
# Following intubation
• Dispose of any consumables in appropriate bins.
• Remove PPE as described below. Remember these items are now heavily contaminated and care must be taken not to transfer the contaminated surfaces to your skin, hands or face. We recommend washing hands at least twice as outlined below, and any time the hands are thought to be soiled. • Always wash hands following the final removal of all PPE items, using alcohol-based cleaners, unless the hands are visibly soiled -soap and water should then be used. Ensure you do not touch your clothes skin or face with your hands prior to the final hand washing.
# Uncertainties
As with any developing disease for which little information is available, approaches and guidelines/ recommendations may differ between groups. Several differences in recommendations are apparent as follows:
1. The use of an AIIRS or negative pressure room to perform intubations. This is recommended by the CDC and suggested by the WHO and PHAC. People with PPE equipment should be protected with or without negative pressure. The airflow out of a room, however, should determine the time required to reduce the risk from air contact precaution to droplet precaution. For positive pressure operating rooms the time to clear aerosol is unclear and ranges from 2-3 hours to 30 minutes depending on the number of air exchanges per hour. Thus, use of N95 masks in a patient room may still be warranted immediately after intubation and for a period after until it is felt that the risk of airborne particles is gone. https://www.cdc.gov/infectioncontrol/guidelines/environmental/appendix/air.html#tableb1.
# The Anesthesia
# Proper Donning and Doffing of PPE
Public Health Ontario suggests that when using a surgical hat, placing and removing the hat would occur with Step 4) Face mask/eye protection https://www.cdc.gov/hai/pdfs/ppe/ppe-sequence.pdf | None | None |
93e2ea32fad562ab8766458e63d4bb2ad9681ec7 | cma | None | To provide practical information on the optimal utilization of ticagrelor in clinical practice.Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP), a selective, reversibly bound P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP)-mediated platelet activation and aggregation. It is characterized as a non-competitive antagonist since its binding site on the platelet P2Y12 receptor is different from that of ADP. Unlike prasugrel and clopidogrel, ticagrelor is active in its unchanged form, not requiring conversion to an active metabolite.# INDICATIONS FOR TICAGRELOR:
Ticagrelor, when co-administered with acetylsalicylic acid (ASA), is indicated for the secondary prevention of atherothrombotic events in patients with an acute coronary syndrome (ACS) treated medically or with percutaneous coronary intervention (PCI) (with or without stent implantation), and/or coronary artery bypass graft (CABG) surgery. It is also indicated for patients with a history of myocardial infarction (MI) at least one year prior, who are at high risk of atherothrombotic events for a duration of up to 3 years.
When ticagrelor was compared with clopidogrel in a large phase 3 randomized clinical trial (PLATO), there was a significant 1.9% absolute risk reduction (ARR) in the combined rate of myocardial infarction (MI), cardiovascular death and stroke in patients presenting with ACS managed by PCI, CABG or medically (number needed to treat = 52). The rates of MI (1.1% ARR, NNT = 91) and all-cause mortality (1.4% ARR, NNT = 71) were also significantly reduced with ticagrelor. However, the efficacy benefit of ticagrelor over clopidogrel may be lost when doses of ASA above 150 mg daily are used.
Ticagrelor (in doses of 90 mg twice daily or 60 mg twice daily) was also compared against placebo in ASA-treated patients who had suffered a MI 1 to 3 years earlier (PEGASUS-TIMI 54). There was a statistically significant reduction in the composite of cardiovascular death, MI, or stroke (ARR of 1.2% with 90 mg twice daily and 1.3% with 60 mg twice daily ). There was no reduction in overall mortality. Ticagrelor (180 mg loading dose, then 90 mg twice daily), when co-administered with acetylsalicylic acid (ASA) (300-325 mg loading dose, then 75-100 mg daily), also has an indication as part of dualantiplatelet therapy (DAPT) for a total duration 30 days for preventing recurrent stroke. This indication is similar to the use of DAPT (e.g. Clopidogrel with ASA in the CHANCE and POINT Trials) for minor stroke and TIA (THALES). Ticagrelor and ASA in combination was shows to be slightly superior to ASA alone (5% vs 6.3%, p=0.004) but was also associated with a significantly increased risk of severe bleeding (0.5% vs 0.1%, p=0.001) . There was a similar increased risk of intracerebral hemorrhage .
Ticagrelor was not found to be superior to ASA in reducing the rate of stroke, MI, or death at 90 days in patients with acute ischemic stroke or transient ischemic attack.
# DOSING OF TICAGRELOR:
In patients with ACS, a loading dose of 180 mg should be administered followed by 90 mg twice daily for up to 1 year. For patients with a history of MI at least 1 year prior, the dose is 60 mg twice daily for a duration of up to 3 years. Absorption is not affected by food intake and no dosing adjustment is required in patients with chronic renal disease or in patients with mild hepatic impairment. Patients taking ticagrelor should also take ASA 81 mg daily, unless specifically contraindicated.
Strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) and inducers (e.g. phenytoin, carbamazepine, rifampin) are expected to affect the pharmacokinetics of ticagrelor; patients on these agents were excluded from the ticagrelor trials and are contraindicated from taking ticagrelor.
# ADVERSE EFFECTS OF TICAGRELOR:
As with all antiplatelet agents, ticagrelor increases the risk of major bleeding, including intracerebral hemorrhage. In the large phase 3 randomized PLATO trial, major bleeding unrelated to CABG occurred in approximately 4.5% of subjects taking ticagrelor, an absolute risk increase (ARI) of 0.7% (number needed to harm = 143) over clopidogrel. In the large phase 3 randomized PEGASUS-TIMI 54 trial, the ARI for TIMI major bleeding was 1.2% with ticagrelor 60 mg twice daily and ASA (NNH=81) compared to ASA alone. Bleeding risks increase with age and ticagrelor has been associated with more frequent bleeding events than clopidogrel among older patients. In the POPular AGE trial, in which 1002 patients 70 years of age and older with non ST-elevation ACS were randomized to clopidogrel or either ticagrelor or prasugrel (95% received ticagrelor), the primary bleeding outcome (composite of PLATO major or minor bleeding) occurred less frequently in the clopidogrel group (18% versus 24%, HR 0.71, 95% CI 0.54-0.94, P = 0.02) but with a similar net clinical benefit outcome between the two groups (28% versus 32%), suggesting that clopidogrel may be preferred for older patients at increased risk of bleeding. Ticagrelor is contraindicated in patients with a history of intracranial hemorrhage. Dyspnea, not related to cardiac or pulmonary causes, was observed in 14% of subjects taking ticagrelor in PLATO and 16% of subjects in PEGASUS-TIMI 54. Dyspnea is usually mild to moderate in intensity and often resolves during continued treatment. The mechanism of dyspnea is thought to be due to ticagrelor-related increased circulating adenosine leading to increased stimulation of pulmonary vagal C fibers. With the observation of bradycardia and ventricular pauses, caution should be exercised in patients with baseline bradycardia and heart block who have been given ticagrelor. Bradycardia is usually seen early in treatment and has not been associated with syncope, heart block or need for pacemaker insertion. Small but statistically significant increases in serum creatinine, uric acid, and gout have been observed.
# PERIPROCEDURAL MANAGEMENT FOR PATIENTS TAKING TICAGRELOR
The periprocedural use of antiplatelet agents may increase the risk of bleeding and transfusion requirements associated with surgery and other invasive procedures. However, discontinuation of dual antiplatelet therapy within 12 months of stent implantation is associated with an increased risk of major adverse cardiovascular events and stent thrombosis.
Following medically managed ACS, dual antiplatelet therapy should be continued for a minimum of 3 months and preferably 1 year. For this reason, procedures associated with significant bleeding risk should be delayed beyond these time frames, if possible, and if not possible, done with consideration of the patient remaining on therapy. When appropriate, ticagrelor should be stopped 5 days prior to surgery. In general, consultation with a specialist is advised before discontinuing ticagrelor in patients with a coronary stent. In patients undergoing a minor procedure (e.g. dental, skin, cataract, arthrocentesis), discontinuation is not necessary. See Clinical Guide Perioperative Management of Antiplatelet Therapy.
# SPECIAL CONSIDERATIONS:
Unlike clopidogrel and prasugrel, ticagrelor does not require conversion to an active metabolite; therefore, activity is not affected by proton pump inhibitors or in individuals with CYP2C19 loss of function alleles. The safety of ticagrelor in pregnancy has not been established. It is not known if ticagrelor is excreted in human milk; however, the use of this drug while breastfeeding is not recommended as studies in rats have shown that ticagrelor and its metabolites are excreted in breast milk.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of Version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide practical information on the optimal utilization of ticagrelor in clinical practice.Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP), a selective, reversibly bound P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP)-mediated platelet activation and aggregation. It is characterized as a non-competitive antagonist since its binding site on the platelet P2Y12 receptor is different from that of ADP. Unlike prasugrel and clopidogrel, ticagrelor is active in its unchanged form, not requiring conversion to an active metabolite.# INDICATIONS FOR TICAGRELOR:
Ticagrelor, when co-administered with acetylsalicylic acid (ASA), is indicated for the secondary prevention of atherothrombotic events in patients with an acute coronary syndrome (ACS) treated medically or with percutaneous coronary intervention (PCI) (with or without stent implantation), and/or coronary artery bypass graft (CABG) surgery. It is also indicated for patients with a history of myocardial infarction (MI) at least one year prior, who are at high risk of atherothrombotic events for a duration of up to 3 years.
When ticagrelor was compared with clopidogrel in a large phase 3 randomized clinical trial (PLATO), there was a significant 1.9% absolute risk reduction (ARR) in the combined rate of myocardial infarction (MI), cardiovascular death and stroke in patients presenting with ACS managed by PCI, CABG or medically (number needed to treat [NNT] = 52). The rates of MI (1.1% ARR, NNT = 91) and all-cause mortality (1.4% ARR, NNT = 71) were also significantly reduced with ticagrelor. However, the efficacy benefit of ticagrelor over clopidogrel may be lost when doses of ASA above 150 mg daily are used.
Ticagrelor (in doses of 90 mg twice daily or 60 mg twice daily) was also compared against placebo in ASA-treated patients who had suffered a MI 1 to 3 years earlier (PEGASUS-TIMI 54). There was a statistically significant reduction in the composite of cardiovascular death, MI, or stroke (ARR of 1.2% with 90 mg twice daily [NNT=84] and 1.3% with 60 mg twice daily [NNT=79]). There was no reduction in overall mortality. Ticagrelor (180 mg loading dose, then 90 mg twice daily), when co-administered with acetylsalicylic acid (ASA) (300-325 mg loading dose, then 75-100 mg daily), also has an indication as part of dualantiplatelet therapy (DAPT) for a total duration 30 days for preventing recurrent stroke. This indication is similar to the use of DAPT (e.g. Clopidogrel with ASA in the CHANCE and POINT Trials) for minor stroke and TIA (THALES). Ticagrelor and ASA in combination was shows to be slightly superior to ASA alone (5% vs 6.3%, p=0.004) but was also associated with a significantly increased risk of severe bleeding (0.5% vs 0.1%, p=0.001) [NNT=92]. There was a similar increased risk of intracerebral hemorrhage [NNH=263].
Ticagrelor was not found to be superior to ASA in reducing the rate of stroke, MI, or death at 90 days in patients with acute ischemic stroke or transient ischemic attack.
# DOSING OF TICAGRELOR:
In patients with ACS, a loading dose of 180 mg should be administered followed by 90 mg twice daily for up to 1 year. For patients with a history of MI at least 1 year prior, the dose is 60 mg twice daily for a duration of up to 3 years. Absorption is not affected by food intake and no dosing adjustment is required in patients with chronic renal disease or in patients with mild hepatic impairment. Patients taking ticagrelor should also take ASA 81 mg daily, unless specifically contraindicated.
Strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) and inducers (e.g. phenytoin, carbamazepine, rifampin) are expected to affect the pharmacokinetics of ticagrelor; patients on these agents were excluded from the ticagrelor trials and are contraindicated from taking ticagrelor.
# ADVERSE EFFECTS OF TICAGRELOR:
As with all antiplatelet agents, ticagrelor increases the risk of major bleeding, including intracerebral hemorrhage. In the large phase 3 randomized PLATO trial, major bleeding unrelated to CABG occurred in approximately 4.5% of subjects taking ticagrelor, an absolute risk increase (ARI) of 0.7% (number needed to harm [NNH] = 143) over clopidogrel. In the large phase 3 randomized PEGASUS-TIMI 54 trial, the ARI for TIMI major bleeding was 1.2% with ticagrelor 60 mg twice daily and ASA (NNH=81) compared to ASA alone. Bleeding risks increase with age and ticagrelor has been associated with more frequent bleeding events than clopidogrel among older patients. In the POPular AGE trial, in which 1002 patients 70 years of age and older with non ST-elevation ACS were randomized to clopidogrel or either ticagrelor or prasugrel (95% received ticagrelor), the primary bleeding outcome (composite of PLATO major or minor bleeding) occurred less frequently in the clopidogrel group (18% versus 24%, HR 0.71, 95% CI 0.54-0.94, P = 0.02) but with a similar net clinical benefit outcome between the two groups (28% versus 32%), suggesting that clopidogrel may be preferred for older patients at increased risk of bleeding. Ticagrelor is contraindicated in patients with a history of intracranial hemorrhage. Dyspnea, not related to cardiac or pulmonary causes, was observed in 14% of subjects taking ticagrelor in PLATO and 16% of subjects in PEGASUS-TIMI 54. Dyspnea is usually mild to moderate in intensity and often resolves during continued treatment. The mechanism of dyspnea is thought to be due to ticagrelor-related increased circulating adenosine leading to increased stimulation of pulmonary vagal C fibers. With the observation of bradycardia and ventricular pauses, caution should be exercised in patients with baseline bradycardia and heart block who have been given ticagrelor. Bradycardia is usually seen early in treatment and has not been associated with syncope, heart block or need for pacemaker insertion. Small but statistically significant increases in serum creatinine, uric acid, and gout have been observed.
# PERIPROCEDURAL MANAGEMENT FOR PATIENTS TAKING TICAGRELOR
The periprocedural use of antiplatelet agents may increase the risk of bleeding and transfusion requirements associated with surgery and other invasive procedures. However, discontinuation of dual antiplatelet therapy within 12 months of stent implantation is associated with an increased risk of major adverse cardiovascular events and stent thrombosis.
Following medically managed ACS, dual antiplatelet therapy should be continued for a minimum of 3 months and preferably 1 year. For this reason, procedures associated with significant bleeding risk should be delayed beyond these time frames, if possible, and if not possible, done with consideration of the patient remaining on therapy. When appropriate, ticagrelor should be stopped 5 days prior to surgery. In general, consultation with a specialist is advised before discontinuing ticagrelor in patients with a coronary stent. In patients undergoing a minor procedure (e.g. dental, skin, cataract, arthrocentesis), discontinuation is not necessary. See Clinical Guide Perioperative Management of Antiplatelet Therapy.
# SPECIAL CONSIDERATIONS:
Unlike clopidogrel and prasugrel, ticagrelor does not require conversion to an active metabolite; therefore, activity is not affected by proton pump inhibitors or in individuals with CYP2C19 loss of function alleles. The safety of ticagrelor in pregnancy has not been established. It is not known if ticagrelor is excreted in human milk; however, the use of this drug while breastfeeding is not recommended as studies in rats have shown that ticagrelor and its metabolites are excreted in breast milk.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of Version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
1196b9fbaafde5daecd796392fcb52ef9bdc2a43 | cma | None | # Background
In transit disease is a Stage III regional metastatic disease consisting of intradermal or subcutaneous nodules. The probability of in transit disease varies with melanoma thickness (Table 1). Although many treatment modalities exist and have been described in the literature, high level evidence is still lacking and there is little consensus on a standard approach for patients 1 . The treatment strategies described in this guideline are currently the most effective options for patients with this disease; however, further clinical trials in this area are needed. Guideline Questions
- What are the best treatment and management options for improving the progression-free survival and overall survival of patients with melanoma with in-transit disease?
# Search Strategy
The MEDLINE, Cochrane, ASCO Abstracts and proceedings, and CANCERLIT databases were searched (1985 through November 2009) for clinical trials. Search terms included: "primary cutaneous melanoma" or "regional metastatic disease" or "in-transit disease" or "intradermal nodules" or "subcutaneous nodules" AND "isolated limb perfusion" or "isolated limb infusion" or "hyperthermic limb perfusion" or "tumor necrosis factor alpha" or "melphalan" or "radiation therapy" or "tamoxifen" or "cryotherapy" or "laser therapy" or "bacillus calmette guerin" or "interferon" or "chemotherapy." A total of 585 clinical trials (limits: human and English language) were returned, from which 35 documents were selected. In addition, the National Guidelines Clearinghouse and individual guideline organizations were searched for practice guidelines relevant to this topic.
For the 2013 update of the guideline, PubMed was searched for evidence on in-transit melanoma. The search term "melanoma" was used and results were limited to clinical trials, published between December 2009 and January 2013. Citations were hand-searched for studies pertaining to in-transit disease, resulting in three relevant studies. Following a review of the evidence by the Alberta Cutaneous Tumour Team, no major changes to the recommendations were made.
# Target Population
This guideline outlines treatment and management strategies for patients with stage III regional metastatic disease that are intradermal or subcutaneous nodules growing within lymphatics and not in nodal basins.
# Recommendations
For staging please refer to the Appendix.
# Regional Therapy
- Isolated limb infusion/ perfusion with melphalan
# Second-Line Treatment Options
Patients who experience disease progression during or shortly after primary treatment, should be considered for second-line treatment. Second-line treatment agents should be different than the primary treatment and not of the same class. Patients who experience disease control without residual toxicity followed by disease progression more than 3 months after primary treatment ceases, can be considered for second-line treatment with the same agent or same class of agents used for primary treatment 1 .
# Post Surgery
- No evidence of disease: Adjuvant treatment (see below) or observation - Less than complete resection:
- Local therapy options:
- Intralesional injection options: Interleukin-2, talimogene laherparepvec*, PV-10*, bacillus calmette guerin - Local ablation therapy - Topical imiquimod for superficial dermal lesions - Radiation therapy (see below) o Regional therapy options:
- Isolated limb infusion/perfusion with melphalan o Adjuvant therapy (see below) following local or regional therapy 2. Post Non-Surgical Primary Therapy
- No evidence of disease: Adjuvant treatment (see below) or observation - Residual/progressive disease o Choose an alternative local therapy option:
- Intralesional injection options: Interleukin-2, talimogene laherparepvec*, PV-10*, bacillus calmette guerin - Local ablation therapy - Topical imiquimod for superficial dermal lesions - Radiation therapy (see below) o Or choose a regional therapy option:
- Isolated limb infusion/perfusion with melphalan - Adjuvant therapy (see below) following local or regional therapy
# *not currently available in Canada
Adjuvant Treatment - Nivolumab - Pembrolizumab - Dabrafenib/trametinib (BRAFV600-activating mutation)
# Radiation Therapy
- Treatment to tumour bed, regions of in-transit disease and nodal drainage basin can be considered based on the pathology after resection and other patient and disease factors. - Electron beam and/or orthovoltage radiotherapy are appropriate for smaller volume superficial targets; more complex photon beam arrangements may be needed depending on the clinical target volume. - Hypofractionated treatment (e.g. 32 Gy in 4 fractions or 30-36 Gy in 6 fractions over 3 weeks) may be relevant in some situations of in-transit disease. Hypofractionation is more convenient for patients, but has potential for greater chronic toxicity.
- Standard treatment (50-60 Gy) and observation have not been compared in randomized studies for in-transit disease, and thus efficacy of radiation in improving local control (e.g. 5-year axillary control rate of 88% with post-operative RT to 30-36 Gy in 5-6 fractions; complete response rate of 24% with RT to 50 Gy in 20 fractions and 32 Gy in 4 fractions) must be extrapolated from case series in other situations.
# Discussion
# Intralesional Injections Interleukin-2 (IL-2):
The effect of IL-2 in patients with in-transit melanoma was studied in a systematic review of six trials 13 . In total, 2182 lesions in 140 patients were included and response rates were reported by lesion and by subject (Table 2). This review found that by lesion, a mean complete response rate of 78% (range 40.7% to 96%), a partial response rate of 2.5%, and a no response/progression rate of 19.6%. By subject, the complete response rate ranged from 0% to 69% 13 . Another retrospective study of 31 in-transit melanoma patients treated with intralesional IL-2 found a pathologic complete response was reached in 32% of patients, a partial response in 55% of patients, and 19% of patients had progressive disease 14 .
# Other Local Therapies Topical Therapy with Diphencycprone (DPCP):
A retrospective review of 15 patients with in-transit melanoma lesions studied the effect of treatment with DPCP 21 . This study observed that 13% of patients experienced a complete response, 27% had a partial response, 40% had stable disease and 20% had disease progression. A similar prospective study of 54 patients with in-transit disease, found comparable results 22 . A complete response was observed in 22% of patients, a partial response in 39%, stable disease in 24% and progressive disease in 15%. A similar retrospective study of 50 patients observed a complete response of 46%, a partial response of 28% and 18% experienced no response 23 .
# Local Ablation:
The efficacy of carbon dioxide lasers was retrospectively reviewed in 22 patients with in-transit and satellite metastases 24 . The median overall survival was observed to be 14 months (rang 1-41months). 18 patients experienced regional control with a median duration of 14 weeks (range 3-117 weeks), though all 22 patients developed distant metastases and died of disease progression.
# Regional Therapy Isolated Limb Infusion and Perfusion:
There are currently no prospective randomized phase III trials on the use of isolated limb infusion (ILI); however, phase II studies using this technique with melphalan, with or without actinomycin-D, have shown promising complete response rates (ranging from 23 to 38%) with relatively mild toxicity (e.g. mostly grade II/III erythema and edema) 32 . A median survival time of 38 months was reported for patients treated with repeat ILI (median 11 months between procedures) with use melphalan and actinomycin-D 27 . As compared with hyperthermic isolated limb perfusion (HILP) with melphalan, ILI was shown in a retrospective analysis to be less effective, in terms of three-month complete response rate (57% vs. 30%), but to be associated with much less high-grade toxicity (grade 3+: 18% of ILI pts vs. 32% of HILP pts; P = 0.037) 28 . In a similar study, ILP was found to offer an improved overall response rate (80% vs 53%, p<0.001) compared to ILI, but this did not translate into an improved overall survival (40 months vs 46 months, p=0.31) 33 .
There is limited data on the ILI for in-transit recurrences. Repeat regional chemotherapy was evaluated retrospectively among 44 patients undergoing repeat hyperthermic ILP or ILI. After a median follow-up of 21.4 months, the response rate between procedures (HILP vs. ILI), between sequence (initial vs. repeat), and among their interactions showed no statistically significant differences. Furthermore, time to progression after initial procedure did not differ between HILP and ILI (P=0.08), and no survival difference was seen (P=0.65) 34 . Another retrospective study found that recurrent patients treated with ILI had a 70% overall response rate with low limb toxicities and no amputation required 35 .
Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (TM-HILP) has also been evaluated retrospectively for its safety and feasibility in inoperable in-transit melanoma of the extremities. Patients with locally advanced in-transit melanoma (n=14) underwent a 90-min ILP with melphalan (10 mg/l limb volume) and TNF-alpha (1-2 mg) under mild hyperthermia (39-40 degrees C). All melanoma patients showed a response to TM-HILP with 7 (62%) of them experiencing complete response. The median disease specific and limb-relapse-free survival was 15 and 12 months, respectively 36 . A similar study (n=32) of melanoma patients with recurrent in transit metastases undergoing TNF-alpha and melphalan-based ILP, showed a good response (overall response 86%, complete response 65%) and the overall MeV
# Systemic Therapy
Currently there are no in-transit disease specific studies on the effect of checkpoint immunotherapy. Clinical judgement should be used when considering these therapies. If there is concern that in-transit disease is a prognosticator of relapse or that the patient also has internal metastasis, there are systemic options that can be used. Nivolumab is approved for treatment of patients with unresectable or metastatic BRAF wild-type melanoma who have not previously received ipilimumab or pembrolizumab 37 . Pembrolizumab is approved for treatment of patients with unresectable or metastatic melanoma regardless of BRAF status 37 . Dabrafenib and/or trametinib have been approved for treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation (not to be used after progression on an alternate BRAF inhibitor and/or MEK inhibitor) 37 . For more information please see our guideline on Systemic Therapy for Unresectable Stage III or Metastatic Cutaneous Melanoma.
# Therapies Not Currently Approved in Canada Talimogene Laherparepvec (T-VEC):
The OPTiM phase III trial studied the effect of T-VEC versus granulocyte macrophage colonystimulating factor (GM-CSF) in 436 patients with injectable unresectable melanoma 38 39 . Preliminary results found that patients treated with T-VEC prior to surgery had a higher rate of R0 resections (56.1%) versus surgery alone (40.6%) and lower disease progression and recurrence (14.5%) compared to surgery alone (23%). Although there is noteworthy data on T-VEC, it may not be available to providers and patients.
# Rose Bengal (PV-10):
A phase II trial studied PV-10 followed by hypofractionated radiotherapy in patients with in-transit melanoma metastases 40 . The overall response rate was 86.8%, with a complete response in 33.3% of patients and a clinical benefit rate of 93.3%. The mean time to response was 3.8 months and the melanoma specific survival was 65.5 months. Another phase II trial studied PV-10 for patients with satellite or in-transit melanoma metastases 41 . The responses were reported per patient and per treatment episode. The overall response rate per patient was 86.6%, with a complete response of 42.2% and a clinical benefit of 93.3%. The overall response rate per treatment episode was 78.1%, with a complete response of 30.5% and a clinical benefit of 87.9%. The medium overall survival was 25 months and the mortality rate was 48.9%.
# Electrochemotherapy:
A prospective study observed the effect of electrochemotherapy in patients with in-transit melanoma skin metastases 42 . In the intend-to-treat population, the overall tumour response was 46% of tumours treated with electroporation and bleomycin, versus 25% of tumours treated by bleomycin alone (p=0.10). Complete responses were obtained in 36% versus 8% of metastases (p=0.016), respectively. In the per protocol population, the overall tumour response was 87% of metastases treated by electroporation and bleomycin, versus 53% of the metastases treated by bleomycin (p=0.35). Complete responses were obtained in 74% versus 13% of metastases (p=0.017), respectively. A more recent retrospective study found similar results. Electrochemotherapy was used to treat 60 patients with in-transit melanoma 43 . Three months after treatment, 48.4% of patients had a complete response and 38.3% had a partial response.
- Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases. Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial (i.e., sentinel node biopsy) or complete lymphadenectomy. Pathologic stage 0 or IA patients are the exception; they do not require pathologic evaluation of their lymph nodes. *Pathological Stage 0 and T1 do not require pathological evaluation of lymph nodes to complete staging.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Cutaneous Tumour Team. Members include .
Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010.
# Maintenance
A formal review of the guideline will be conducted in 2021. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
BCG, bacillus calmette guerin; Gy, grey; IFN, interferon; IL-2, interleukin; ILI, isolated limb infusion; ILP, isolated limb perfusion; MeV, mega electron volt. | # Background
In transit disease is a Stage III regional metastatic disease consisting of intradermal or subcutaneous nodules. The probability of in transit disease varies with melanoma thickness (Table 1). Although many treatment modalities exist and have been described in the literature, high level evidence is still lacking and there is little consensus on a standard approach for patients 1 . The treatment strategies described in this guideline are currently the most effective options for patients with this disease; however, further clinical trials in this area are needed. Guideline Questions
• What are the best treatment and management options for improving the progression-free survival and overall survival of patients with melanoma with in-transit disease?
# Search Strategy
The MEDLINE, Cochrane, ASCO Abstracts and proceedings, and CANCERLIT databases were searched (1985 through November 2009) for clinical trials. Search terms included: "primary cutaneous melanoma" or "regional metastatic disease" or "in-transit disease" or "intradermal nodules" or "subcutaneous nodules" AND "isolated limb perfusion" or "isolated limb infusion" or "hyperthermic limb perfusion" or "tumor necrosis factor alpha" or "melphalan" or "radiation therapy" or "tamoxifen" or "cryotherapy" or "laser therapy" or "bacillus calmette guerin" or "interferon" or "chemotherapy." A total of 585 clinical trials (limits: human and English language) were returned, from which 35 documents were selected. In addition, the National Guidelines Clearinghouse and individual guideline organizations were searched for practice guidelines relevant to this topic.
For the 2013 update of the guideline, PubMed was searched for evidence on in-transit melanoma. The search term "melanoma" was used and results were limited to clinical trials, published between December 2009 and January 2013. Citations were hand-searched for studies pertaining to in-transit disease, resulting in three relevant studies. Following a review of the evidence by the Alberta Cutaneous Tumour Team, no major changes to the recommendations were made.
# Target Population
This guideline outlines treatment and management strategies for patients with stage III regional metastatic disease that are intradermal or subcutaneous nodules growing within lymphatics and not in nodal basins.
# Recommendations
For staging please refer to the Appendix.
# Regional Therapy
• Isolated limb infusion/ perfusion with melphalan
# Second-Line Treatment Options
Patients who experience disease progression during or shortly after primary treatment, should be considered for second-line treatment. Second-line treatment agents should be different than the primary treatment and not of the same class. Patients who experience disease control without residual toxicity followed by disease progression more than 3 months after primary treatment ceases, can be considered for second-line treatment with the same agent or same class of agents used for primary treatment 1 .
# Post Surgery
• No evidence of disease: Adjuvant treatment (see below) or observation • Less than complete resection:
o Local therapy options:
• Intralesional injection options: Interleukin-2, talimogene laherparepvec*, PV-10*, bacillus calmette guerin • Local ablation therapy • Topical imiquimod for superficial dermal lesions • Radiation therapy (see below) o Regional therapy options:
• Isolated limb infusion/perfusion with melphalan o Adjuvant therapy (see below) following local or regional therapy 2. Post Non-Surgical Primary Therapy
• No evidence of disease: Adjuvant treatment (see below) or observation • Residual/progressive disease o Choose an alternative local therapy option:
• Intralesional injection options: Interleukin-2, talimogene laherparepvec*, PV-10*, bacillus calmette guerin • Local ablation therapy • Topical imiquimod for superficial dermal lesions • Radiation therapy (see below) o Or choose a regional therapy option:
• Isolated limb infusion/perfusion with melphalan • Adjuvant therapy (see below) following local or regional therapy
# *not currently available in Canada
Adjuvant Treatment • Nivolumab • Pembrolizumab • Dabrafenib/trametinib (BRAFV600-activating mutation)
# Radiation Therapy
• Treatment to tumour bed, regions of in-transit disease and nodal drainage basin can be considered based on the pathology after resection and other patient and disease factors. • Electron beam and/or orthovoltage radiotherapy are appropriate for smaller volume superficial targets; more complex photon beam arrangements may be needed depending on the clinical target volume. • Hypofractionated treatment (e.g. 32 Gy in 4 fractions or 30-36 Gy in 6 fractions over 3 weeks) may be relevant in some situations of in-transit disease. Hypofractionation is more convenient for patients, but has potential for greater chronic toxicity.
o Standard treatment (50-60 Gy) and observation have not been compared in randomized studies for in-transit disease, and thus efficacy of radiation in improving local control (e.g. 5-year axillary control rate of 88% with post-operative RT to 30-36 Gy in 5-6 fractions; complete response rate of 24% with RT to 50 Gy in 20 fractions and 32 Gy in 4 fractions) must be extrapolated from case series in other situations.
# Discussion
# Intralesional Injections Interleukin-2 (IL-2):
The effect of IL-2 in patients with in-transit melanoma was studied in a systematic review of six trials 13 . In total, 2182 lesions in 140 patients were included and response rates were reported by lesion and by subject (Table 2). This review found that by lesion, a mean complete response rate of 78% (range 40.7% to 96%), a partial response rate of 2.5%, and a no response/progression rate of 19.6%. By subject, the complete response rate ranged from 0% to 69% 13 . Another retrospective study of 31 in-transit melanoma patients treated with intralesional IL-2 found a pathologic complete response was reached in 32% of patients, a partial response in 55% of patients, and 19% of patients had progressive disease 14 .
# Other Local Therapies Topical Therapy with Diphencycprone (DPCP):
A retrospective review of 15 patients with in-transit melanoma lesions studied the effect of treatment with DPCP 21 . This study observed that 13% of patients experienced a complete response, 27% had a partial response, 40% had stable disease and 20% had disease progression. A similar prospective study of 54 patients with in-transit disease, found comparable results 22 . A complete response was observed in 22% of patients, a partial response in 39%, stable disease in 24% and progressive disease in 15%. A similar retrospective study of 50 patients observed a complete response of 46%, a partial response of 28% and 18% experienced no response 23 .
# Local Ablation:
The efficacy of carbon dioxide lasers was retrospectively reviewed in 22 patients with in-transit and satellite metastases 24 . The median overall survival was observed to be 14 months (rang 1-41months). 18 patients experienced regional control with a median duration of 14 weeks (range 3-117 weeks), though all 22 patients developed distant metastases and died of disease progression.
# Regional Therapy Isolated Limb Infusion and Perfusion:
There are currently no prospective randomized phase III trials on the use of isolated limb infusion (ILI); however, phase II studies using this technique with melphalan, with or without actinomycin-D, have shown promising complete response rates (ranging from 23 to 38%) [25][26][27][28][29][30][31] with relatively mild toxicity (e.g. mostly grade II/III erythema and edema) 32 . A median survival time of 38 months was reported for patients treated with repeat ILI (median 11 months between procedures) with use melphalan and actinomycin-D 27 . As compared with hyperthermic isolated limb perfusion (HILP) with melphalan, ILI was shown in a retrospective analysis to be less effective, in terms of three-month complete response rate (57% vs. 30%), but to be associated with much less high-grade toxicity (grade 3+: 18% of ILI pts vs. 32% of HILP pts; P = 0.037) 28 . In a similar study, ILP was found to offer an improved overall response rate (80% vs 53%, p<0.001) compared to ILI, but this did not translate into an improved overall survival (40 months vs 46 months, p=0.31) 33 .
There is limited data on the ILI for in-transit recurrences. Repeat regional chemotherapy was evaluated retrospectively among 44 patients undergoing repeat hyperthermic ILP or ILI. After a median follow-up of 21.4 months, the response rate between procedures (HILP vs. ILI), between sequence (initial vs. repeat), and among their interactions showed no statistically significant differences. Furthermore, time to progression after initial procedure did not differ between HILP and ILI (P=0.08), and no survival difference was seen (P=0.65) 34 . Another retrospective study found that recurrent patients treated with ILI had a 70% overall response rate with low limb toxicities and no amputation required 35 .
Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (TM-HILP) has also been evaluated retrospectively for its safety and feasibility in inoperable in-transit melanoma of the extremities. Patients with locally advanced in-transit melanoma (n=14) underwent a 90-min ILP with melphalan (10 mg/l limb volume) and TNF-alpha (1-2 mg) under mild hyperthermia (39-40 degrees C). All melanoma patients showed a response to TM-HILP with 7 (62%) of them experiencing complete response. The median disease specific and limb-relapse-free survival was 15 and 12 months, respectively 36 . A similar study (n=32) of melanoma patients with recurrent in transit metastases undergoing TNF-alpha and melphalan-based ILP, showed a good response (overall response 86%, complete response 65%) and the overall MeV
# Systemic Therapy
Currently there are no in-transit disease specific studies on the effect of checkpoint immunotherapy. Clinical judgement should be used when considering these therapies. If there is concern that in-transit disease is a prognosticator of relapse or that the patient also has internal metastasis, there are systemic options that can be used. Nivolumab is approved for treatment of patients with unresectable or metastatic BRAF wild-type melanoma who have not previously received ipilimumab or pembrolizumab 37 . Pembrolizumab is approved for treatment of patients with unresectable or metastatic melanoma regardless of BRAF status 37 . Dabrafenib and/or trametinib have been approved for treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation (not to be used after progression on an alternate BRAF inhibitor and/or MEK inhibitor) 37 . For more information please see our guideline on Systemic Therapy for Unresectable Stage III or Metastatic Cutaneous Melanoma.
# Therapies Not Currently Approved in Canada Talimogene Laherparepvec (T-VEC):
The OPTiM phase III trial studied the effect of T-VEC versus granulocyte macrophage colonystimulating factor (GM-CSF) in 436 patients with injectable unresectable melanoma 38 39 . Preliminary results found that patients treated with T-VEC prior to surgery had a higher rate of R0 resections (56.1%) versus surgery alone (40.6%) and lower disease progression and recurrence (14.5%) compared to surgery alone (23%). Although there is noteworthy data on T-VEC, it may not be available to providers and patients.
# Rose Bengal (PV-10):
A phase II trial studied PV-10 followed by hypofractionated radiotherapy in patients with in-transit melanoma metastases 40 . The overall response rate was 86.8%, with a complete response in 33.3% of patients and a clinical benefit rate of 93.3%. The mean time to response was 3.8 months and the melanoma specific survival was 65.5 months. Another phase II trial studied PV-10 for patients with satellite or in-transit melanoma metastases 41 . The responses were reported per patient and per treatment episode. The overall response rate per patient was 86.6%, with a complete response of 42.2% and a clinical benefit of 93.3%. The overall response rate per treatment episode was 78.1%, with a complete response of 30.5% and a clinical benefit of 87.9%. The medium overall survival was 25 months and the mortality rate was 48.9%.
# Electrochemotherapy:
A prospective study observed the effect of electrochemotherapy in patients with in-transit melanoma skin metastases 42 . In the intend-to-treat population, the overall tumour response was 46% of tumours treated with electroporation and bleomycin, versus 25% of tumours treated by bleomycin alone (p=0.10). Complete responses were obtained in 36% versus 8% of metastases (p=0.016), respectively. In the per protocol population, the overall tumour response was 87% of metastases treated by electroporation and bleomycin, versus 53% of the metastases treated by bleomycin (p=0.35). Complete responses were obtained in 74% versus 13% of metastases (p=0.017), respectively. A more recent retrospective study found similar results. Electrochemotherapy was used to treat 60 patients with in-transit melanoma 43 . Three months after treatment, 48.4% of patients had a complete response and 38.3% had a partial response.
#
* Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases. ** Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial (i.e., sentinel node biopsy) or complete lymphadenectomy. Pathologic stage 0 or IA patients are the exception; they do not require pathologic evaluation of their lymph nodes. ***Pathological Stage 0 and T1 do not require pathological evaluation of lymph nodes to complete staging.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Cutaneous Tumour Team. Members include [surgical oncologists, radiation oncologists, medical oncologists, dermatologists, nurses, pathologists, and pharmacists].
Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010.
# Maintenance
A formal review of the guideline will be conducted in 2021. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
BCG, bacillus calmette guerin; Gy, grey; IFN, interferon; IL-2, interleukin; ILI, isolated limb infusion; ILP, isolated limb perfusion; MeV, mega electron volt.
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial Cutaneous Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2019) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/.
The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of CancerControl Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerControl Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Generated using the standard COI form.
Dr. Muhammad Faruqi has nothing to disclose.
# Dr. J. Gregory Mckinnon has nothing to disclose.
Dr. Tom Salopek reports grants and other from BMS, grants, personal fees, non-financial support and other from Merck, grants, personal fees, non-financial support and other from Novartis , personal fees and other from EMD Serono, personal fees from Leo, personal fees from Johnson & Johnson, personal fees from Abbvie, personal fees from UCB, outside the submitted work .
Dr. Claire Temple-Oberle has nothing to disclose. | None | None |
e2468bb05850fb3e6ee533d66c26bc5b5ef4b5c6 | cma | None | COVID-19 has an initial phase of viral replication and a significant inflammatory response in moderate illness. This inflammation can lead to poor outcomes, including hospitalization, invasive ventilation, and death. However, treatments that target SARS-CoV-2 replication, if administered before the inflammatory phase of COVID-19, can improve outcomes. Nirmatrelvir works by binding to the SARS-CoV-2 3CL protease, which ultimately causes viral replication to stop. Ritonavir is a potent CYP3A4 inhibitor. It is not active against SARS-CoV-2 but is administered as a "boosting agent" to slow the metabolism of nirmatrelvir, thus increasing concentrations of nirmatrelvir.# What is the benefit of nirmatrelvir/ritonavir for COVID 19?
No peer-reviewed studies are available for analysis. However, the drug was approved based on data from the unpublished EPIC-HR study 1 which was done in unvaccinated, high-risk patients prior to circulation of the Omicron variant.
Based on regulatory submissions, nirmatrelvir/ritonavir reduces hospitalization in adult outpatients (with laboratoryproven SARS-CoV-2 infection, who were not on supplemental oxygen, and who were within 5 days of symptom onset).
With Health Canada's approval of nirmatrelvir/ritonavir, the Ontario Science Advisory Table has made a conditional recommendation that nirmatrelvir/ritonavir be used in COVID-19 patients who are not on supplemental oxygen but are at high risk of progression to moderate or severe This recommendation is based on incomplete data. It will be revised with the publication of peer-reviewed data.
Nirmatrelvir/ritonavir is a highly e ective outpatient therapy based on available data, but there is uncertainty about e ect magnitude in target populations and high certainty for harm with ritonavir if drug interactions are not mitigated.
Nirmatrelvir/ritonavir should be o ered preferentially to patients with mild COVID-19 at higher risk of severe disease or complications from COVID-19:
In times of drug shortage, nirmatrelvir/ritonavir should be o ered preferentially to patients with mild disease at highest risk of severe disease or complications from COVID-19:
Nirmatrelvir/ritonavir should be deployed preferentially to regions where there are barriers to intravenous administration of other recommended outpatient therapies (i.e., sotrovimab, remdesivir Ritonavir is a potent inhibitor of CYP3A4 isoenzyme and various drug transporters (e.g., P-glycoprotein).
Ritonavir and nirmatrelvir are both CYP3A4 substrates.
Nirmatrelvir/ritonavir is contraindicated in patients taking drugs that are:
If the patient is taking or has taken a CYP3A4 enzyme inducer in the last 28 days (e.g., certain anticonvulsants, antineoplastics, a rifamycin, St. John's wort): Do NOT prescribe nirmatrelvir/ ritonavir.
If the patient takes an interacting drug with a long plasma half-life and narrow therapeutic window (e.g., certain antiarrhythmics, antipsychotics, antineoplastics), the interacting drug will persist in the body after the last dose and may still interact with nirmatrelvir/ritonavir: Do NOT prescribe nirmatrelvir/ritonavir even if the interacting drug can be held.
If the patient takes an interacting drug that can be held, hold the medication starting the first day of nirmatrelvir/ritonavir therapy, and resume 2 days after the last dose of nirmatrelvir/ritonavir treatment.
A specialist prescriber or pharmacist may be able to help adjust the dose or dosing interval, replace the drug with an alternative agent, manage side e ects, and guide therapeutic drug monitoring.
Page 2 of 3 Paxlovid consists of 2 drugs packaged together: Each carton contains 5 blister cards. One blister card is used each day. The full course of treatment is 5 days. eGFR 30 to 59 mL/min: The dose is 1 each of nirmatrelvir 150 mg and ritonavir 100 mg, with both tablets taken together orally BID x 5 days. eGFR <30 mL/min: Nirmatrelvir/ritonavir is not recommended.
Severe hepatic impairment (Child-Pugh Class C): Nirmatrelvir/ritonavir is not recommended. † †
# Special Dosing Considerations:
Take 2 pink tablets of nirmatrelvir and 1 white tablet of ritonavir (3 tablets total) together at the same time, once in the morning and once in the evening for 5 days (i.e., 6 tablets per day).
Nirmatrelvir (pink) 150 mg tablet Ritonavir (white) 100 mg tablet
# What if my patient is taking therapy for human immunodeficiency virus (HIV)?
Patients taking ritonavir or cobicistat for HIV therapy should continue their complete antiretroviral regimen at usual dosing while taking nirmatrelvir/ritonavir.
Nirmatrelvir/ritonavir may be taken with or without food. What side effects should I be aware of?
Common side e ects of nirmatrelvir/ritonavir are generally mild and can include dysgeusia (taste disturbance), diarrhea, hypertension, myalgia, vomiting and headache.
Not many people have taken this drug, and it is still being studied -so it is possible that all the side e ects are not yet known, or that rare, but serious side e ects may happen. Continue with standard dosing. Drug interaction not likely to be clinically relevant Although mentioned in the monograph, interaction is not anticipated (e.g., minimal impact on certain metabolic pathways, wide therapeutic index, and short course of nirmatrelvir/ritonavir therapy).
Try to avoid coadministering due to risk of serious toxicity. Ideally, only start nirmatrelvir/ritonavir if drug can be safely held or replaced. In some instances, dose-adjustment is possible (refer to product monograph).
Additional information may be found in the prescribing monograph: or the University of Liverpool COVID-19 drug interaction checker: /.
This is not an exhaustive list. Consultation with a pharmacist who can get a complete medication, recreational, and natural health product history from the patient is recommended prior to prescribing nirmatrelvir/ritonavir. | COVID-19 has an initial phase of viral replication and a significant inflammatory response in moderate illness. This inflammation can lead to poor outcomes, including hospitalization, invasive ventilation, and death. However, treatments that target SARS-CoV-2 replication, if administered before the inflammatory phase of COVID-19, can improve outcomes. Nirmatrelvir works by binding to the SARS-CoV-2 3CL protease, which ultimately causes viral replication to stop. Ritonavir is a potent CYP3A4 inhibitor. It is not active against SARS-CoV-2 but is administered as a "boosting agent" to slow the metabolism of nirmatrelvir, thus increasing concentrations of nirmatrelvir.# What is the benefit of nirmatrelvir/ritonavir for COVID 19?
No peer-reviewed studies are available for analysis. However, the drug was approved based on data from the unpublished EPIC-HR study 1 which was done in unvaccinated, high-risk patients prior to circulation of the Omicron variant.
Based on regulatory submissions, nirmatrelvir/ritonavir reduces hospitalization in adult outpatients (with laboratoryproven SARS-CoV-2 infection, who were not on supplemental oxygen, and who were within 5 days of symptom onset).
With Health Canada's approval of nirmatrelvir/ritonavir, the Ontario Science Advisory Table has made a conditional recommendation that nirmatrelvir/ritonavir be used in COVID-19 patients who are not on supplemental oxygen but are at high risk of progression to moderate or severe This recommendation is based on incomplete data. It will be revised with the publication of peer-reviewed data.
Nirmatrelvir/ritonavir is a highly e ective outpatient therapy based on available data, but there is uncertainty about e ect magnitude in target populations and high certainty for harm with ritonavir if drug interactions are not mitigated.
Nirmatrelvir/ritonavir should be o ered preferentially to patients with mild COVID-19 at higher risk of severe disease or complications from COVID-19:
In times of drug shortage, nirmatrelvir/ritonavir should be o ered preferentially to patients with mild disease at highest risk of severe disease or complications from COVID-19:
Nirmatrelvir/ritonavir should be deployed preferentially to regions where there are barriers to intravenous administration of other recommended outpatient therapies (i.e., sotrovimab, remdesivir Ritonavir is a potent inhibitor of CYP3A4 isoenzyme and various drug transporters (e.g., P-glycoprotein).
Ritonavir and nirmatrelvir are both CYP3A4 substrates.
Nirmatrelvir/ritonavir is contraindicated in patients taking drugs that are:
If the patient is taking or has taken a CYP3A4 enzyme inducer in the last 28 days (e.g., certain anticonvulsants, antineoplastics, a rifamycin, St. John's wort): Do NOT prescribe nirmatrelvir/ ritonavir.
If the patient takes an interacting drug with a long plasma half-life and narrow therapeutic window (e.g., certain antiarrhythmics, antipsychotics, antineoplastics), the interacting drug will persist in the body after the last dose and may still interact with nirmatrelvir/ritonavir: Do NOT prescribe nirmatrelvir/ritonavir even if the interacting drug can be held.
If the patient takes an interacting drug that can be held, hold the medication starting the first day of nirmatrelvir/ritonavir therapy, and resume 2 days after the last dose of nirmatrelvir/ritonavir treatment.
A specialist prescriber or pharmacist may be able to help adjust the dose or dosing interval, replace the drug with an alternative agent, manage side e ects, and guide therapeutic drug monitoring.
Page 2 of 3 Paxlovid consists of 2 drugs packaged together: Each carton contains 5 blister cards. One blister card is used each day. The full course of treatment is 5 days. eGFR 30 to 59 mL/min: The dose is 1 each of nirmatrelvir 150 mg and ritonavir 100 mg, with both tablets taken together orally BID x 5 days. eGFR <30 mL/min: Nirmatrelvir/ritonavir is not recommended.
Severe hepatic impairment (Child-Pugh Class C): Nirmatrelvir/ritonavir is not recommended. † †
# Special Dosing Considerations:
Take 2 pink tablets of nirmatrelvir and 1 white tablet of ritonavir (3 tablets total) together at the same time, once in the morning and once in the evening for 5 days (i.e., 6 tablets per day).
Nirmatrelvir (pink) 150 mg tablet Ritonavir (white) 100 mg tablet
# What if my patient is taking therapy for human immunodeficiency virus (HIV)?
Patients taking ritonavir or cobicistat for HIV therapy should continue their complete antiretroviral regimen at usual dosing while taking nirmatrelvir/ritonavir.
Nirmatrelvir/ritonavir may be taken with or without food. What side effects should I be aware of?
Common side e ects of nirmatrelvir/ritonavir are generally mild and can include dysgeusia (taste disturbance), diarrhea, hypertension, myalgia, vomiting and headache.
Not many people have taken this drug, and it is still being studied -so it is possible that all the side e ects are not yet known, or that rare, but serious side e ects may happen. Continue with standard dosing. Drug interaction not likely to be clinically relevant Although mentioned in the monograph, interaction is not anticipated (e.g., minimal impact on certain metabolic pathways, wide therapeutic index, and short course of nirmatrelvir/ritonavir therapy).
Try to avoid coadministering due to risk of serious toxicity. Ideally, only start nirmatrelvir/ritonavir if drug can be safely held or replaced. In some instances, dose-adjustment is possible (refer to product monograph).
#
Additional information may be found in the prescribing monograph: https://covid-vaccine.canada.ca/info/pdf/paxlovid-pm-en.pdf or the University of Liverpool COVID-19 drug interaction checker: https://www.covid19-druginteractions.org/.
#
This is not an exhaustive list. Consultation with a pharmacist who can get a complete medication, recreational, and natural health product history from the patient is recommended prior to prescribing nirmatrelvir/ritonavir. | None | None |
4eb07eb52472b6e463b5e34a33f0b180a88c6972 | cma | None | This guideline summarizes suggested wait times for common indications where Magnetic Resonance Imaging (MRI) is the recommended first imaging test. The purpose is to inform primary care practitioners of how referrals are prioritized by Radiologists and Radiology departments across the province. This guideline is an adaptation of the British Columbia Radiological Society (BCRS) MRI Prioritization Guidelines (2013). 1 Management of the listed clinical problems is beyond the scope of this guideline. However, in some cases, notes and alternative tests are provided for additional clinical context. Primary care practitioners are encouraged to consult a Radiologist if they have any concerns or questions regarding which appropriate imaging test to choose for a problem. If in doubt consult with a Radiologist and review provincial guidance materials. 2 # Background
The 2013 BCRS MRI Prioritization Guidelines were developed to provide imaging departments with a consistent, provincial approach to prioritizing commonly ordered MRI tests according to suggested maximum wait times. The BCRS guidelines were developed by consensus and are based on BC expert opinion with representation of Radiologists from across the province. Several considerations apply:
- These are guidelines, and as such, are designed to apply in general terms. They are not intended to replace clinical judgement or practitioner-to-practitioner discussion. - Prioritization levels were selected to match other similar guidelines for Computed Tomography (CT) and Ultrasound (US) and are typically assigned by Radiologists rather than referring practitioners. - These guidelines should not be applied rigidly to each case, as varying clinical factors may shift an indication from one priority level to another. - Access to MRI and the ability to respond to MRI requests will depend on resourcing or local availability.
- Providing detailed patient information is essential to aid with the prioritization process.
- The clinical topics included in this guideline represent broad examples, and do not encompass all possible scenarios or all requirements for MRI examinations.
# Priority Level Definitions
The priority levels defined below (Table 1) are in alignment with the Canadian Association of Radiologists national designation Five Point Classification System. 3
# P1
An examination immediately necessary to diagnose and/or treat life-threatening disease. Such an examination will need to be done either stat or not later than the day of the request.
Immediately to 24 hours
# P2
An examination indicated within one week of a request to resolve a clinical management imperative. Maximum 7 calendar days
# P3
An examination indicated to investigate symptoms of potential importance. Maximum 30 calendar days
# P4
An examination indicated for long-range management or for prevention.
# Abdomen and Pelvis: Notes and Alternative Tests Potential Diagnosis
Notes and Alternative Tests
# P1
Acute abdomen in pregnancy (e.g. appendicitis, renal colic)
- CT is usually the best first test for acute abdomen, except for pregnant patients where MRI is preferred to reduce fetal radiation exposure Pelvic imaging for young women <35 years old (e.g. ovarian torsion, appendicitis)
- US is usually the best first test. MRI should be considered for young women to reduce radiation exposure if US equivocal | This guideline summarizes suggested wait times for common indications where Magnetic Resonance Imaging (MRI) is the recommended first imaging test. The purpose is to inform primary care practitioners of how referrals are prioritized by Radiologists and Radiology departments across the province. This guideline is an adaptation of the British Columbia Radiological Society (BCRS) MRI Prioritization Guidelines (2013). 1 Management of the listed clinical problems is beyond the scope of this guideline. However, in some cases, notes and alternative tests are provided for additional clinical context. Primary care practitioners are encouraged to consult a Radiologist if they have any concerns or questions regarding which appropriate imaging test to choose for a problem. If in doubt consult with a Radiologist and review provincial guidance materials. 2 # Background
The 2013 BCRS MRI Prioritization Guidelines were developed to provide imaging departments with a consistent, provincial approach to prioritizing commonly ordered MRI tests according to suggested maximum wait times. The BCRS guidelines were developed by consensus and are based on BC expert opinion with representation of Radiologists from across the province. Several considerations apply:
• These are guidelines, and as such, are designed to apply in general terms. They are not intended to replace clinical judgement or practitioner-to-practitioner discussion. • Prioritization levels were selected to match other similar guidelines for Computed Tomography (CT) and Ultrasound (US) and are typically assigned by Radiologists rather than referring practitioners. • These guidelines should not be applied rigidly to each case, as varying clinical factors may shift an indication from one priority level to another. • Access to MRI and the ability to respond to MRI requests will depend on resourcing or local availability.
• Providing detailed patient information is essential to aid with the prioritization process.
• The clinical topics included in this guideline represent broad examples, and do not encompass all possible scenarios or all requirements for MRI examinations.
# Priority Level Definitions
The priority levels defined below (Table 1) are in alignment with the Canadian Association of Radiologists national designation Five Point Classification System. 3
# P1
An examination immediately necessary to diagnose and/or treat life-threatening disease. Such an examination will need to be done either stat or not later than the day of the request.
Immediately to 24 hours
# P2
An examination indicated within one week of a request to resolve a clinical management imperative. Maximum 7 calendar days
# P3
An examination indicated to investigate symptoms of potential importance. Maximum 30 calendar days
# P4
An examination indicated for long-range management or for prevention.
# Abdomen and Pelvis: Notes and Alternative Tests Potential Diagnosis
Notes and Alternative Tests
# P1
Acute abdomen in pregnancy (e.g. appendicitis, renal colic)
• CT is usually the best first test for acute abdomen, except for pregnant patients where MRI is preferred to reduce fetal radiation exposure Pelvic imaging for young women <35 years old (e.g. ovarian torsion, appendicitis)
• US is usually the best first test. MRI should be considered for young women to reduce radiation exposure if US equivocal
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This guideline is based on expert BC clinical practice current as of the effective date. This guideline was developed by the Guidelines and Protocols Advisory Committee based on the British Columbia Radiological Society MRI Prioritization Guidelines (2013), and approved by the Medical Services Commission. | None | None |
cd7cdf1048c8c2f9c1b5923ac008b8deaf01bee4 | cma | None | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY# Introduction
The management of venous thromboembolism (VTE) is a frequent and important clinical issue in patients with cancer. The 6-month VTE risk for patients with cancer is 12-fold higher compared to the general population, and as much as 23-fold higher in patients receiving chemotherapy or targeted therapy . Over the past two decades, the 12-month cumulative incidence for VTE has increased three-fold in cancer patients . Furthermore, thromboembolism has been reported to be the second leading cause of death in patients with cancer, highlighting the importance of urgently initiating therapeutic dosing of anticoagulation . However, the management of anticoagulant therapy for cancer-associated thrombosis (CAT) is complex due to an increased risk of both recurrent Curr. Oncol. 2021, 28
VTE and major bleeding in patients with cancer as compared to those without cancer . Selection and dosing of anticoagulant therapy for CAT needs to be individualized based on the patient's risk for both recurrent VTE and bleeding. This can be influenced by patient characteristics, type and stage of cancer, and anticancer treatment .
Several classes of anticoagulants have been studied in the treatment of CAT, including vitamin K antagonists (VKAs), subcutaneous low-molecular-weight heparins (LMWHs), and direct oral anticoagulants (DOACs). For many years, LMWHs were the standard of care for the acute and extended treatment of CAT based on the results of trials comparing LMWH with VKA . Patients with cancer were underrepresented in initial trials comparing DOACs to VKA for the acute treatment of VTE . However, the recent publication of clinical trials comparing DOACs with LMWH in the cancer-patient population has expanded the therapeutic options for the acute and extended treatment of CAT, but also introduced a layer of complexity . To provide guidance to health care professionals on tailoring anticoagulant treatment in patients with CAT, an evidence-based risk stratification treatment algorithm was developed in 2018 . The consensus process reported here was undertaken to up-date this treatment algorithm based on the evolving body of evidence.
# Methods
# Literature Review
To update the treatment algorithm, the committee used, as a starting point, the previously published 2018 Canadian expert consensus treatment algorithm in CAT . A systematic review of the literature published since 2018 was performed using the search strategies outlined in supplemental Appendix A. All abstracts were reviewed. References of narrative reviews identified by the search strategy also were reviewed to ensure that all potentially relevant articles were captured.
# Revision of Treatment Algorithm
The multidisciplinary consensus group, which included 11 physicians with expertise in the areas of hematology, medical oncology, and general internal medicine, met in April 2021 via Web-based teleconference to discuss how the results of the literature search would impact the 2018 treatment algorithm. The revised treatment algorithm and manuscript were then circulated by email on two occasions so that committee members could review them and provide comments. The final version of updated algorithm was approved by all members.
# Role of the Funding Sources
The revision of the algorithm was funded by unrestricted grants from Pfizer Canada, Hospital Business Unit (Kirkland, QC, Canada), Bayer Canada Inc (Montreal, QC, Canada), LEO Pharma Inc (Thornhill, ON, Canada) and Servier Canada (Ottawa, ON, Canada) to Thrombosis Canada. The authors administered all aspects of revising the treatment algorithm, and the funding sources had no role in drafting, editing, or approving the treatment algorithm.
# Results
The search of the PubMed database identified 420 articles, 22 of which were selected for review according to pre-specified criteria, while the search of the American Society of Hematology abstract database identified 27 abstracts, one of which was selected for review. The committee included an additional 12 articles not identified by the search strategy. Following review of the 35 selected articles and abstracts and discussion of the new evidence, the revisions to the algorithm were recommended. The resulting treatment algorithm (Figure 1) provides guidance on the selection of anticoagulant therapy for cancer patients with incidental or symptomatic upper extremity or lower limb deep vein thrombosis (DVT) or pulmonary embolism (PE).
patients with incidental or symptomatic upper extremity or lower limb deep vein thrombosis (DVT) or pulmonary embolism (PE). Apixaban should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B), while these patients exhibited comparable pharmacokinetics and pharmacodynamics to healthy controls when treated with edoxaban. b Use of antiplatelet agents should be assessed, and discontinuation should be considered in the absence of a strong indication. Shared decision-making with other health care providers is warranted. c Currently, dalteparin, enoxaparin, and tinzaparin have randomized controlled trial evidence in cancer-associated thrombosis, with the evidence base being stronger for dalteparin and tinzaparin. Refer to the relevant product monograph for appropriate dosing. d Currently, apixaban, edoxaban, and rivaroxaban have randomized controlled trial evidence in cancer-associated thrombosis, with stronger evidence for apixaban and edoxaban. Refer to the relevant product monograph for appropriate dosing. DVT = deep vein thrombosis; PE = pulmonary embolism; GI = gastrointestinal; GU = genitourinary; DOAC = direct-acting oral anticoagulant; LMWH = low molecular weight heparin; VTE = venous thromboembolism. Apixaban should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B), while these patients exhibited comparable pharmacokinetics and pharmacodynamics to healthy controls when treated with edoxaban. b Use of antiplatelet agents should be assessed, and discontinuation should be considered in the absence of a strong indication. Shared decision-making with other health care providers is warranted. c Currently, dalteparin, enoxaparin, and tinzaparin have randomized controlled trial evidence in cancerassociated thrombosis, with the evidence base being stronger for dalteparin and tinzaparin. Refer to the relevant product monograph for appropriate dosing. d Currently, apixaban, edoxaban, and rivaroxaban have randomized controlled trial evidence in cancer-associated thrombosis, with stronger evidence for apixaban and edoxaban. Refer to the relevant product monograph for appropriate dosing. DVT = deep vein thrombosis; PE = pulmonary embolism; GI = gastrointestinal; GU = genitourinary; DOAC = direct-acting oral anticoagulant; LMWH = low molecular weight heparin; VTE = venous thromboembolism.
According to the treatment algorithm, LMWH is preferred in patients at high risk of bleeding, with unresected intraluminal gastrointestinal (GI) or genitourinary (GU) cancer, or with significant drug-drug interactions with DOACs. In contrast, DOACs are preferred in patients at low risk of bleeding, with other cancer types, and without significant drugdrug interactions. Other factors to consider include patient and clinician preference, drug cost and coverage, body weight, burden of cancer, burden of VTE, and history of abnormal uterine bleeding, significant GI surgery, or absorption disorders. Anticoagulant therapy should be reassessed regularly (e.g., every 3 months), and sooner if there are changes in the patient's management or condition. In general, anticoagulation should be continued in patients with active cancer (underlying cancer present or on-going anti-cancer treatment), while discontinuation may be considered in those whose cancer is no longer active.
# Discussion
# Efficacy and Safety of Anticoagulants
Until the publication of randomized controlled trials (RCTs) comparing DOACs with LMWH for the acute treatment of CAT (Table 1), clinical practice guidelines recommended the use of LMWH over DOACs or VKA for the acute and secondary prevention of VTE in patients with cancer . Recent guidelines, on the other hand, have suggested that either a DOAC or LMWH can be used for the acute treatment of CAT , with recommendations that treatment be individualized based on patient characteristics. A meta-analysis of the results of all RCTs comparing LMWH with VKA for the management of CAT reported a 44% reduction in the risk of recurrent VTE (relative risk (RR): 0.56; 95% confidence interval (CI): 0.43 to 0.74), without a significant increase in the risk of major bleeding (RR: 1.07; 95% CI: 0.66 to 1.79) in patients treated with LMWH . A similar meta-analysis of the results of all RCTs comparing DOACs with LMWH for the treatment of acute CAT reported a significantly lower risk of recurrent VTE (hazard ratio (HR): 0.63; 95% CI: 0.47 to 0.86) and a non-significantly higher risk of major bleeding (HR: 1.26; 95% CI: 0.84 to 1.90) with DOACs as compared to LMWH . An analysis of 29 studies including a total of 8000 patients with cancer found that case fatality rates were higher for recurrent VTE than those for major bleeding at 15.0% (95% CI 6.6 to 30.1%) and 8.9% (95% CI 3.5 to 21.1%), respectively . Although case fatality rates varied by type of anticoagulation in this analysis, the differences were not statistically significant . Taken together, these data highlight the importance of preventing recurrent VTE while minimizing the risk of major bleeding complications in patients with cancer. LMWH is more effective than VKA without any increase in bleeding complications. DOACs are noninferior to LMWHs in terms of overall safety and efficacy. No data comparing the direct thrombin inhibitor dabigatran with LMWH for the management of CAT are available.
# Incidental VTE
Although patients with incidental VTE (i.e., asymptomatic thrombosis found on screening imaging tests) were not included in the RCTs of LMWH vs. VKA , between 20% and 53% of patients included in the RCTs of DOACs vs. LMWH had incidental VTE at baseline . Although the rate of recurrent VTE is lower in patients with incidental VTE compared to those with symptomatic events (RR: 0.62; 95% CI 0.44 to 0.87), the rate of recurrent events despite anticoagulation remains high . For example, the results of a subanalysis of patients with incidental vs. symptomatic VTE in the Hokusai-VTE Cancer trial found recurrent VTE occurred in 7.9% of patients with incidental VTE as compared to 10.9% of those with symptomatic VTE . Additionally, an analysis of data from the Swiss Venous Thromboembolism Registry (SWIVTER) reported that the rates of both mortality and VTE recurrence in these patients were lower if they received anticoagulation therapy for at least 3 months . In this study, mortality rates were 4% in patients receiving anticoagulation as compared to 41% in those without anticoagulation, while recurrence rates were 1% and 18%, respectively . These findings support managing patients with incidentally detected CAT in a similar manner as symptomatic CAT.
# Upper Extremity and Catheter-Related VTE
Even though catheter-related VTE is a common complication in patients with cancer, there is limited evidence to guide the management of upper extremity and catheter-related VTE as these patients were excluded from all RCTs of LMWH vs. VKA and DOAC vs. LMWH except for the ADAM-VTE trial . Two studies of cancer patients with upper extremity catheter-related DVT suggested that LMWH and VKA are safe and effective, with no recurrent VTE events reported in either study and major bleeding event rates of 4% and 2% at 3 months . In contrast, a prospective cohort study evaluating rivaroxaban monotherapy in 70 cancer patients with upper extremity catheter-related DVT demonstrated a VTE recurrence rate of 1.4%, including one fatal PE, and a bleeding rate of 12.9% at 12 weeks . More recently, a prospective cohort study of 188 patients with upper extremity DVT treated with DOACs (54% rivaroxaban; 30% apixaban; 10% edoxaban; 6% dabigatran), including 29% with active cancer and 33% with catheter-related or pacemakerrelated DVTs, reported more reassuring findings, although the results are not specific to patients with cancer . During treatment with DOACs, recurrent VTE occurred in 0.9 per 100 patient-years, major bleeding in 1.7 per 100 patient-years and all-cause deaths in 6.0 per 100 patient-years . Based on the available evidence and expert opinion, the consensus group recommends that choice of anticoagulant for the treatment of upper extremity and catheter-related VTE be individualized similarly as for proximal lower limb DVT and PE based on the factors discussed in this paper.
# Risk of Bleeding
The risk of major bleeding was higher with DOACs than LMWH in both the Hokusai-VTE Cancer and SELECT-D trials, although rates of major bleeding were similar in the CARAVAGGIO, ADAM-VTE, and CASTA-DIVA trials (Table 1) 27,28]. Overall, pooled estimates from meta-analyses have reported a non-significantly higher rate of major bleeding complications among patients with CAT receiving a DOAC as compared to LMWH (HR:1.26; 95% CI 0.84-1.90 and RR: 1.36; 95% CI 0.55 to 3.35) . Hence, identifying patients at higher risk of bleeding complications might be helpful to tailor anticoagulation in this patient population. In the Hokusai-VTE Cancer trial, the excess bleeding risk was attributable mainly to patients with GI cancer, of whom 12.7% (21/165) in the edoxaban arm experienced major bleeding as compared to 3.6% (5/140) in the dalteparin arm . Additionally, for most of the edoxaban-treated patients with major bleeding, the site of the bleed was the upper GI tract (16 of 21 cases), with the remaining sites being the lower GI tract, epistaxis, and retro-peritoneum. By contrast, only one of the five cases of major bleeding in the dalteparin-treated patients was at a GI site . Similarly, in SELECT-D, 45.5% (5/11) of all major bleeding episodes in rivaroxaban-treated patients occurred in the GI tract . Like Hokusai-VTE Cancer, the SELECT-D trial also showed a signal for a higher risk of bleeding in patients with GI cancer, with the data safety monitoring committee of the SELECT-D trial noting a non-significant increase in major bleeding events in 19 patients with esophageal or gastroesophageal junction cancers after a safety review of the first 220 patients . Patients with those cancers were subsequently excluded from enrolment. The CARAVAGGIO trial did not report any difference in major bleeding complications between patients receiving apixaban or dalteparin . A total of 1.9% (11/576) and 1.7% (10/579) of patients had GI major bleeding complications among those receiving apixaban and dalteparin, respectively . The reasons for the discrepancy in GI major bleeding are unclear and may be related to differences in baseline characteristics (tumor types, etc.) among the included patients in the different studies or related to the properties of the individual DOACs (once vs. twice a day, topical mucosal anticoagulant effect, etc.). A recent observational study reported that apixaban had a higher rate of major bleeding complications in patients with luminal GI cancers compared to those with non-GI cancers (15.6 vs. 3.7 per 100 person-years, p = 0.004) and compared to enoxaparin in patients with luminal GI cancer (15.6 vs. 3.2, p = 0.04) . Hence, all DOACs should be use cautiously in patients with GI cancers, especially in those with unresected luminal tumors.
Other patient characteristics are also important for clinicians to consider. Subgroup analyses of major bleeding in the Hokusai-VTE Cancer safety population suggest that, in addition to GI cancer, other features associated with a higher risk of major bleeding include urothelial cancer, renal impairment, thrombocytopenia, intracranial malignancy, regionally advanced or metastatic cancer, recent surgery, and use of antiplatelet agents or bevacizumab . Analysis of clinically relevant bleeding events in the CATCH trial confirmed that intracranial malignancy increases the risk of bleeding regardless of the type of anticoagulation . Age > 75 years was also significantly associated with an increased risk of clinically relevant bleeding in this analysis .
The Hokusai-VTE Cancer, SELECT-D, and CARAVAGGIO trials have reported greater proportions of DOAC-treated patients who experienced clinically relevant non-major bleeding (CRNMB) events with HRs of 1.38 (95% CI 0.98 to 1.94), 3.76 (95% CI 1.63 to 8.69), and 1.42 (95% CI 0.88 to 2.30) for edoxaban, rivaroxaban, and apixaban, respectively . In the Hokusai-VTE Cancer trial, CRNMB events were numerically more common for GI, epistaxis, hematuria, or abnormal uterine bleeding in patients receiving edoxaban compared to those receiving dalteparin . In SELECT-D, the significantly higher rates of CRNMB in patients receiving rivaroxaban were due to GI and GU bleeding, which accounted for 9 and 11 of the 25 CRNMB events, respectively . In CARAVAGGIO, the numerical increase in CRNMB was largely due to bleeding in the GU and upper airway tracts, which accounted for 20 and 14 cases, respectively, of the 59 CRNMB events in patients receiving apixaban . Additionally, patients with GI cancer appeared to be at higher risk of bleeding events with DOAC, with 13.2% (19/144) of patients with GI cancer who were treated with apixaban experiencing CRNMB as compared to 4.9% (7/144) in the dalteparin arm . Overall, GI or GU CRNMB may be more common in patients receiving a DOAC than in those treated with LMWH.
# Features Consistent with a High Risk of GI Bleeding
Given that bleeding rates appear to be higher with DOACs in patients with GI tumors or those on treatments such as bevacizumab that are associated with tumor necrosis and bleeding , the committee suggests considering the use of LMWH for patients with these or other features that are associated with a high risk of GI bleeding, such as angiodysplasia, GI lesion, previous variceal bleed, or treatment-associated mucosal toxicity. The risk of GI perforation and/or hemorrhage associated with a patient's anticancer therapies should be taken into consideration regardless of which anticoagulant is selected.
# Thrombocytopenia
Thrombocytopenia increases the risk of bleeding complications in patients with CAT . Unfortunately, there is limited evidence to guide management in patients with platelet counts <50,000 platelets/mL. The CLOT trial excluded patients with baseline platelet counts <75,000 platelets/mL, while the Hokusai-VTE Cancer, CARAVAGGIO, and SELECT-D trials excluded patients with baseline platelet counts of less than 50,000, 75,000, and 100,000 platelets/mL, respectively . Guidance from the SSC of the ISTH suggests that therapeutic dose of anticoagulation can be used for patients with platelet count of ≥50,000 platelets/mL . In patients with platelet counts of less than 50,000 platelets/mL, 50% or prophylactic dose LMWH may be used or full-dose anticoagulation with platelet transfusion support may be considered . The Canadian consensus committee suggests that LMWH is preferred in these patients but recommends seeking an expert opinion from a specialized physician when initiating anticoagulation in the setting of severe thrombocytopenia (i.e., platelet counts <50,000/mL). In cases of transient thrombocytopenia due to anticancer therapies, clinical judgment should be used to determine whether the anticoagulant needs to be dose-reduced or temporarily held until platelet levels recover to ≥50,000 platelets/mL.
# Intracranial Lesions
As there were few patients with intracranial tumors (primary brain tumor or brain metastasis) included in the DOAC trials (none in CARAVAGGIO, 7% of patients (74/1046) in Hokusai VTE Cancer, and only 1% of patients in SELECT-D), there are limited data regarding the safety of this anticoagulant class in these patients . Some reassurance may be provided by a retrospective cohort study of the cumulative incidence of intracranial hemorrhage (ICH) with DOAC vs. LMWH in patients with brain tumors and VTE . In this study, no ICH was noted among 20 patients with primary brain tumors treated with DOACs, while the cumulative incidence among the 47 patients treated with LMWH was 37%. Among 105 patients with brain metastases, the cumulative incidence of ICH was 11% among those treated with DOAC and 18% in those treated with LMWH . Similarly, an international two-center study suggested comparable safety of LMWH and DOACs in patients with brain metastases. The 12-month cumulative incidence of major ICH was 5.1% in DOAC-treated patients and 11.1% in those treated with LMWH (HR: 0.45; 95% CI 0.09 to 2.21) . When anticoagulation was analyzed as a time-varying covariate, the risk of any ICH did not differ between DOAC-and LMWH-treated patients (HR: 0.98; 95% CI 0.28 to 3.40) . Finally, a single-center retrospective chart review of 125 patients with primary and metastatic brain tumors on anticoagulation reported rates of major bleeding of 26% and 9.6% in patients receiving LMWH or DOAC, respectively . Patients receiving DOAC also had a lower rate of ICH compared to those receiving LMWH (5.8% vs. 15%) . Nevertheless, given the small numbers and the limitations of retrospective studies, as well the shorter half-life of LMWH, the consensus committee suggests considering the initial use of LMWH for patients with CAT and high-risk intracranial lesions (e.g., glioma).
# Hepatic and Renal Impairment
Patients with functional hepatic impairment may have reduced ability to metabolize DOACs, all of which are at least partially metabolized by cytochrome P450 (CYP) enzymes . Patients with significant liver disease are thus considered to be at higher risk of bleeding when treated with DOACs and were excluded from clinical trials. For these reasons, none of the DOACs are recommended for use in patients meeting criteria for Child-Pugh class C . Rivaroxaban is contraindicated in patients with hepatic disease (including Child-Pugh class B and C) associated with coagulopathy and having clinically relevant bleeding risk . Apixaban should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) . With edoxaban, patients with Child-Pugh class A or B exhibited comparable pharmacokinetics and pharmacodynamics to healthy controls .
The previous iteration of the Canadian expert consensus treatment algorithm suggested that LMWH might be preferable to DOAC in patients with CAT and a creatinine clearance of 30-50 mL/min, especially if additional risk factors for bleeding were present . This recommendation was based on the limited evidence available at the time suggesting a potentially elevated risk of bleeding with edoxaban in these patients . However, this recommendation was not supported by the CARAVAGGIO trial, which found no significant between-treatment differences in rates of major bleeding in patients with creatinine clearance of 30-80 mL/min treated with apixaban or LMWH . Thus, the consensus committee currently recommends that clinicians follow product monograph recommendations for contraindications and dose adjustment of anticoagulants in patients with impaired renal function (Table 2).
# Use of Antiplatelet Agents
The use of either dual antiplatelet therapy or higher doses of acetylsalicylic acid (ASA) was not permitted in the DOAC vs. LMWH RCTs, with concomitant ASA at doses >75 mg, >100 mg, and >165 mg daily being exclusion criteria in the SELECT-D, Hokusai-VTE Cancer, and CARAVAGGIO trials, respectively . However, even at low doses, ASA is known to increase the risk of upper GI bleeds, a risk which appears to be increased when it is used in conjunction with oral anticoagulants . This was confirmed by subgroup analysis of data from the Hokusai-VTE cancer trial, which showed a numerical increase in the risk of major bleeding in DOAC-treated patients on concomitant antiplatelet therapy . Similarly, in the CARAVAGGIO trial, 22.7% (5/22) of patients on concomitant antiplatelet therapy treated with apixaban experienced major bleeding as compared to 11.8% (68/576) of apixaban-treated patients without antiplatelet therapy . No major bleeding events were reported among the 23 patients in the LMWH arm on concomitant antiplatelet therapy, while 12.8% (74/579) of those without antiplatelet therapy had a major bleed . Given this, the consensus committee recommends that the indication for antiplatelet agents be reassessed, and discontinuation should be considered in the absence of a strong indication in patients with new diagnosis of CAT. Shared decision-making with other health care providers would be warranted in these circumstances.
# Drug-Drug Interactions
Polypharmacy is common in patients with cancer, who are often treated with multiple anticancer and supportive therapies. It is thus important to evaluate the potential for drug-drug interactions when selecting the appropriate anticoagulant therapy for CAT. All DOACs are substrates of P-glycoprotein, and apixaban and rivaroxaban are also substrates of CYP3A4, so therapies that affect P-glycoprotein or CYP3A4 metabolism have the potential to interact with DOACs . Numerous anticancer therapies are inhibitors or inducers of the P-glycoprotein and/or CYP3A4 pathways, with the potential to interact with DOACs . Anticancer therapies for which the potential for drug-drug interactions with DOACs should be considered include abiraterone, acalabrutinib, afatinib, ceritinib, cyclosporine, cobimetinib, crizotinib, dabrafenib, dasatinib, dexamethasone, doxorubicin, enzalutamide, erdafitinib, ibrutinib, idelalisib, imatinib, ipilimumab, lapatinib, mitotane, neratinib, nilotinib, nintedanib, niraparib, olaparib, panobinostat, ponatinib, ribociclib, sunitinib, tacrolimus, tamoxifen, trametinib, trastuzumab emtansine, vandetanib, vemurafenib, and vinblastine .
However, assessing the potential for clinically significant interactions is complex as not all potential interactions appear to be clinically important . In fact, sub-analysis of patients treated concomitantly with anticancer agents and anticoagulants in the CARAVAG-GIO trial found no significant differences in rates of major bleeding, recurrent VTE, or death between the DOAC and LMWH arms . Table 3 lists drug-drug interactions with DOACs that have been shown to have clinical relevance. Notably, a recent registry of the ISTH including 202 patients receiving concurrent DOACs and targeted anticancer therapies has reported a high rate of bleeding complications in patients receiving Bruton's tyrosine kinase (BTK) inhibitors . A recent observational study has also reported a higher risk of bleeding in patients receiving concurrent vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and LMWH . The study sample size was inadequate for between-treatment comparisons with concurrent TKIs and DOACs. Given the complexity of the therapeutic regimens used to treat many patients with cancer, the consensus committee recommends that patients with CAT be referred for a pharmacist-led drug interaction evaluation, which should be repeated if cancer management changes. Alternatively, online drug-drug interaction applications or websites can be helpful, although previous publications have highlighted important differences in the accuracy and quality of these tools . However, when using such tools, clinicians must keep in mind that the majority of reported interactions are theoretical rather than having been proven to be associated with decreased drug levels (and thus thrombosis) or increased drug levels (and thus bleeding). In addition to efficacy, safety, and potential for drug-drug interactions, clinicians and patients should together consider drug cost and accessibility, taking into account the patient's individual situation, as well as publicly or privately funded drug plan coverage. Shared decision-making may help improve adherence to therapy, and, in turn, lead to improved anticoagulant effectiveness.
# Body Weight
There is a paucity of evidence regarding the use of DOACs or LMWHs in patients with cancer at the extremes of body weight. In the Hokusai-VTE Cancer and CARAVAGGIO trials, neither low (≤60 kg) nor high (>90 kg) body weight had a significant impact on the risk of recurrent VTE or major bleeding, although there were few patients in these extreme weight categories who were included in the trials . It should be noted that the daily dose of edoxaban was reduced in the Hokusai-VTE Cancer trial to 30 mg from 60 mg in patients with a body weight ≤60 kg . Dose adjustment based on body weight is not recommended in the product monographs for apixaban or rivaroxaban .
Per the approved indication, the dose of the LMWH dalteparin was capped at 18,000 IU daily in the DOAC trials in CAT . However, prior non-cancer studies have shown that body weight does not have an important effect on anti-Xa activity levels achieved with weight-based doses of enoxaparin, dalteparin, and tinzaparin for patients weighing up to 144 kg, 190 kg, and 165 kg, respectively . Furthermore, a meta-analysis of data including 921 patients with a body mass index (BMI) of 30 kg/m 2 or more showed no increased risk of bleeding compared with non-obese patients (BMI < 30 kg/m 2 ) who received weight-adjusted, "uncapped" LMWH . Therapeutic weight-adjusted dosing, without capping, is therefore suggested for LMWH use .
Based on meta-analyses and phase 4 studies, the SCC of the ISTH suggests that standard doses of rivaroxaban or apixaban are among appropriate anticoagulant options for the treatment and prevention of VTE in the general, non-cancer population, regardless of BMI and weight . Fewer supportive data exist for apixaban than rivaroxaban. VKA and weight based LMWH are also considered options. The SCC suggests not to use dabigatran or edoxaban in patients with BMI > 40 kg/m 2 or weight > 120 kg, given unconvincing data for dabigatran, and lack of clinical or pharmacokinetic and pharmacodynamic data for edoxaban . These suggestions are not specifically for CAT but for the overall management of VTE. Based on the limited evidence base, the consensus committee recommends that LMWH be considered in patients with weight > 150 kg and an agent with weight-adjustable dosing, such as edoxaban or LMWH, be considered in patients with weight < 50 kg.
# Burden of Cancer and Burden of VTE
Limited data are available regarding the effects of the burden of cancer and burden of VTE on the efficacy and safety of anticoagulation. Cross-study comparison is limited by differences between clinical trials in baseline characteristics reflecting cancer burden (Table 4), as well as in overall mortality rates (Table 1), which suggest the overall burden of cancer may have been higher in the LMWH vs. VKA trials than in the DOAC vs. LMWH trials . It is also important to note that patients who required thrombolysis or who underwent inferior vena cava filter insertion were excluded from the trials. In the absence of RCT data, the consensus committee recommends that initial therapy with LMWH be considered for patients with severe symptoms of thrombosis, including patients with iliofemoral DVT, extensive PE, or sub-massive PE, and any patients who received thrombolysis.
# Abnormal Uterine Bleeding
Abnormal uterine bleeding is a common but under-reported complication of anticoagulation that is thought to occur in up to 70% of women of reproductive age receiving anticoagulation . The risk of anticoagulant-related abnormal uterine bleeding varies by DOAC, with apixaban and edoxaban having statistically similar relative risks to VKA and rivaroxaban appearing to double the risk as compared to VKA (RR: 2.10; p < 0.01) . Estimates of the risk of abnormal uterine bleeding with LMWH monotherapy are not available. However, despite the lack of data for LMWH, for women who experience abnormal uterine bleeding while on DOAC or with a history of abnormal uterine bleeding associated with a DOAC, the consensus committee recommends consideration of LMWH. Other management options for abnormal uterine bleeding secondary to anticoagulation include tranexamic acid, and hormonal therapy, such as combined oral contraceptives, the levonorgestrel intrauterine device, and depo-medroxyprogesterone acetate, although estrogen-based regimens should be avoided in patients who are no longer on anticoagulation . Adjunctive iron therapy to manage iron deficiency anemia, as well as consultation with gynecology may also be considered.
# Significant GI Surgery or Absorption Disorders
DOACs are absorbed by different sites throughout the GI tract, with edoxaban being primarily absorbed by the proximal small intestine, rivaroxaban absorbed by both the stomach and proximal intestine and apixaban absorbed throughout the GI tract including significant (>50%) absorption in the distal small bowel or ascending colon . Given the GI absorption of DOACs, there is concern regarding their use in patients who, because of GI surgery or other disorders, have a significant reduction in intestinal absorptive surface. However, there is limited evidence regarding the pharmacodynamics or clinical outcomes associated with DOACs in these patients . The SSC of the ISTH recommends not using DOACs for treatment or prevention of VTE in the acute setting after bariatric surgery due to concerns of decreased gastric absorption . Such a recommendation might apply to cancer patients who have undergone a Whipple's procedure. Initiation of anticoagulation with LMWH or another parenteral agent is recommended in such cases. Until a greater evidence base is available, it is reasonable to consider LMWH for patients with impaired GI absorption.
# Reassessing Treatment for Secondary Prophylaxis
Prospective studies that evaluated anticoagulation therapy beyond 6 months include the DALTECAN, TICAT, Hokusai-VTE Cancer, and SELECT-D studies . In the DALTECAN prospective cohort study, 55% of the 334 patients with VTE and active cancer who were treated with dalteparin completed 6 months of therapy, and 33% completed 12 months . Therapy beyond 6 months was not associated with an increased risk of major bleeding or recurrent VTE as compared to the first 6 months. Similarly, the TICAT study, which evaluated the safety of long-term tinzaparin in 247 patients with CAT, reported no significant difference in recurrent VTE or clinically relevant bleeding for months 1 to 6 compared with months 7 to 12 . The Hokusai-VTE Cancer trial demonstrated acceptable efficacy and safety profiles during the 12-month treatment period . However, the median therapy duration was approximately 6 months, and rates of recurrent VTE and major bleeding beyond the initial 6 months were not reported. After 6 months of treatment in the SELECT-D trial, patients with active cancer and residual DVT or index PE were eligible for re-randomization to rivaroxaban or placebo . Of the 92 patients who were re-randomized, 4% of those treated with rivaroxaban experienced recurrent VTE as compared to 14% of those treated with placebo (HR: 0.32; 95% CI 0.06 to 1.58), while major bleeding occurred in 0% of patients treated with placebo and 5% of those randomized to rivaroxaban . Although there are no prospective data assessing the efficacy and safety of anticoagulation for secondary prevention of recurrent VTE beyond 12 months, retrospective cohort studies have shown that the risk of recurrent VTE and major bleeding remains elevated beyond 12 months in this patient population .
Several studies have also investigated the safety and efficacy of prophylactic doses of DOACs for the extended treatment of VTE . However, few patients with active cancer were included in these trials. and it is unclear whether the results can be generalized to this population. The ongoing API-CAT study, which aims to determine whether a low-dose regimen of apixaban is non inferior to a full-dose regimen of apixaban for the prevention of recurrent VTE in patients with active cancer who have completed at least 6 months of anticoagulant therapy for treating VTE, may help clarify this issue .
Considering the weak evidence supporting long-term secondary prophylaxis in patients with CAT, most guidelines suggest that the decision to continue anticoagulation beyond the initial 6 months should be individualized . Most of the studies supporting long-term secondary prevention in patients with cancer assessed therapeutic dosing of anticoagulation (LMWH or DOAC). However, decision on duration and dosing of anticoagulation for long-term secondary prevention should be made based on the patient's risk factors for VTE recurrence and bleeding complications and re-assessed on a regular basis. The consensus committee suggests that patients' risk factors for VTE recurrence and bleeding should be reassessed regularly (e.g., at least every 3 months or sooner if there are changes in cancer status or management).
# Conclusions
Selection of anticoagulation for the treatment of CAT should be individualized based on the patient's bleeding risk, type of cancer, and potential for drug-drug interactions, as well as patient and clinician preferences. Anticoagulant therapy should be reassessed on a regular basis as the patient's cancer status and management change over time. | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY# Introduction
The management of venous thromboembolism (VTE) is a frequent and important clinical issue in patients with cancer. The 6-month VTE risk for patients with cancer is 12-fold higher compared to the general population, and as much as 23-fold higher in patients receiving chemotherapy or targeted therapy [1]. Over the past two decades, the 12-month cumulative incidence for VTE has increased three-fold in cancer patients [1]. Furthermore, thromboembolism has been reported to be the second leading cause of death in patients with cancer, highlighting the importance of urgently initiating therapeutic dosing of anticoagulation [2,3]. However, the management of anticoagulant therapy for cancer-associated thrombosis (CAT) is complex due to an increased risk of both recurrent Curr. Oncol. 2021, 28
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VTE and major bleeding in patients with cancer as compared to those without cancer [4,5]. Selection and dosing of anticoagulant therapy for CAT needs to be individualized based on the patient's risk for both recurrent VTE and bleeding. This can be influenced by patient characteristics, type and stage of cancer, and anticancer treatment [4,5].
Several classes of anticoagulants have been studied in the treatment of CAT, including vitamin K antagonists (VKAs), subcutaneous low-molecular-weight heparins (LMWHs), and direct oral anticoagulants (DOACs). For many years, LMWHs were the standard of care for the acute and extended treatment of CAT based on the results of trials comparing LMWH with VKA [6][7][8][9]. Patients with cancer were underrepresented in initial trials comparing DOACs to VKA for the acute treatment of VTE [10][11][12][13][14][15]. However, the recent publication of clinical trials comparing DOACs with LMWH in the cancer-patient population has expanded the therapeutic options for the acute and extended treatment of CAT, but also introduced a layer of complexity [16][17][18]. To provide guidance to health care professionals on tailoring anticoagulant treatment in patients with CAT, an evidence-based risk stratification treatment algorithm was developed in 2018 [19]. The consensus process reported here was undertaken to up-date this treatment algorithm based on the evolving body of evidence.
# Methods
# Literature Review
To update the treatment algorithm, the committee used, as a starting point, the previously published 2018 Canadian expert consensus treatment algorithm in CAT [19]. A systematic review of the literature published since 2018 was performed using the search strategies outlined in supplemental Appendix A. All abstracts were reviewed. References of narrative reviews identified by the search strategy also were reviewed to ensure that all potentially relevant articles were captured.
# Revision of Treatment Algorithm
The multidisciplinary consensus group, which included 11 physicians with expertise in the areas of hematology, medical oncology, and general internal medicine, met in April 2021 via Web-based teleconference to discuss how the results of the literature search would impact the 2018 treatment algorithm. The revised treatment algorithm and manuscript were then circulated by email on two occasions so that committee members could review them and provide comments. The final version of updated algorithm was approved by all members.
# Role of the Funding Sources
The revision of the algorithm was funded by unrestricted grants from Pfizer Canada, Hospital Business Unit (Kirkland, QC, Canada), Bayer Canada Inc (Montreal, QC, Canada), LEO Pharma Inc (Thornhill, ON, Canada) and Servier Canada (Ottawa, ON, Canada) to Thrombosis Canada. The authors administered all aspects of revising the treatment algorithm, and the funding sources had no role in drafting, editing, or approving the treatment algorithm.
# Results
The search of the PubMed database identified 420 articles, 22 of which were selected for review according to pre-specified criteria, while the search of the American Society of Hematology abstract database identified 27 abstracts, one of which was selected for review. The committee included an additional 12 articles not identified by the search strategy. Following review of the 35 selected articles and abstracts and discussion of the new evidence, the revisions to the algorithm were recommended. The resulting treatment algorithm (Figure 1) provides guidance on the selection of anticoagulant therapy for cancer patients with incidental or symptomatic upper extremity or lower limb deep vein thrombosis (DVT) or pulmonary embolism (PE).
patients with incidental or symptomatic upper extremity or lower limb deep vein thrombosis (DVT) or pulmonary embolism (PE). Apixaban should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B), while these patients exhibited comparable pharmacokinetics and pharmacodynamics to healthy controls when treated with edoxaban. b Use of antiplatelet agents should be assessed, and discontinuation should be considered in the absence of a strong indication. Shared decision-making with other health care providers is warranted. c Currently, dalteparin, enoxaparin, and tinzaparin have randomized controlled trial evidence in cancer-associated thrombosis, with the evidence base being stronger for dalteparin and tinzaparin. Refer to the relevant product monograph for appropriate dosing. d Currently, apixaban, edoxaban, and rivaroxaban have randomized controlled trial evidence in cancer-associated thrombosis, with stronger evidence for apixaban and edoxaban. Refer to the relevant product monograph for appropriate dosing. DVT = deep vein thrombosis; PE = pulmonary embolism; GI = gastrointestinal; GU = genitourinary; DOAC = direct-acting oral anticoagulant; LMWH = low molecular weight heparin; VTE = venous thromboembolism. Apixaban should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B), while these patients exhibited comparable pharmacokinetics and pharmacodynamics to healthy controls when treated with edoxaban. b Use of antiplatelet agents should be assessed, and discontinuation should be considered in the absence of a strong indication. Shared decision-making with other health care providers is warranted. c Currently, dalteparin, enoxaparin, and tinzaparin have randomized controlled trial evidence in cancerassociated thrombosis, with the evidence base being stronger for dalteparin and tinzaparin. Refer to the relevant product monograph for appropriate dosing. d Currently, apixaban, edoxaban, and rivaroxaban have randomized controlled trial evidence in cancer-associated thrombosis, with stronger evidence for apixaban and edoxaban. Refer to the relevant product monograph for appropriate dosing. DVT = deep vein thrombosis; PE = pulmonary embolism; GI = gastrointestinal; GU = genitourinary; DOAC = direct-acting oral anticoagulant; LMWH = low molecular weight heparin; VTE = venous thromboembolism.
According to the treatment algorithm, LMWH is preferred in patients at high risk of bleeding, with unresected intraluminal gastrointestinal (GI) or genitourinary (GU) cancer, or with significant drug-drug interactions with DOACs. In contrast, DOACs are preferred in patients at low risk of bleeding, with other cancer types, and without significant drugdrug interactions. Other factors to consider include patient and clinician preference, drug cost and coverage, body weight, burden of cancer, burden of VTE, and history of abnormal uterine bleeding, significant GI surgery, or absorption disorders. Anticoagulant therapy should be reassessed regularly (e.g., every 3 months), and sooner if there are changes in the patient's management or condition. In general, anticoagulation should be continued in patients with active cancer (underlying cancer present or on-going anti-cancer treatment), while discontinuation may be considered in those whose cancer is no longer active.
# Discussion
# Efficacy and Safety of Anticoagulants
Until the publication of randomized controlled trials (RCTs) comparing DOACs with LMWH for the acute treatment of CAT (Table 1), clinical practice guidelines recommended the use of LMWH over DOACs or VKA for the acute and secondary prevention of VTE in patients with cancer [6,7]. Recent guidelines, on the other hand, have suggested that either a DOAC or LMWH can be used for the acute treatment of CAT [19][20][21][22][23], with recommendations that treatment be individualized based on patient characteristics. A meta-analysis of the results of all RCTs comparing LMWH with VKA for the management of CAT reported a 44% reduction in the risk of recurrent VTE (relative risk (RR): 0.56; 95% confidence interval (CI): 0.43 to 0.74), without a significant increase in the risk of major bleeding (RR: 1.07; 95% CI: 0.66 to 1.79) in patients treated with LMWH [29]. A similar meta-analysis of the results of all RCTs comparing DOACs with LMWH for the treatment of acute CAT reported a significantly lower risk of recurrent VTE (hazard ratio (HR): 0.63; 95% CI: 0.47 to 0.86) and a non-significantly higher risk of major bleeding (HR: 1.26; 95% CI: 0.84 to 1.90) with DOACs as compared to LMWH [28]. An analysis of 29 studies including a total of 8000 patients with cancer found that case fatality rates were higher for recurrent VTE than those for major bleeding at 15.0% (95% CI 6.6 to 30.1%) and 8.9% (95% CI 3.5 to 21.1%), respectively [30]. Although case fatality rates varied by type of anticoagulation in this analysis, the differences were not statistically significant [30]. Taken together, these data highlight the importance of preventing recurrent VTE while minimizing the risk of major bleeding complications in patients with cancer. LMWH is more effective than VKA without any increase in bleeding complications. DOACs are noninferior to LMWHs in terms of overall safety and efficacy. No data comparing the direct thrombin inhibitor dabigatran with LMWH for the management of CAT are available.
# Incidental VTE
Although patients with incidental VTE (i.e., asymptomatic thrombosis found on screening imaging tests) were not included in the RCTs of LMWH vs. VKA [8,9,[24][25][26], between 20% and 53% of patients included in the RCTs of DOACs vs. LMWH had incidental VTE at baseline [16][17][18]. Although the rate of recurrent VTE is lower in patients with incidental VTE compared to those with symptomatic events (RR: 0.62; 95% CI 0.44 to 0.87), the rate of recurrent events despite anticoagulation remains high [31]. For example, the results of a subanalysis of patients with incidental vs. symptomatic VTE in the Hokusai-VTE Cancer trial found recurrent VTE occurred in 7.9% of patients with incidental VTE as compared to 10.9% of those with symptomatic VTE [32]. Additionally, an analysis of data from the Swiss Venous Thromboembolism Registry (SWIVTER) reported that the rates of both mortality and VTE recurrence in these patients were lower if they received anticoagulation therapy for at least 3 months [33]. In this study, mortality rates were 4% in patients receiving anticoagulation as compared to 41% in those without anticoagulation, while recurrence rates were 1% and 18%, respectively [33]. These findings support managing patients with incidentally detected CAT in a similar manner as symptomatic CAT.
# Upper Extremity and Catheter-Related VTE
Even though catheter-related VTE is a common complication in patients with cancer, there is limited evidence to guide the management of upper extremity and catheter-related VTE as these patients were excluded from all RCTs of LMWH vs. VKA and DOAC vs. LMWH except for the ADAM-VTE trial [8,9,[16][17][18][24][25][26][27][28]. Two studies of cancer patients with upper extremity catheter-related DVT suggested that LMWH and VKA are safe and effective, with no recurrent VTE events reported in either study and major bleeding event rates of 4% and 2% at 3 months [34,35]. In contrast, a prospective cohort study evaluating rivaroxaban monotherapy in 70 cancer patients with upper extremity catheter-related DVT demonstrated a VTE recurrence rate of 1.4%, including one fatal PE, and a bleeding rate of 12.9% at 12 weeks [36]. More recently, a prospective cohort study of 188 patients with upper extremity DVT treated with DOACs (54% rivaroxaban; 30% apixaban; 10% edoxaban; 6% dabigatran), including 29% with active cancer and 33% with catheter-related or pacemakerrelated DVTs, reported more reassuring findings, although the results are not specific to patients with cancer [37]. During treatment with DOACs, recurrent VTE occurred in 0.9 per 100 patient-years, major bleeding in 1.7 per 100 patient-years and all-cause deaths in 6.0 per 100 patient-years [37]. Based on the available evidence and expert opinion, the consensus group recommends that choice of anticoagulant for the treatment of upper extremity and catheter-related VTE be individualized similarly as for proximal lower limb DVT and PE based on the factors discussed in this paper.
# Risk of Bleeding
The risk of major bleeding was higher with DOACs than LMWH in both the Hokusai-VTE Cancer and SELECT-D trials, although rates of major bleeding were similar in the CARAVAGGIO, ADAM-VTE, and CASTA-DIVA trials (Table 1) [16][17][18]27,28]. Overall, pooled estimates from meta-analyses have reported a non-significantly higher rate of major bleeding complications among patients with CAT receiving a DOAC as compared to LMWH (HR:1.26; 95% CI 0.84-1.90 and RR: 1.36; 95% CI 0.55 to 3.35) [28,38]. Hence, identifying patients at higher risk of bleeding complications might be helpful to tailor anticoagulation in this patient population. In the Hokusai-VTE Cancer trial, the excess bleeding risk was attributable mainly to patients with GI cancer, of whom 12.7% (21/165) in the edoxaban arm experienced major bleeding as compared to 3.6% (5/140) in the dalteparin arm [39]. Additionally, for most of the edoxaban-treated patients with major bleeding, the site of the bleed was the upper GI tract (16 of 21 cases), with the remaining sites being the lower GI tract, epistaxis, and retro-peritoneum. By contrast, only one of the five cases of major bleeding in the dalteparin-treated patients was at a GI site [39]. Similarly, in SELECT-D, 45.5% (5/11) of all major bleeding episodes in rivaroxaban-treated patients occurred in the GI tract [17]. Like Hokusai-VTE Cancer, the SELECT-D trial also showed a signal for a higher risk of bleeding in patients with GI cancer, with the data safety monitoring committee of the SELECT-D trial noting a non-significant increase in major bleeding events in 19 patients with esophageal or gastroesophageal junction cancers after a safety review of the first 220 patients [17]. Patients with those cancers were subsequently excluded from enrolment. The CARAVAGGIO trial did not report any difference in major bleeding complications between patients receiving apixaban or dalteparin [18,40]. A total of 1.9% (11/576) and 1.7% (10/579) of patients had GI major bleeding complications among those receiving apixaban and dalteparin, respectively [40]. The reasons for the discrepancy in GI major bleeding are unclear and may be related to differences in baseline characteristics (tumor types, etc.) among the included patients in the different studies or related to the properties of the individual DOACs (once vs. twice a day, topical mucosal anticoagulant effect, etc.). A recent observational study reported that apixaban had a higher rate of major bleeding complications in patients with luminal GI cancers compared to those with non-GI cancers (15.6 vs. 3.7 per 100 person-years, p = 0.004) and compared to enoxaparin in patients with luminal GI cancer (15.6 vs. 3.2, p = 0.04) [41]. Hence, all DOACs should be use cautiously in patients with GI cancers, especially in those with unresected luminal tumors.
Other patient characteristics are also important for clinicians to consider. Subgroup analyses of major bleeding in the Hokusai-VTE Cancer safety population suggest that, in addition to GI cancer, other features associated with a higher risk of major bleeding include urothelial cancer, renal impairment, thrombocytopenia, intracranial malignancy, regionally advanced or metastatic cancer, recent surgery, and use of antiplatelet agents or bevacizumab [16]. Analysis of clinically relevant bleeding events in the CATCH trial confirmed that intracranial malignancy increases the risk of bleeding regardless of the type of anticoagulation [42]. Age > 75 years was also significantly associated with an increased risk of clinically relevant bleeding in this analysis [42].
The Hokusai-VTE Cancer, SELECT-D, and CARAVAGGIO trials have reported greater proportions of DOAC-treated patients who experienced clinically relevant non-major bleeding (CRNMB) events with HRs of 1.38 (95% CI 0.98 to 1.94), 3.76 (95% CI 1.63 to 8.69), and 1.42 (95% CI 0.88 to 2.30) for edoxaban, rivaroxaban, and apixaban, respectively [16][17][18]. In the Hokusai-VTE Cancer trial, CRNMB events were numerically more common for GI, epistaxis, hematuria, or abnormal uterine bleeding in patients receiving edoxaban compared to those receiving dalteparin [39]. In SELECT-D, the significantly higher rates of CRNMB in patients receiving rivaroxaban were due to GI and GU bleeding, which accounted for 9 and 11 of the 25 CRNMB events, respectively [17]. In CARAVAGGIO, the numerical increase in CRNMB was largely due to bleeding in the GU and upper airway tracts, which accounted for 20 and 14 cases, respectively, of the 59 CRNMB events in patients receiving apixaban [40]. Additionally, patients with GI cancer appeared to be at higher risk of bleeding events with DOAC, with 13.2% (19/144) of patients with GI cancer who were treated with apixaban experiencing CRNMB as compared to 4.9% (7/144) in the dalteparin arm [40]. Overall, GI or GU CRNMB may be more common in patients receiving a DOAC than in those treated with LMWH.
# Features Consistent with a High Risk of GI Bleeding
Given that bleeding rates appear to be higher with DOACs in patients with GI tumors or those on treatments such as bevacizumab that are associated with tumor necrosis and bleeding [16,17,39,40], the committee suggests considering the use of LMWH for patients with these or other features that are associated with a high risk of GI bleeding, such as angiodysplasia, GI lesion, previous variceal bleed, or treatment-associated mucosal toxicity. The risk of GI perforation and/or hemorrhage associated with a patient's anticancer therapies should be taken into consideration regardless of which anticoagulant is selected.
# Thrombocytopenia
Thrombocytopenia increases the risk of bleeding complications in patients with CAT [43]. Unfortunately, there is limited evidence to guide management in patients with platelet counts <50,000 platelets/mL. The CLOT trial excluded patients with baseline platelet counts <75,000 platelets/mL, while the Hokusai-VTE Cancer, CARAVAGGIO, and SELECT-D trials excluded patients with baseline platelet counts of less than 50,000, 75,000, and 100,000 platelets/mL, respectively [8,[16][17][18]. Guidance from the SSC of the ISTH suggests that therapeutic dose of anticoagulation can be used for patients with platelet count of ≥50,000 platelets/mL [44]. In patients with platelet counts of less than 50,000 platelets/mL, 50% or prophylactic dose LMWH may be used or full-dose anticoagulation with platelet transfusion support may be considered [44]. The Canadian consensus committee suggests that LMWH is preferred in these patients but recommends seeking an expert opinion from a specialized physician when initiating anticoagulation in the setting of severe thrombocytopenia (i.e., platelet counts <50,000/mL). In cases of transient thrombocytopenia due to anticancer therapies, clinical judgment should be used to determine whether the anticoagulant needs to be dose-reduced or temporarily held until platelet levels recover to ≥50,000 platelets/mL.
# Intracranial Lesions
As there were few patients with intracranial tumors (primary brain tumor or brain metastasis) included in the DOAC trials (none in CARAVAGGIO, 7% of patients (74/1046) in Hokusai VTE Cancer, and only 1% of patients in SELECT-D), there are limited data regarding the safety of this anticoagulant class in these patients [16][17][18]. Some reassurance may be provided by a retrospective cohort study of the cumulative incidence of intracranial hemorrhage (ICH) with DOAC vs. LMWH in patients with brain tumors and VTE [45]. In this study, no ICH was noted among 20 patients with primary brain tumors treated with DOACs, while the cumulative incidence among the 47 patients treated with LMWH was 37%. Among 105 patients with brain metastases, the cumulative incidence of ICH was 11% among those treated with DOAC and 18% in those treated with LMWH [45]. Similarly, an international two-center study suggested comparable safety of LMWH and DOACs in patients with brain metastases. The 12-month cumulative incidence of major ICH was 5.1% in DOAC-treated patients and 11.1% in those treated with LMWH (HR: 0.45; 95% CI 0.09 to 2.21) [46]. When anticoagulation was analyzed as a time-varying covariate, the risk of any ICH did not differ between DOAC-and LMWH-treated patients (HR: 0.98; 95% CI 0.28 to 3.40) [46]. Finally, a single-center retrospective chart review of 125 patients with primary and metastatic brain tumors on anticoagulation reported rates of major bleeding of 26% and 9.6% in patients receiving LMWH or DOAC, respectively [47]. Patients receiving DOAC also had a lower rate of ICH compared to those receiving LMWH (5.8% vs. 15%) [47]. Nevertheless, given the small numbers and the limitations of retrospective studies, as well the shorter half-life of LMWH, the consensus committee suggests considering the initial use of LMWH for patients with CAT and high-risk intracranial lesions (e.g., glioma).
# Hepatic and Renal Impairment
Patients with functional hepatic impairment may have reduced ability to metabolize DOACs, all of which are at least partially metabolized by cytochrome P450 (CYP) enzymes [48][49][50]. Patients with significant liver disease are thus considered to be at higher risk of bleeding when treated with DOACs and were excluded from clinical trials. For these reasons, none of the DOACs are recommended for use in patients meeting criteria for Child-Pugh class C [48][49][50]. Rivaroxaban is contraindicated in patients with hepatic disease (including Child-Pugh class B and C) associated with coagulopathy and having clinically relevant bleeding risk [48]. Apixaban should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) [49]. With edoxaban, patients with Child-Pugh class A or B exhibited comparable pharmacokinetics and pharmacodynamics to healthy controls [50].
The previous iteration of the Canadian expert consensus treatment algorithm suggested that LMWH might be preferable to DOAC in patients with CAT and a creatinine clearance of 30-50 mL/min, especially if additional risk factors for bleeding were present [19]. This recommendation was based on the limited evidence available at the time suggesting a potentially elevated risk of bleeding with edoxaban in these patients [16,19]. However, this recommendation was not supported by the CARAVAGGIO trial, which found no significant between-treatment differences in rates of major bleeding in patients with creatinine clearance of 30-80 mL/min treated with apixaban or LMWH [18]. Thus, the consensus committee currently recommends that clinicians follow product monograph recommendations for contraindications and dose adjustment of anticoagulants in patients with impaired renal function (Table 2).
# Use of Antiplatelet Agents
The use of either dual antiplatelet therapy or higher doses of acetylsalicylic acid (ASA) was not permitted in the DOAC vs. LMWH RCTs, with concomitant ASA at doses >75 mg, >100 mg, and >165 mg daily being exclusion criteria in the SELECT-D, Hokusai-VTE Cancer, and CARAVAGGIO trials, respectively [16][17][18]. However, even at low doses, ASA is known to increase the risk of upper GI bleeds, a risk which appears to be increased when it is used in conjunction with oral anticoagulants [54,55]. This was confirmed by subgroup analysis of data from the Hokusai-VTE cancer trial, which showed a numerical increase in the risk of major bleeding in DOAC-treated patients on concomitant antiplatelet therapy [16]. Similarly, in the CARAVAGGIO trial, 22.7% (5/22) of patients on concomitant antiplatelet therapy treated with apixaban experienced major bleeding as compared to 11.8% (68/576) of apixaban-treated patients without antiplatelet therapy [40]. No major bleeding events were reported among the 23 patients in the LMWH arm on concomitant antiplatelet therapy, while 12.8% (74/579) of those without antiplatelet therapy had a major bleed [40]. Given this, the consensus committee recommends that the indication for antiplatelet agents be reassessed, and discontinuation should be considered in the absence of a strong indication in patients with new diagnosis of CAT. Shared decision-making with other health care providers would be warranted in these circumstances.
# Drug-Drug Interactions
Polypharmacy is common in patients with cancer, who are often treated with multiple anticancer and supportive therapies. It is thus important to evaluate the potential for drug-drug interactions when selecting the appropriate anticoagulant therapy for CAT. All DOACs are substrates of P-glycoprotein, and apixaban and rivaroxaban are also substrates of CYP3A4, so therapies that affect P-glycoprotein or CYP3A4 metabolism have the potential to interact with DOACs [56]. Numerous anticancer therapies are inhibitors or inducers of the P-glycoprotein and/or CYP3A4 pathways, with the potential to interact with DOACs [57]. Anticancer therapies for which the potential for drug-drug interactions with DOACs should be considered include abiraterone, acalabrutinib, afatinib, ceritinib, cyclosporine, cobimetinib, crizotinib, dabrafenib, dasatinib, dexamethasone, doxorubicin, enzalutamide, erdafitinib, ibrutinib, idelalisib, imatinib, ipilimumab, lapatinib, mitotane, neratinib, nilotinib, nintedanib, niraparib, olaparib, panobinostat, ponatinib, ribociclib, sunitinib, tacrolimus, tamoxifen, trametinib, trastuzumab emtansine, vandetanib, vemurafenib, and vinblastine [57].
However, assessing the potential for clinically significant interactions is complex as not all potential interactions appear to be clinically important [58]. In fact, sub-analysis of patients treated concomitantly with anticancer agents and anticoagulants in the CARAVAG-GIO trial found no significant differences in rates of major bleeding, recurrent VTE, or death between the DOAC and LMWH arms [59]. Table 3 lists drug-drug interactions with DOACs that have been shown to have clinical relevance. Notably, a recent registry of the ISTH including 202 patients receiving concurrent DOACs and targeted anticancer therapies has reported a high rate of bleeding complications in patients receiving Bruton's tyrosine kinase (BTK) inhibitors [60]. A recent observational study has also reported a higher risk of bleeding in patients receiving concurrent vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and LMWH [61]. The study sample size was inadequate for between-treatment comparisons with concurrent TKIs and DOACs. Given the complexity of the therapeutic regimens used to treat many patients with cancer, the consensus committee recommends that patients with CAT be referred for a pharmacist-led drug interaction evaluation, which should be repeated if cancer management changes. Alternatively, online drug-drug interaction applications or websites can be helpful, although previous publications have highlighted important differences in the accuracy and quality of these tools [62,63]. However, when using such tools, clinicians must keep in mind that the majority of reported interactions are theoretical rather than having been proven to be associated with decreased drug levels (and thus thrombosis) or increased drug levels (and thus bleeding). In addition to efficacy, safety, and potential for drug-drug interactions, clinicians and patients should together consider drug cost and accessibility, taking into account the patient's individual situation, as well as publicly or privately funded drug plan coverage. Shared decision-making may help improve adherence to therapy, and, in turn, lead to improved anticoagulant effectiveness.
# Body Weight
There is a paucity of evidence regarding the use of DOACs or LMWHs in patients with cancer at the extremes of body weight. In the Hokusai-VTE Cancer and CARAVAGGIO trials, neither low (≤60 kg) nor high (>90 kg) body weight had a significant impact on the risk of recurrent VTE or major bleeding, although there were few patients in these extreme weight categories who were included in the trials [16,18]. It should be noted that the daily dose of edoxaban was reduced in the Hokusai-VTE Cancer trial to 30 mg from 60 mg in patients with a body weight ≤60 kg [16]. Dose adjustment based on body weight is not recommended in the product monographs for apixaban or rivaroxaban [48,49].
Per the approved indication, the dose of the LMWH dalteparin was capped at 18,000 IU daily in the DOAC trials in CAT [16][17][18]. However, prior non-cancer studies have shown that body weight does not have an important effect on anti-Xa activity levels achieved with weight-based doses of enoxaparin, dalteparin, and tinzaparin for patients weighing up to 144 kg, 190 kg, and 165 kg, respectively [64][65][66]. Furthermore, a meta-analysis of data including 921 patients with a body mass index (BMI) of 30 kg/m 2 or more showed no increased risk of bleeding compared with non-obese patients (BMI < 30 kg/m 2 ) who received weight-adjusted, "uncapped" LMWH [67]. Therapeutic weight-adjusted dosing, without capping, is therefore suggested for LMWH use [68].
Based on meta-analyses and phase 4 studies, the SCC of the ISTH suggests that standard doses of rivaroxaban or apixaban are among appropriate anticoagulant options for the treatment and prevention of VTE in the general, non-cancer population, regardless of BMI and weight [69]. Fewer supportive data exist for apixaban than rivaroxaban. VKA and weight based LMWH are also considered options. The SCC suggests not to use dabigatran or edoxaban in patients with BMI > 40 kg/m 2 or weight > 120 kg, given unconvincing data for dabigatran, and lack of clinical or pharmacokinetic and pharmacodynamic data for edoxaban [69]. These suggestions are not specifically for CAT but for the overall management of VTE. Based on the limited evidence base, the consensus committee recommends that LMWH be considered in patients with weight > 150 kg and an agent with weight-adjustable dosing, such as edoxaban or LMWH, be considered in patients with weight < 50 kg.
# Burden of Cancer and Burden of VTE
Limited data are available regarding the effects of the burden of cancer and burden of VTE on the efficacy and safety of anticoagulation. Cross-study comparison is limited by differences between clinical trials in baseline characteristics reflecting cancer burden (Table 4), as well as in overall mortality rates (Table 1), which suggest the overall burden of cancer may have been higher in the LMWH vs. VKA trials than in the DOAC vs. LMWH trials [8,9,[16][17][18][24][25][26][27][28]. It is also important to note that patients who required thrombolysis or who underwent inferior vena cava filter insertion were excluded from the trials. In the absence of RCT data, the consensus committee recommends that initial therapy with LMWH be considered for patients with severe symptoms of thrombosis, including patients with iliofemoral DVT, extensive PE, or sub-massive PE, and any patients who received thrombolysis.
# Abnormal Uterine Bleeding
Abnormal uterine bleeding is a common but under-reported complication of anticoagulation that is thought to occur in up to 70% of women of reproductive age receiving anticoagulation [70]. The risk of anticoagulant-related abnormal uterine bleeding varies by DOAC, with apixaban and edoxaban having statistically similar relative risks to VKA and rivaroxaban appearing to double the risk as compared to VKA (RR: 2.10; p < 0.01) [70,71]. Estimates of the risk of abnormal uterine bleeding with LMWH monotherapy are not available. However, despite the lack of data for LMWH, for women who experience abnormal uterine bleeding while on DOAC or with a history of abnormal uterine bleeding associated with a DOAC, the consensus committee recommends consideration of LMWH. Other management options for abnormal uterine bleeding secondary to anticoagulation include tranexamic acid, and hormonal therapy, such as combined oral contraceptives, the levonorgestrel intrauterine device, and depo-medroxyprogesterone acetate, although estrogen-based regimens should be avoided in patients who are no longer on anticoagulation [70]. Adjunctive iron therapy to manage iron deficiency anemia, as well as consultation with gynecology may also be considered.
# Significant GI Surgery or Absorption Disorders
DOACs are absorbed by different sites throughout the GI tract, with edoxaban being primarily absorbed by the proximal small intestine, rivaroxaban absorbed by both the stomach and proximal intestine and apixaban absorbed throughout the GI tract including significant (>50%) absorption in the distal small bowel or ascending colon [72]. Given the GI absorption of DOACs, there is concern regarding their use in patients who, because of GI surgery or other disorders, have a significant reduction in intestinal absorptive surface. However, there is limited evidence regarding the pharmacodynamics or clinical outcomes associated with DOACs in these patients [72]. The SSC of the ISTH recommends not using DOACs for treatment or prevention of VTE in the acute setting after bariatric surgery due to concerns of decreased gastric absorption [69]. Such a recommendation might apply to cancer patients who have undergone a Whipple's procedure. Initiation of anticoagulation with LMWH or another parenteral agent is recommended in such cases. Until a greater evidence base is available, it is reasonable to consider LMWH for patients with impaired GI absorption.
# Reassessing Treatment for Secondary Prophylaxis
Prospective studies that evaluated anticoagulation therapy beyond 6 months include the DALTECAN, TICAT, Hokusai-VTE Cancer, and SELECT-D studies [16,[73][74][75]. In the DALTECAN prospective cohort study, 55% of the 334 patients with VTE and active cancer who were treated with dalteparin completed 6 months of therapy, and 33% completed 12 months [73]. Therapy beyond 6 months was not associated with an increased risk of major bleeding or recurrent VTE as compared to the first 6 months. Similarly, the TICAT study, which evaluated the safety of long-term tinzaparin in 247 patients with CAT, reported no significant difference in recurrent VTE or clinically relevant bleeding for months 1 to 6 compared with months 7 to 12 [74]. The Hokusai-VTE Cancer trial demonstrated acceptable efficacy and safety profiles during the 12-month treatment period [16]. However, the median therapy duration was approximately 6 months, and rates of recurrent VTE and major bleeding beyond the initial 6 months were not reported. After 6 months of treatment in the SELECT-D trial, patients with active cancer and residual DVT or index PE were eligible for re-randomization to rivaroxaban or placebo [75]. Of the 92 patients who were re-randomized, 4% of those treated with rivaroxaban experienced recurrent VTE as compared to 14% of those treated with placebo (HR: 0.32; 95% CI 0.06 to 1.58), while major bleeding occurred in 0% of patients treated with placebo and 5% of those randomized to rivaroxaban [75]. Although there are no prospective data assessing the efficacy and safety of anticoagulation for secondary prevention of recurrent VTE beyond 12 months, retrospective cohort studies have shown that the risk of recurrent VTE and major bleeding remains elevated beyond 12 months in this patient population [76,77].
Several studies have also investigated the safety and efficacy of prophylactic doses of DOACs for the extended treatment of VTE [78,79]. However, few patients with active cancer were included in these trials. and it is unclear whether the results can be generalized to this population. The ongoing API-CAT study, which aims to determine whether a low-dose regimen of apixaban is non inferior to a full-dose regimen of apixaban for the prevention of recurrent VTE in patients with active cancer who have completed at least 6 months of anticoagulant therapy for treating VTE, may help clarify this issue [80].
Considering the weak evidence supporting long-term secondary prophylaxis in patients with CAT, most guidelines suggest that the decision to continue anticoagulation beyond the initial 6 months should be individualized [19][20][21][22][23]. Most of the studies supporting long-term secondary prevention in patients with cancer assessed therapeutic dosing of anticoagulation (LMWH or DOAC). However, decision on duration and dosing of anticoagulation for long-term secondary prevention should be made based on the patient's risk factors for VTE recurrence and bleeding complications and re-assessed on a regular basis. The consensus committee suggests that patients' risk factors for VTE recurrence and bleeding should be reassessed regularly (e.g., at least every 3 months or sooner if there are changes in cancer status or management).
# Conclusions
Selection of anticoagulation for the treatment of CAT should be individualized based on the patient's bleeding risk, type of cancer, and potential for drug-drug interactions, as well as patient and clinician preferences. Anticoagulant therapy should be reassessed on a regular basis as the patient's cancer status and management change over time.
#
Acknowledgments: Rebecca Cowan of MedPlan Communications Inc. is thanked for editorial support in the preparation of the manuscript. Hollie Devlin and David Airdrie of Thrombosis Canada are thanked for administrative support.
#
OR "Warfarin"[Mesh] OR "apixaban"[Supplementary Concept] OR "Dabigatran"[Mesh] OR "edoxaban"[Supplementary Concept] OR "Rivaroxaban"[Mesh]). The results were restricted to English-language publications focusing on humans.
Abstracts presented at the 2020 American Society of Hematology Annual Meeting were searched using the following terms: (cancer) AND (thromboembolism OR thrombosis OR embolism) AND (anticoagulant OR LMWH OR warfarin OR apixaban OR dabigatran OR edoxaban OR dalteparin OR enoxaparin OR tinzaparin). | None | None |
9a5ec560e740cb6508ab5bdfbe7b02bec70c7980 | cma | None | To provide an evidence-based approach to treatment of patients with acute pulmonary embolism (PE).Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disease and affects approximately 1-2 in 1,000 adults per year. The incidence of PE has increased significantly since the advent of computed tomography pulmonary angiography (CTPA) due to this test's widespread availability and diagnostic sensitivity. The majority of pulmonary emboli are believed to originate in the proximal deep veins of the leg, despite the fact that only 25-50% of patients with PE have clinically evident DVT. Up to 50% of first-time pulmonary emboli are unprovoked, while the remainder are associated with risk factors of varying clinical significance such as active malignancy, surgery (especially orthopedic), trauma, lower extremity plaster casting, immobilization >8 hours, and estrogen use/pregnancy. Symptoms of PE may include sudden onset dyspnea, palpitations, pleuritic chest pain and syncope. Signs of PE may include tachypnea, tachycardia, hypoxemia, hypotension, and features of right ventricular dysfunction (e.g. distended jugular veins). The ECG may show right ventricular strain (S1Q3T3, right bundle branch block and T-inversion in leads V1-V4). Up to 10% of symptomatic PE cases are fatal within the first hour of symptoms. Independent predictors of early mortality include hypotension (systolic blood pressure <90 mmHg), clinical right heart failure, right ventricular dilatation on CT or echocardiography, positive troponin, and elevated brain natriuretic peptide (BNP). Early diagnosis and treatment of PE reduces morbidity and mortality.# TREATMENT OF PE:
Unless bleeding risk is high (e.g. active bleeding, immediate postoperative state), rapid-acting anticoagulant therapy should be initiated in patients with a high pre-test probability of PE while awaiting diagnostic imaging. Treatment can be withheld in patients with intermediate and low pretest probabilities of PE if definitive diagnostic testing will be completed within 4 or 24 hours, respectively.
All patients with confirmed PE should be risk-stratified to determine whether they require in-hospital treatment or if outpatient management is sufficient (see the Pulmonary Embolism Severity Index and Simplified PESI risk models in the Thrombosis Canada Clinical Tools). Patients classified as very low and low risk by the PESI models have a low overall risk of severe morbidity and mortality and can be considered for outpatient management or early discharge. However, other factors, such as need for supplemental oxygen or parenteral pain control, high bleeding risk, severe renal dysfunction, or absence of appropriate social supports may also necessitate initiation of treatment in an inpatient setting. Alternatively, eligible patient for outpatient management can be identified using the HESTIA criteria (). With both methods, approximately 40% of all patients diagnosed in the Emergency Department with PE can be safely discharged with outpatient follow-up and management. However, clinicians should be cautious if the patient deemed at low risk has others higher mortality prognostic markers, such as right ventricular dilation on imaging, elevated troponin or elevated BNP.
Options for initial anticoagulation include direct acting oral anticoagulant (DOAC) monotherapy (for apixaban and rivaroxaban), unfractionated heparin (UFH) or low molecular weight heparin (LMWH) initial therapy followed by DOAC (for dabigatran and edoxaban), LMWH/UFH bridging to therapeutic warfarin, or LMWH monotherapy (Figure 1). Recent guideline recommendations express a preference for DOAC therapy over LMWH bridging to warfarin. While both strategies are effective, DOACs are more convenient and appear to have lower bleeding risk. The extent of PE or clot burden should not influence choice of anticoagulant, unless thrombolysis is being considered; in that case, intravenous (IV) UFH is preferred in the short-term due to its short half-life in the context of the bleeding risk associated with thrombolysis. All patients with PE should be treated with anticoagulation for at least 3 months .
# FIGURE 1 ANTICOAGULANT AGENTS AND DOSING:
NOACs/DOACS (Non-vitamin K antagonist Oral AntiCoagulants/Direct Oral AntiCoagulants) -Apixaban (Eliquis®), Dabigatran (Pradaxa®), Edoxaban (Lixiana®) and Rivaroxaban (Xarelto®) Large phase 3 studies have demonstrated the efficacy and safety of these agents for the acute and extended treatment of PE. Four DOACs have been approved in Canada for the treatment of patients with PE. On the basis of trial design and dosing requirements, an initial 5-to 10-day course of LMWH is required prior to starting dabigatran and edoxaban, but not with apixaban or rivaroxaban.
DOACs should not be used in pregnant or breastfeeding women or in those with significant renal or liver dysfunction . Individual product monographs should be consulted for important drug interactions prior to prescribing.
The recommended initial doses of the DOACs from their product monographs are: Apixaban (Eliquis®): 10 mg twice daily for the first 7 days, followed by 5 mg twice daily. No dose adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min). Apixaban should be used with caution in patients with CrCl 15-29 mL/min as these patients were excluded in clinical trials assessing clinical outcomes. Apixaban is not recommended in those with a CrCl <15 mL/min or undergoing dialysis.
# Dabigatran (Pradaxa®):
After an initial 5-10 days of therapeutic LMWH, recommended dosing is 150 mg twice daily. Dose reduction has not been studied in the setting of VTE; however, consideration may be given to reducing the dose to 110 mg twice daily in patients 80 years or older, and those at higher risk of bleeding (including age at 75 or older with at least one risk factor for bleeding). Use is contraindicated with CrCl <30 mL/min).
# Edoxaban (Lixiana®):
After an initial 5-10 days of therapeutic LMWH, recommended dosing is 60 mg once daily (30 mg if less than or equal to 60 kg, creatinine clearance (CrCL) 30-50 mL/min, concurrent use of potent P-gp inhibitors except amiodarone and verapamil). Use is not recommended with CrCl <30 mL/min). Rivaroxaban (Xarelto®): 15 mg twice daily for the first 21 days, followed by 20 mg once daily for the duration of treatment. No dosing adjustment is recommended in those with CrCl 15-50 mL/min. However, caution is recommended for those with CrCl 15-30 mL/min as these patients were excluded in clinical trials assessing clinical outcomes. Use is not recommended with CrCl <15 mL/min. For patients continuing on long term anticoagulation with apixaban or rivaroxaban beyond 6 months, dose reduction of rivaroxaban to 10 mg once daily or apixaban to 2.5 mg twice daily can be considered based on the results of the EINSTEIN CHOICE and AMPLIFY EXT studies, in which these lower doses were as effective and safe as standard dosing.
# Low molecular weight heparin
LMWH may be used as initial therapy in conjunction with warfarin or may be used as monotherapy for the full duration of treatment in those with active cancer. Most patients have little difficulty with LMWH self-administration. LMWH offers advantages over UFH including better bioavailability when administered subcutaneously, longer duration of anticoagulant effect enabling once or twice daily treatment, lower risk of heparin-induced thrombocytopenia (HIT), predictable anticoagulant effect allowing fixed dosing based on body weight and renal function, less effect on bone metabolism, and no requirement for routine laboratory monitoring. There is no maximum dose of LMWH and dosing should be based on the patient's actual weight. Doses can be rounded off to the nearest prefilled syringe size. Dalteparin (Fragmin®): 200 U/kg subcutaneously (SC) once daily or 100 U/kg SC twice daily (once daily dosing is generally preferred, but twice daily dosing should be considered in patients >100 kg). For patients with severe renal insufficiency (CrCl <30 mL/min), clinical data on the use of LMWH for the treatment of PE are limited and LMWHs should generally be avoided. For tinzaparin, available evidence demonstrates no accumulation in patients with CrCl levels down to 20 mL/min. There are limited data available in patients with an estimated CrCl < 20 mL/min.
# Enoxaparin (Lovenox®
# Unfractionated heparin
UFH use in the treatment of PE is limited by a narrow therapeutic range, inter-individual variation in anticoagulant effect, need for continuous intravenous infusion with laboratory monitoring, and increased risk of HIT. The use of UFH should be limited to: (1) patients with severe renal insufficiency (CrCl <30 mL/min); (2) patients at very high risk for bleeding, in whom rapid reversal of the anticoagulant effect may be needed; and (3) patients who receive thrombolytic therapy. Intravenous UFH is generally started with a bolus of 80 U/kg followed by a continuous infusion starting at 18-20 U/kg/hr. The target therapeutic activated partial thromboplastin time (aPTT) range is defined by the local hospital laboratory. A baseline aPTT should generally be obtained prior to UFH administration as a consumptive coagulopathy or nonspecific inhibitor (e.g. lupus anticoagulant) may falsely elevate the baseline aPTT, resulting in underdosing UFH. Such cases should be discussed with a thrombosis specialist. Some centres adjust IV unfractionated heparin based on heparin anti-Xa levels.
# Warfarin
Initiation of warfarin should be combined with an immediate-acting agent such as LMWH for at least 5 days and until the international normalized ratio (INR) is at least 2.0 for at least 2 days. As warfarin takes several days to take effect, warfarin monotherapy is not an acceptable treatment option. Initial dosing is typically 5 mg once daily, but the therapeutic dose is highly variable. The elderly and those with low body weight typically require a lower dose, such as 2-3 mg. Conversely, relatively young, healthy, and large patients typically require a higher dose, such as 7.5-10 mg. Frequent monitoring is required until a stable, therapeutic-range INR is reached. Once stable, INR testing every 2-6 weeks is usually adequate.
Warfarin is associated with many drug and food interactions that affect the INR. Alterations in concomitant medications and new concurrent illness should prompt more frequent INR testing. Patients should not be encouraged to reduce intake of foods high in vitamin K, but to maintain a consistent, balanced diet. Low intake of vitamin K can be associated with more unstable INR levels.
# THROMBOLYSIS:
Harm with thrombolysis outweighs the benefit in most patients with PE, except in those who present with high risk (massive) PE. High risk (massive) PE is defined as persistent hypotension despite small fluid challenge (SBP 15%, IV thrombolysis should be reserved for patients meeting those criteria and who do not have a contraindication.
Thrombolysis is NOT routinely indicated in intermediate risk (also called sub-massive) PE (normotensive with right ventricular dysfunction on imagery or with elevated cardiac biomarkers), as it increases major bleeding and hemorrhagic stroke. For select patients with intermediate risk PE who are not at high risk of bleeding AND who have severe persistent symptoms with signs of right heart failure or cardiopulmonary deterioration, thrombolysis may be considered after discussion with a thrombosis expert.
Thrombolytic regimens are heterogenous in the literature. Some thrombolysis regimens include:
- recombinant tissue plasminogen activator (rt-PA) 100 mg over 2 hours - rt-PA 0.6 mg/kg (maximum of 50 mg) over 15 minutes - rt-PA 0.5 mg/kg (maximum of 50 mg) given as a 10 mg bolus, then the remainder over 2 hours if ≥50 kg; if <50 kg total rt-PA dose of 0.5 mg/kg, given as a 10-mg initial bolus followed by the remainder within 2 hours - rt-PA 50 mg as a bolus over 1 minute in a patient in cardiac arrest - Tenectaplase (TNK) between 30-50 mg (depending on weight) as a bolus over 5-10 seconds (PEITHO trial regimen)
Intravenous UFH (without a bolus) should be used initially after thrombolytic therapy, followed by a transition to a longer-term agent.
# SPECIAL CONSIDERATIONS:
Catheter-directed thrombolysis for massive PE In some hospitals where there is requisite expertise, catheter-directed thrombolysis may be considered since it is able to deliver a thrombolytic agent directly into one or more large emboli and can rapidly relieve pulmonary artery occlusion with a lower risk of bleeding. Such treatment should be undertaken in consultation with a specialist. There is no published data to guide which patients would benefit most from this emerging therapy; therefore, it should generally not be used routinely in patients with high or intermediate risk PE.
# Pediatrics
The diagnosis of PE in children should always be confirmed with a V/Q scan, CT with contrast or magnetic resonance imaging (MRI). Treatment may be initiated with either age appropriate UFH or LMWH, followed by 3 months (for a provoked VTE) or longer-term anticoagulation for recurrent or unprovoked events using either LMWH or warfarin. Two multicenter, randomized trials compared either rivaroxaban (EINSTEIN-Jr study) or dabigatran (DIVERSITY study) with standard anticoagulants in children (0 to 17 years of age) who have acute venous thromboembolism. All patients initially received at least 5 days of parenteral anticoagulant (up to 9 days in EINSTEIN-Jr and up to 21 days in DIVERSITY). Both studies found a similarly low recurrence risk of the DOAC as standard anticoagulants without an increased risk of bleeding. However, neither rivaroxaban nor dabigatran are currently licensed for the pediatric population in Canada.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of version: 27September2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide an evidence-based approach to treatment of patients with acute pulmonary embolism (PE).Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disease and affects approximately 1-2 in 1,000 adults per year. The incidence of PE has increased significantly since the advent of computed tomography pulmonary angiography (CTPA) due to this test's widespread availability and diagnostic sensitivity. The majority of pulmonary emboli are believed to originate in the proximal deep veins of the leg, despite the fact that only 25-50% of patients with PE have clinically evident DVT. Up to 50% of first-time pulmonary emboli are unprovoked, while the remainder are associated with risk factors of varying clinical significance such as active malignancy, surgery (especially orthopedic), trauma, lower extremity plaster casting, immobilization >8 hours, and estrogen use/pregnancy. Symptoms of PE may include sudden onset dyspnea, palpitations, pleuritic chest pain and syncope. Signs of PE may include tachypnea, tachycardia, hypoxemia, hypotension, and features of right ventricular dysfunction (e.g. distended jugular veins). The ECG may show right ventricular strain (S1Q3T3, right bundle branch block and T-inversion in leads V1-V4). Up to 10% of symptomatic PE cases are fatal within the first hour of symptoms. Independent predictors of early mortality include hypotension (systolic blood pressure <90 mmHg), clinical right heart failure, right ventricular dilatation on CT or echocardiography, positive troponin, and elevated brain natriuretic peptide (BNP). Early diagnosis and treatment of PE reduces morbidity and mortality.# TREATMENT OF PE:
Unless bleeding risk is high (e.g. active bleeding, immediate postoperative state), rapid-acting anticoagulant therapy should be initiated in patients with a high pre-test probability of PE while awaiting diagnostic imaging. Treatment can be withheld in patients with intermediate and low pretest probabilities of PE if definitive diagnostic testing will be completed within 4 or 24 hours, respectively.
All patients with confirmed PE should be risk-stratified to determine whether they require in-hospital treatment or if outpatient management is sufficient (see the Pulmonary Embolism Severity Index [PESI] and Simplified PESI risk models in the Thrombosis Canada Clinical Tools). Patients classified as very low and low risk by the PESI models have a low overall risk of severe morbidity and mortality and can be considered for outpatient management or early discharge. However, other factors, such as need for supplemental oxygen or parenteral pain control, high bleeding risk, severe renal dysfunction, or absence of appropriate social supports may also necessitate initiation of treatment in an inpatient setting. Alternatively, eligible patient for outpatient management can be identified using the HESTIA criteria (https://www.mdcalc.com/hestia-criteria-outpatient-pulmonary-embolism-treatment). With both methods, approximately 40% of all patients diagnosed in the Emergency Department with PE can be safely discharged with outpatient follow-up and management. However, clinicians should be cautious if the patient deemed at low risk has others higher mortality prognostic markers, such as right ventricular dilation on imaging, elevated troponin or elevated BNP.
Options for initial anticoagulation include direct acting oral anticoagulant (DOAC) monotherapy (for apixaban and rivaroxaban), unfractionated heparin (UFH) or low molecular weight heparin (LMWH) initial therapy followed by DOAC (for dabigatran and edoxaban), LMWH/UFH bridging to therapeutic warfarin, or LMWH monotherapy (Figure 1). Recent guideline recommendations express a preference for DOAC therapy over LMWH bridging to warfarin. While both strategies are effective, DOACs are more convenient and appear to have lower bleeding risk. The extent of PE or clot burden should not influence choice of anticoagulant, unless thrombolysis is being considered; in that case, intravenous (IV) UFH is preferred in the short-term due to its short half-life in the context of the bleeding risk associated with thrombolysis. All patients with PE should be treated with anticoagulation for at least 3 months [see Clinical Guide Venous Thromboembolism: Duration of Treatment guide].
# FIGURE 1 ANTICOAGULANT AGENTS AND DOSING:
NOACs/DOACS (Non-vitamin K antagonist Oral AntiCoagulants/Direct Oral AntiCoagulants) -Apixaban (Eliquis®), Dabigatran (Pradaxa®), Edoxaban (Lixiana®) and Rivaroxaban (Xarelto®) Large phase 3 studies have demonstrated the efficacy and safety of these agents for the acute and extended treatment of PE. Four DOACs have been approved in Canada for the treatment of patients with PE. On the basis of trial design and dosing requirements, an initial 5-to 10-day course of LMWH is required prior to starting dabigatran and edoxaban, but not with apixaban or rivaroxaban.
DOACs should not be used in pregnant or breastfeeding women or in those with significant renal or liver dysfunction [see Clinical Guides for Apixaban (Eliquis®), Dabigatran (Pradaxa®), Edoxaban (Lixiana®), Rivaroxaban (Xarelto®) ]. Individual product monographs should be consulted for important drug interactions prior to prescribing.
The recommended initial doses of the DOACs from their product monographs are: Apixaban (Eliquis®): 10 mg twice daily for the first 7 days, followed by 5 mg twice daily. No dose adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance [CrCl] ≥ 30 mL/min). Apixaban should be used with caution in patients with CrCl 15-29 mL/min as these patients were excluded in clinical trials assessing clinical outcomes. Apixaban is not recommended in those with a CrCl <15 mL/min or undergoing dialysis.
# Dabigatran (Pradaxa®):
After an initial 5-10 days of therapeutic LMWH, recommended dosing is 150 mg twice daily. Dose reduction has not been studied in the setting of VTE; however, consideration may be given to reducing the dose to 110 mg twice daily in patients 80 years or older, and those at higher risk of bleeding (including age at 75 or older with at least one risk factor for bleeding). Use is contraindicated with CrCl <30 mL/min).
# Edoxaban (Lixiana®):
After an initial 5-10 days of therapeutic LMWH, recommended dosing is 60 mg once daily (30 mg if less than or equal to 60 kg, creatinine clearance (CrCL) 30-50 mL/min, concurrent use of potent P-gp inhibitors except amiodarone and verapamil). Use is not recommended with CrCl <30 mL/min). Rivaroxaban (Xarelto®): 15 mg twice daily for the first 21 days, followed by 20 mg once daily for the duration of treatment. No dosing adjustment is recommended in those with CrCl 15-50 mL/min. However, caution is recommended for those with CrCl 15-30 mL/min as these patients were excluded in clinical trials assessing clinical outcomes. Use is not recommended with CrCl <15 mL/min. For patients continuing on long term anticoagulation with apixaban or rivaroxaban beyond 6 months, dose reduction of rivaroxaban to 10 mg once daily or apixaban to 2.5 mg twice daily can be considered based on the results of the EINSTEIN CHOICE and AMPLIFY EXT studies, in which these lower doses were as effective and safe as standard dosing.
# Low molecular weight heparin
LMWH may be used as initial therapy in conjunction with warfarin or may be used as monotherapy for the full duration of treatment in those with active cancer. Most patients have little difficulty with LMWH self-administration. LMWH offers advantages over UFH including better bioavailability when administered subcutaneously, longer duration of anticoagulant effect enabling once or twice daily treatment, lower risk of heparin-induced thrombocytopenia (HIT), predictable anticoagulant effect allowing fixed dosing based on body weight and renal function, less effect on bone metabolism, and no requirement for routine laboratory monitoring. There is no maximum dose of LMWH and dosing should be based on the patient's actual weight. Doses can be rounded off to the nearest prefilled syringe size. Dalteparin (Fragmin®): 200 U/kg subcutaneously (SC) once daily or 100 U/kg SC twice daily (once daily dosing is generally preferred, but twice daily dosing should be considered in patients >100 kg). For patients with severe renal insufficiency (CrCl <30 mL/min), clinical data on the use of LMWH for the treatment of PE are limited and LMWHs should generally be avoided. For tinzaparin, available evidence demonstrates no accumulation in patients with CrCl levels down to 20 mL/min. There are limited data available in patients with an estimated CrCl < 20 mL/min.
# Enoxaparin (Lovenox®
# Unfractionated heparin
UFH use in the treatment of PE is limited by a narrow therapeutic range, inter-individual variation in anticoagulant effect, need for continuous intravenous infusion with laboratory monitoring, and increased risk of HIT. The use of UFH should be limited to: (1) patients with severe renal insufficiency (CrCl <30 mL/min); (2) patients at very high risk for bleeding, in whom rapid reversal of the anticoagulant effect may be needed; and (3) patients who receive thrombolytic therapy. Intravenous UFH is generally started with a bolus of 80 U/kg followed by a continuous infusion starting at 18-20 U/kg/hr. The target therapeutic activated partial thromboplastin time (aPTT) range is defined by the local hospital laboratory. A baseline aPTT should generally be obtained prior to UFH administration as a consumptive coagulopathy or nonspecific inhibitor (e.g. lupus anticoagulant) may falsely elevate the baseline aPTT, resulting in underdosing UFH. Such cases should be discussed with a thrombosis specialist. Some centres adjust IV unfractionated heparin based on heparin anti-Xa levels.
# Warfarin
Initiation of warfarin should be combined with an immediate-acting agent such as LMWH for at least 5 days and until the international normalized ratio (INR) is at least 2.0 for at least 2 days. As warfarin takes several days to take effect, warfarin monotherapy is not an acceptable treatment option. Initial dosing is typically 5 mg once daily, but the therapeutic dose is highly variable. The elderly and those with low body weight typically require a lower dose, such as 2-3 mg. Conversely, relatively young, healthy, and large patients typically require a higher dose, such as 7.5-10 mg. Frequent monitoring is required until a stable, therapeutic-range INR is reached. Once stable, INR testing every 2-6 weeks is usually adequate.
Warfarin is associated with many drug and food interactions that affect the INR. Alterations in concomitant medications and new concurrent illness should prompt more frequent INR testing. Patients should not be encouraged to reduce intake of foods high in vitamin K, but to maintain a consistent, balanced diet. Low intake of vitamin K can be associated with more unstable INR levels.
# THROMBOLYSIS:
Harm with thrombolysis outweighs the benefit in most patients with PE, except in those who present with high risk (massive) PE. High risk (massive) PE is defined as persistent hypotension despite small fluid challenge (SBP <90 mmHg, a 40 mmHg drop from baseline, or vasopressor requirement) or cardiac arrest not caused by an alternative diagnosis. Since the short-term mortality risk is >15%, IV thrombolysis should be reserved for patients meeting those criteria and who do not have a contraindication.
Thrombolysis is NOT routinely indicated in intermediate risk (also called sub-massive) PE (normotensive with right ventricular dysfunction on imagery or with elevated cardiac biomarkers), as it increases major bleeding and hemorrhagic stroke. For select patients with intermediate risk PE who are not at high risk of bleeding AND who have severe persistent symptoms with signs of right heart failure or cardiopulmonary deterioration, thrombolysis may be considered after discussion with a thrombosis expert.
Thrombolytic regimens are heterogenous in the literature. Some thrombolysis regimens include:
• recombinant tissue plasminogen activator (rt-PA) 100 mg over 2 hours • rt-PA 0.6 mg/kg (maximum of 50 mg) over 15 minutes • rt-PA 0.5 mg/kg (maximum of 50 mg) given as a 10 mg bolus, then the remainder over 2 hours if ≥50 kg; if <50 kg total rt-PA dose of 0.5 mg/kg, given as a 10-mg initial bolus followed by the remainder within 2 hours • rt-PA 50 mg as a bolus over 1 minute in a patient in cardiac arrest • Tenectaplase (TNK) between 30-50 mg (depending on weight) as a bolus over 5-10 seconds (PEITHO trial regimen)
Intravenous UFH (without a bolus) should be used initially after thrombolytic therapy, followed by a transition to a longer-term agent.
# SPECIAL CONSIDERATIONS:
Catheter-directed thrombolysis for massive PE In some hospitals where there is requisite expertise, catheter-directed thrombolysis may be considered since it is able to deliver a thrombolytic agent directly into one or more large emboli and can rapidly relieve pulmonary artery occlusion with a lower risk of bleeding. Such treatment should be undertaken in consultation with a specialist. There is no published data to guide which patients would benefit most from this emerging therapy; therefore, it should generally not be used routinely in patients with high or intermediate risk PE.
# Pediatrics
The diagnosis of PE in children should always be confirmed with a V/Q scan, CT with contrast or magnetic resonance imaging (MRI). Treatment may be initiated with either age appropriate UFH or LMWH, followed by 3 months (for a provoked VTE) or longer-term anticoagulation for recurrent or unprovoked events using either LMWH or warfarin. Two multicenter, randomized trials compared either rivaroxaban (EINSTEIN-Jr study) or dabigatran (DIVERSITY study) with standard anticoagulants in children (0 to 17 years of age) who have acute venous thromboembolism. All patients initially received at least 5 days of parenteral anticoagulant (up to 9 days in EINSTEIN-Jr and up to 21 days in DIVERSITY). Both studies found a similarly low recurrence risk of the DOAC as standard anticoagulants without an increased risk of bleeding. However, neither rivaroxaban nor dabigatran are currently licensed for the pediatric population in Canada.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of version: 27September2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
656863eb71b6aa6666f482cd3f8638a551489c9c | cma | None | To provide an overview of the mechanism of action, dosing regimens and side-effects of warfarin and other vitamin K antagonists.Warfarin is an indirect anticoagulant producing its effect by decreasing the ability of the liver to produce fully functional coagulation factors II, VII, IX, and X, as well as the endogenous anticoagulants, protein C and protein S. Current Clinical Practice Guidelines generally recommend direct oral anticoagulants (DOACs) over warfarin for most patients with venous thromboembolism (VTE) and atrial fibrillation (AF) as DOACs are as effective and cause similar or less bleeding, but there are still circumstances where warfarin is preferable or indicated. This guide will try to address these issues.# INDICATIONS:
Common uses of warfarin include:
- prevention of stroke or systemic embolism in patients with AF, especially those with rheumatic mitral stenosis - treatment of acute VTE (overlapped with parenteral anticoagulation) - long-term secondary prevention of VTE - prevention of thrombosis or systemic embolization in patients with mechanical heart valves or with certain diseases of the native heart valves Less common uses include:
- management of patients with acute anterior myocardial infarction - prevention of systemic embolization from the heart, e.g. mural thrombus - prevention of recurrent stroke in selected patients without AF - to maintain hemodialysis access and arterial graft patency - prevention of VTE in high risk patients, e.g. hip or knee arthroplasty - prevention of recurrent venous and arterial embolism in those with antiphospholipid antibody syndrome DOSING:
- The maintenance dose of warfarin varies widely among patients, from less than 1 mg/day to greater than 20 mg/day. - In general, warfarin should be started at the dose estimated to be required for long-term therapy. For most adults, a reasonable starting dose is 5 mg daily. In those who are frail, underweight or of Asian descent, starting a lower dose at 1 -2 mg daily may be more suitable.
- Factors affecting the maintenance dose of warfarin include:
- Age - Body weight - Race - Nutritional status, diet
- Genetic variation in the enzyme that is the site of warfarin action (VKOR)
- Genetic variation in the enzyme system that metabolizes warfarin (CYP450)
- Concomitant drugs - Alcohol intake - Comorbidity, e.g. liver disease, heart failure - Activity level MONITORING:
- Routine laboratory monitoring is required for all patients taking warfarin.
- The target INR (international normalizing ratio) for most patients is 2.0-3.0. For most patients with mechanical mitral valves the target INR is 2.5-3.5. - The time it takes for warfarin to produce a change in the INR depends on the time for preexisting vitamin K-dependent clotting factors to be metabolized. Depending on the dose of warfarin and individual factors, the timeframe for this process is approximately 3 to 7 days. Therefore, it is recommended that monitoring be performed no earlier than 2 to 3 days after the first dose and subsequent dose changes. - There are a variety of tools to aid in the management of warfarin therapy, including:
- Computerized monitoring - Paper-based dosing algorithms - Point-of-care INR testing A summary of advantages, disadvantages and examples of each of these approaches is provided in the Table 1. All approaches used to monitor the effectiveness and safety of warfarin therapy should incorporate clear patient education and a system of data management to record and track all INRs and warfarin doses.
# DRUG INTERACTIONS:
- Most drug interactions with warfarin occur because of concurrent antiplatelet effect or drugs that compete for cytochrome P450, the enzyme system that metabolizes warfarin. - Antiplatelet agents: Most patients who take warfarin should not also use an antiplatelet agent, since the risk of bleeding is more than doubled and many patients do not derive additional protection with the combination. Reasons for use of an antiplatelet agent in patients who also have an indication for anticoagulation include, but are not limited to: patients with acute coronary syndrome and/or those with new coronary artery stents, some patients with high-risk mechanical heart valves, and patients with a proven stroke or transient ischemic attack (TIA) while therapeutically anticoagulated with warfarin. For each patient, the risk-benefit of using warfarin with an antiplatelet agent must be carefully and repeatedly assessed. - Non-steroidal anti-inflammatory drugs (NSAIDs): The risk-benefit assessment also applies to using traditional NSAIDs with warfarin. In addition, many of these NSAIDs are metabolized in the liver by CYP 2C9 which also metabolizes warfarin. For patients who require both anticoagulation and an NSAID, strategies to reduce the risk of gastrointestinal bleeding include a COX2 inhibitor such as celecoxib or a traditional NSAID plus a proton pump inhibitor. - Alterations in concomitant medications and new concurrent illness should result in more frequent INR testing. - Antibiotics typically increase INR through multiple mechanisms.
- For drugs that may affect warfarin metabolism or clearance, the simplest approach is to obtain an INR 3-4 days after the addition of the new drug and then adjust the dose, if necessary. In general, very few drugs will need to be avoided when using this approach. - Acute infections or other changes in health status (e.g. diarrhea, vomiting, heart failure) can also alter warfarin response and should also prompt more frequent INR monitoring. - Alcohol and a number of health supplements (e.g. St. John's Wort) can also change the INR.
# ADVERSE EFFECTS:
- The major adverse effect of warfarin is bleeding. On average, the annual rate of major bleeding is 1-2% in patients on chronic warfarin, while minor bleeding events occur in 10-20% of warfarin users per year. - Other, uncommon, side effects include hair loss and skin rash.
# INITIAL TREATMENT OF ACUTE VTE
Initial treatment of acute VTE with warfarin should be combined with an immediate-acting parenteral anticoagulant such as low molecular weight heparin (LMWH) for at least 5 days and until the INR reaches at least 2.0 for 2 consecutive days. Initial dosing is best guided by using standardized nomograms. Frequent monitoring is required until a stable, in-range INR is reached, after which time reduced frequency of testing is appropriate.
# SPECIAL CONSIDERATIONS:
- The anticoagulant effect of warfarin can be reversed using vitamin K. For emergency reversal, intravenous vitamin K should be administered along with a four-factor prothrombin complex concentrate (Octaplex , Beriplex
# PEDIATRICS:
- Warfarin can be used for the treatment and prevention of thrombosis in children.
- Therapy is complicated by the need for regular blood work, which may be difficult to obtain in small children. Point-of-care devices may be of assistance in this setting. - Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of Version: 07August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide an overview of the mechanism of action, dosing regimens and side-effects of warfarin and other vitamin K antagonists.Warfarin is an indirect anticoagulant producing its effect by decreasing the ability of the liver to produce fully functional coagulation factors II, VII, IX, and X, as well as the endogenous anticoagulants, protein C and protein S. Current Clinical Practice Guidelines generally recommend direct oral anticoagulants (DOACs) over warfarin for most patients with venous thromboembolism (VTE) and atrial fibrillation (AF) as DOACs are as effective and cause similar or less bleeding, but there are still circumstances where warfarin is preferable or indicated. This guide will try to address these issues.# INDICATIONS:
Common uses of warfarin include:
• prevention of stroke or systemic embolism in patients with AF, especially those with rheumatic mitral stenosis • treatment of acute VTE (overlapped with parenteral anticoagulation) • long-term secondary prevention of VTE • prevention of thrombosis or systemic embolization in patients with mechanical heart valves or with certain diseases of the native heart valves Less common uses include:
• management of patients with acute anterior myocardial infarction • prevention of systemic embolization from the heart, e.g. mural thrombus • prevention of recurrent stroke in selected patients without AF • to maintain hemodialysis access and arterial graft patency • prevention of VTE in high risk patients, e.g. hip or knee arthroplasty • prevention of recurrent venous and arterial embolism in those with antiphospholipid antibody syndrome DOSING:
• The maintenance dose of warfarin varies widely among patients, from less than 1 mg/day to greater than 20 mg/day. • In general, warfarin should be started at the dose estimated to be required for long-term therapy. For most adults, a reasonable starting dose is 5 mg daily. In those who are frail, underweight or of Asian descent, starting a lower dose at 1 -2 mg daily may be more suitable.
• Factors affecting the maintenance dose of warfarin include:
• Age • Body weight • Race • Nutritional status, diet
• Genetic variation in the enzyme that is the site of warfarin action (VKOR)
• Genetic variation in the enzyme system that metabolizes warfarin (CYP450)
• Concomitant drugs • Alcohol intake • Comorbidity, e.g. liver disease, heart failure • Activity level MONITORING:
• Routine laboratory monitoring is required for all patients taking warfarin.
• The target INR (international normalizing ratio) for most patients is 2.0-3.0. For most patients with mechanical mitral valves the target INR is 2.5-3.5. • The time it takes for warfarin to produce a change in the INR depends on the time for preexisting vitamin K-dependent clotting factors to be metabolized. Depending on the dose of warfarin and individual factors, the timeframe for this process is approximately 3 to 7 days. Therefore, it is recommended that monitoring be performed no earlier than 2 to 3 days after the first dose and subsequent dose changes. • There are a variety of tools to aid in the management of warfarin therapy, including:
• Computerized monitoring • Paper-based dosing algorithms • Point-of-care INR testing A summary of advantages, disadvantages and examples of each of these approaches is provided in the Table 1. All approaches used to monitor the effectiveness and safety of warfarin therapy should incorporate clear patient education and a system of data management to record and track all INRs and warfarin doses.
# DRUG INTERACTIONS:
• Most drug interactions with warfarin occur because of concurrent antiplatelet effect or drugs that compete for cytochrome P450, the enzyme system that metabolizes warfarin. • Antiplatelet agents: Most patients who take warfarin should not also use an antiplatelet agent, since the risk of bleeding is more than doubled and many patients do not derive additional protection with the combination. Reasons for use of an antiplatelet agent in patients who also have an indication for anticoagulation include, but are not limited to: patients with acute coronary syndrome and/or those with new coronary artery stents, some patients with high-risk mechanical heart valves, and patients with a proven stroke or transient ischemic attack (TIA) while therapeutically anticoagulated with warfarin. For each patient, the risk-benefit of using warfarin with an antiplatelet agent must be carefully and repeatedly assessed. • Non-steroidal anti-inflammatory drugs (NSAIDs): The risk-benefit assessment also applies to using traditional NSAIDs with warfarin. In addition, many of these NSAIDs are metabolized in the liver by CYP 2C9 which also metabolizes warfarin. For patients who require both anticoagulation and an NSAID, strategies to reduce the risk of gastrointestinal bleeding include a COX2 inhibitor such as celecoxib or a traditional NSAID plus a proton pump inhibitor. • Alterations in concomitant medications and new concurrent illness should result in more frequent INR testing. • Antibiotics typically increase INR through multiple mechanisms.
• For drugs that may affect warfarin metabolism or clearance, the simplest approach is to obtain an INR 3-4 days after the addition of the new drug and then adjust the dose, if necessary. In general, very few drugs will need to be avoided when using this approach. • Acute infections or other changes in health status (e.g. diarrhea, vomiting, heart failure) can also alter warfarin response and should also prompt more frequent INR monitoring. • Alcohol and a number of health supplements (e.g. St. John's Wort) can also change the INR.
# ADVERSE EFFECTS:
• The major adverse effect of warfarin is bleeding. On average, the annual rate of major bleeding is 1-2% in patients on chronic warfarin, while minor bleeding events occur in 10-20% of warfarin users per year. • Other, uncommon, side effects include hair loss and skin rash.
# INITIAL TREATMENT OF ACUTE VTE
Initial treatment of acute VTE with warfarin should be combined with an immediate-acting parenteral anticoagulant such as low molecular weight heparin (LMWH) for at least 5 days and until the INR reaches at least 2.0 for 2 consecutive days. Initial dosing is best guided by using standardized nomograms. Frequent monitoring is required until a stable, in-range INR is reached, after which time reduced frequency of testing is appropriate.
# SPECIAL CONSIDERATIONS:
• The anticoagulant effect of warfarin can be reversed using vitamin K. For emergency reversal, intravenous vitamin K should be administered along with a four-factor prothrombin complex concentrate (Octaplex , Beriplex
# PEDIATRICS:
• Warfarin can be used for the treatment and prevention of thrombosis in children.
• Therapy is complicated by the need for regular blood work, which may be difficult to obtain in small children. Point-of-care devices may be of assistance in this setting. • Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
•
# Date of Version: 07August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
f541264c3b4e9218cf9a43de3e70a522f6c95c4e | cma | None | To assist health care professionals in the management of cancer-associated thrombosis (CAT).Low molecular weight heparin (LMWH) has been the treatment of choice in patients with CAT because it offers superior efficacy over warfarin. Other non-anticoagulant effects of LMWH (e.g. antiinflammatory properties) may also make it more effective than warfarin in CAT. The major barriers for LMWH use are drug cost and discomfort of daily injections; however, studies have shown that LMWH is well accepted by patients, while warfarin is associated with a reduced quality of life. LMWH is also recommended over unfractionated heparin (UFH) and fondaparinux. Recently, trials comparing antifactor Xa direct oral anticoagulants (DOACs), including apixaban, edoxaban and rivaroxaban, with LMWH have shown that these agents are reasonable alternatives to LMWH in many cases of CAT. Treatment of thrombosis in patients with primary or metastatic brain lesions, hematological malignancies, and at unusual sites, such as splanchnic vein thrombosis, is not well studied. A thorough review of the relative risks and benefits of available anticoagulant options, in addition to patient preference and values, is prudent prior to prescribing anticoagulant therapy in patients with CAT.#
- Dalteparin 200 U/kg daily for the first month then continue at ~150 U/kg daily. Alternatively, continuing at 200 U/kg for the duration of treatment can also be considered. - Tinzaparin 175 IU/kg daily.
- Enoxaparin 1 mg/kg twice daily.
- The calculated dose should be rounded up to the nearest prefilled syringe available.
- The dose of LMWH in obese patients should not be capped but based on actual body weight. For patients weighing more than the upper limit accommodated by a single pre-filled syringe (i.e., 90 kg for dalteparin, 100 kg for enoxaparin and 103 kg for tinzaparin), twice daily dosing or use of multi-dose vials (available for all 3 LMWHs) is recommended.
- In patients with severe renal insufficiency (creatinine clearance 0.4 IU/mL; however, high quality data showing a correlation between these levels and poor clinical outcomes is lacking. 2. For tinzaparin, available evidence demonstrates no accumulation in patients with CrCl levels down to 20 mL/min. There are limited data available in patients with an estimated CrCl < 20 mL/min. 3. For some patients (for example, those who do not have a high risk of recurrent thrombosis or have an increased risk of bleeding), the dose of LMWH may be empirically reduced if this is consistent with the priorities of care. 4. If none of the above criteria are satisfied, then warfarin can be considered. Consultation with a hematologist or thrombosis expert is recommended. 5. One could consider apixaban, edoxaban or rivaroxaban as per clinical trials below (see product monographs for dosing)
# DIRECT ORAL ANTICOAGULANTS (DOACS):
Edoxaban (HOKUSAI-VTE Cancer), rivaroxaban (SELECT-D), and apixaban (Caravaggio) have all been compared to LMWH for CAT in separate randomized clinical trials. The primary outcome was recurrent VTE in the SELECT-D and Caravaggio trials, whereas the primary outcome was a composite of recurrent VTE or major bleeding in HOKUSAI-VTE cancer. The assigned treatment periods were either 6 months (SELECT-D and Caravaggio) or at least 6 months and up to 12 months (HOKUSAI-VTE Cancer). SELECT-D was designed as a pilot study and included 406 patients while the HOKUSAI-VTE Cancer and Caravaggio studies had over 1000 patients each. No similar such randomized trials assessing the use of dabigatran in CAT that have been published.
# Recurrent VTE:
Generally, the anti-Xa inhibitors were found to have similar to and potentially lower rates of recurrent VTE when compared with LMWH, with rates between 4% -8% with the anti-Xa inhibitors. Hazard ratios (HR) varied from 0.43 to 0.72 with statistical significance being found only with rivaroxaban (3.9% versus 8.9%, HR, 0.43 ).
# Bleeding:
The rates of major bleeding with the anti-Xa inhibitors varied from 4% to 7%. There was more major bleeding with edoxaban as compared with LMWH (HR 1.77), whereas there was no significant difference in major bleeding when rivaroxaban or apixaban were individually compared with LMWH.
In addition, there were more gastrointestinal (GI) bleeds in patients with upper GI cancers in those who were on edoxaban or rivaroxaban, suggesting physicians should be cautious when prescribing these anti-Xa inhibitors in patients with GI malignancies and those at increased risk of GI bleeding. Apixaban had similar rates of GI bleeding compared with LMWH. Risks of intracranial and fatal bleeding were low and similar with the individual anti-Xa inhibitors and LMWH.
The rates of clinically relevant nonmajor bleeding (CRNMB -bleeding that requires medical attention or impairs quality of life) varied from 9% to 15% with the anti-Xa inhibitors. Apixaban and edoxaban had nonsignificantly higher rates of CRNMB compared with LMWH, whereas there was more CRNMB with rivaroxaban compared with LMWH (HR 3.76).
Important study exclusion criteria that may impact bleeding risk included thrombocytopenia (either below 75 x 10 9 /L ) or 50 x 10 9 /L ), concomitant ASA use (above 75 mg daily with rivaroxaban or above 165 mg daily with apixaban), and presence of intracranial malignancy or leukemia (apixaban).
# Other outcomes:
Similar to the trials that compared LMWH with warfarin in CAT, there was no survival benefit seen with the use of any anti-Xa inhibitor compared with LMWH. Event-free survival (absence of recurrent VTE, major bleeding, or death) was found to be higher with apixaban compared to LMWH (73.3% vs 68.6%; HR 1.36). There was no statistical difference in this outcome with edoxaban compared with LMWH, and this outcome was not reported with rivaroxaban.
# Dosing:
Apixaban: Initial LMWH is not required. Dosing is as usual at 10 mg twice daily for 1 week followed by 5 mg twice daily. For further information on dosing and drug interactions, see Clinical Guide: Apixaban (Eliquis®). Dose reduction to 2.5 mg twice daily after initial therapy has not been studied in this population.
Edoxaban: After an initial 5-day treatment with therapeutic LMWH, edoxaban 60 mg once daily is given. The dose is reduced to 30 mg once daily in those who have creatinine clearance between 30 and 50 mL/min, weigh 60 kg or less, or are taking potent P-glycoprotein inhibitors (such as erythromycin, cyclosporine, dronedarone, quinidine, or ketoconazole). For further information on dosing and drug interactions, see Clinical Guide: Edoxaban (Lixiana®).
Rivaroxaban: Initial LMWH is not required. Dosing is as usual at 15 mg twice daily for 3 weeks followed by a daily dose of 20 mg. For further information on dosing and drug interactions, see Clinical Guide: Rivaroxaban (Xarelto®). Dose reduction to 10 mg once daily after initial therapy has not been studied in this patient population.
# DURATION OF THERAPY:
Optimal duration has not been studied. Patients should receive anticoagulation for a minimum of 3 to 6 months. At that time, continued anticoagulation is recommended if the patient: 1) is receiving systemic chemotherapy; 2) has metastatic disease; 3) has progressive or relapsed disease; or 4) has other ongoing risk factors that increase the risk of recurrent thrombosis (e.g. central venous catheter). Thereafter, reassessment should be done every 3 -6 months.
Even after 6 months of treatment, the risk of recurrent thrombosis remains high at ~0.5 -0.7%/month while on LMWH therapy (so the risk is expected to be much higher if no anticoagulation was used).
Bleeding risk also remains increased throughout anticoagulation. These risks must be considered along with patient preference, quality of life, and life expectancy when making a decision about continuation of anticoagulation. Many patients near the end of life may benefit from anticoagulation discontinuation as bleeding risk approaches 10% in this population.
# MONITORING:
Patient weight, CBC, and renal function should be checked at least every 3 months. Drug-drug interactions should be reviewed with any change in medication if patient is receiving a DOAC. Whether drug-drug interactions are clinically significant is difficult to determine in some cases. Drugs that are potent inhibitors or inducers of P-glycoprotein 1 and CYP3A4 pathways can increase or reduce the serum levels of DOACs, respectively, and are absolutely contraindicated when relevant DOACs are used.
Laboratory monitoring with anti-Xa levels is not routinely required for patients receiving LMWH and is not recommended for those prescribed the anti-factor Xa DOACs. Heparin-induced thrombocytopenia is uncommon, occurring in <0.5% of patients who are receiving long-term, full-dose LMWH.
# SPECIAL CONSIDERATIONS:
Injection site hematoma and bruising: Injection site bruising and hematomas can be minimized by applying firm pressure to the injection site for 2-5 minutes after an injection and injecting very slowly.
Applying ice to the injection area before and/or after an injection may also reduce bruising and discomfort. Switching to smaller gauge needles (e.g., 30-gauge insulin syringes) and using multi-dose vials (instead of prefilled syringes) will help to reduce bruising.
Perioperative management: Cancer patients are at higher risk for developing post-operative VTE.
Stopping anticoagulants is unnecessary for procedures associated with a very low risk of bleeding, such as skin biopsy. For major surgery or other procedures associated with an increased bleeding risk, the last injection of therapeutic-dose LMWH should NOT be given within 24 hours of the procedure. Provided that hemostasis is achieved, a prophylactic dose of LMWH can be restarted 12-24 hours after the procedure. If there is no bleeding, then the dose can be escalated towards the therapeutic dose over the next 24-72 hours. For procedures or surgeries associated with a very high risk of bleeding (e.g. transurethral resection of the prostate), it is important to be conservative when reintroducing full-dose anticoagulation to avoid causing serious bleeding that will lead to prolonged withholding of anticoagulation. For perioperative management of DOAC therapy, see the Clinical Guide: NOACs/DOACs -Perioperative Management.
Medication Absorption: A potential benefit of LMWH is parenteral administration. This would be the preferred anticoagulant in those with significant nausea and vomiting as it may affect oral medication absorption. In addition, DOACs should be avoided in those who do not have an intact upper GI tract, as absorption is unpredictable and may be subtherapeutic.
# Recurrent thrombosis despite anticoagulation:
Insertion of a vena cava filter is not recommended for recurrent thrombosis in patients receiving therapeutic anticoagulation, as this has been shown to increase the risk of DVT while offering no reduction in PE or survival benefit. If heparin-induced thrombocytopenia has been excluded and adherence has been confirmed, increasing the dose of LMWH by approximately 25% is suggested by experts. Those who develop recurrence on warfarin or DOAC should switch to LMWH. Consultation with a hematologist or thrombosis expert is recommended for further management guidance.
# Thrombocytopenia:
In patients who develop thrombocytopenia, full-dose anticoagulation can generally be continued unless the platelet count is <50 x 10 9 /L. Data are available to support dose modification for more severe thrombocytopenia for LMWH but not for the DOACs. Half-dose LMWH is recommended for patients with a platelet count between 20 and 50 x 10 9 /L. For patients with a platelet count <20 x10 9 /L, anticoagulants are usually withheld until the platelet count increases.
During the first month of therapy when the risk of recurrent thrombosis is highest, platelet transfusions can be considered to maintain the platelet count above 50 x 10 9 /L to allow full-dose administration of LMWH if the thrombotic load is large or threatens hemodynamics. Consultation with a hematologist or thrombosis expert is recommended.
Active bleeding: Hold anticoagulant therapy until the bleeding source is treated or bleeding stops. If bleeding was not in a critical site or came from a local lesion that has been treated, then anticoagulant therapy can be reintroduced once bleeding stops. Avoid insertion of an IVC filter if bleeding is expected to be transient.
# Catheter-related thrombosis:
Anticoagulant therapy generally involves the same regimen as for lower extremity DVT/PE, and LMWH therapy is preferred. Warfarin is an option for patients who cannot tolerate long-term subcutaneous injections. In a pilot study using rivaroxaban for 12 weeks, there was one case of fatal PE and the risk of clinically relevant bleeding was a higher than anticipated at 12.9%. These results suggest that further studies are required prior to recommending routine use of Incidental thrombosis: Incidental thrombosis is common during imaging of the chest or abdomen to assess for cancer recurrence or response to cancer treatment. Patients may or may not have symptoms consistent with thrombosis.
- Pulmonary embolism: involvement of segmental or more proximal pulmonary arteries warrants anticoagulant therapy with the same treatment regimen as for symptomatic thrombosis. This generally also applies to patients with cancer associated isolated subsegmental PE but there may be exceptions when anticoagulation may not be warranted. A preference to treat most cancer associated isolated subsegmental PE is supported by a meta-analysis showing that patients with cancer and subsegmental PE have a risk of recurrent venous thromboembolism comparable to that of patients with more proximal clots). - Portal or splenic vein thrombosis: Differing from the recommendations in the non-cancer population, anticoagulant therapy for most asymptomatic cancer associated portal or splenic vein thrombosis is suggested. Anticoagulation may not be required when the thrombus is localized or there are signs that it is chronic (e.g. cavernous transformation). Acute symptomatic portal vein thrombosis warrants anticoagulant therapy using a standard treatment regimen.
- Mesenteric, renal, cerebral vein thrombosis: such thrombi warrant anticoagulant therapy with the same treatment regimen as for symptomatic thrombosis given the high risk of end organ damage.
Primary prevention of thrombosis in ambulatory cancer patients: Randomized trials and metaanalyses have shown that LMWH reduces the occurrence of symptomatic venous thromboembolism (VTE) in ambulatory cancer patients; however, this intervention is not routinely used or even recommended because of the cost and inconvenience associated with injections, as well as the difficulty in selecting patients most likely to benefit. A meta-analysis of two studies that utilized the Khorana score to select patients at higher risk of VTE who might benefit from prophylaxis with a DOAC (e.g., rivaroxaban and apixaban) showed that while low dose DOAC therapy reduces the overall risk of VTE, it may also increase the risk of major bleeding. Therefore, clinicians need to assess the risk-benefit ratio of prophylaxis on a case-by-case basis to select patients most likely to benefit from a low dose DOAC; this will depend on calculated VTE risk, whether or not the patient has a high risk lesion for bleeding (e.g., gastrointestinal, genitourinary or gynecologic), cost to the patient (and healthcare system), as well as patient values and preferences.
# Cancer-associated thrombosis in children:
Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism. When this is not possible, a combination of a neonatologist/pediatrician and an adult or pediatric hematologist is recommended.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of Version: 27Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To assist health care professionals in the management of cancer-associated thrombosis (CAT).Low molecular weight heparin (LMWH) has been the treatment of choice in patients with CAT because it offers superior efficacy over warfarin. Other non-anticoagulant effects of LMWH (e.g. antiinflammatory properties) may also make it more effective than warfarin in CAT. The major barriers for LMWH use are drug cost and discomfort of daily injections; however, studies have shown that LMWH is well accepted by patients, while warfarin is associated with a reduced quality of life. LMWH is also recommended over unfractionated heparin (UFH) and fondaparinux. Recently, trials comparing antifactor Xa direct oral anticoagulants (DOACs), including apixaban, edoxaban and rivaroxaban, with LMWH have shown that these agents are reasonable alternatives to LMWH in many cases of CAT. Treatment of thrombosis in patients with primary or metastatic brain lesions, hematological malignancies, and at unusual sites, such as splanchnic vein thrombosis, is not well studied. A thorough review of the relative risks and benefits of available anticoagulant options, in addition to patient preference and values, is prudent prior to prescribing anticoagulant therapy in patients with CAT.#
• Dalteparin 200 U/kg daily for the first month then continue at ~150 U/kg daily. Alternatively, continuing at 200 U/kg for the duration of treatment can also be considered. • Tinzaparin 175 IU/kg daily.
• Enoxaparin 1 mg/kg twice daily.
• The calculated dose should be rounded up to the nearest prefilled syringe available.
• The dose of LMWH in obese patients should not be capped but based on actual body weight. For patients weighing more than the upper limit accommodated by a single pre-filled syringe (i.e., 90 kg for dalteparin, 100 kg for enoxaparin and 103 kg for tinzaparin), twice daily dosing or use of multi-dose vials (available for all 3 LMWHs) is recommended.
• In patients with severe renal insufficiency (creatinine clearance [CrCl] <30 mL/min), LMWH is generally avoided because of its dependence on renal clearance. However, the following options may be considered if appropriate in the specific case: 1. It is possible to use LMWH if anti-Xa level measurement of is available to guide dose adjustment. Some experts suggest that a dose reduction should be considered if the trough anti-Xa level is >0.4 IU/mL; however, high quality data showing a correlation between these levels and poor clinical outcomes is lacking. 2. For tinzaparin, available evidence demonstrates no accumulation in patients with CrCl levels down to 20 mL/min. There are limited data available in patients with an estimated CrCl < 20 mL/min. 3. For some patients (for example, those who do not have a high risk of recurrent thrombosis or have an increased risk of bleeding), the dose of LMWH may be empirically reduced if this is consistent with the priorities of care. 4. If none of the above criteria are satisfied, then warfarin can be considered. Consultation with a hematologist or thrombosis expert is recommended. 5. One could consider apixaban, edoxaban or rivaroxaban as per clinical trials below (see product monographs for dosing)
# DIRECT ORAL ANTICOAGULANTS (DOACS):
Edoxaban (HOKUSAI-VTE Cancer), rivaroxaban (SELECT-D), and apixaban (Caravaggio) have all been compared to LMWH for CAT in separate randomized clinical trials. The primary outcome was recurrent VTE in the SELECT-D and Caravaggio trials, whereas the primary outcome was a composite of recurrent VTE or major bleeding in HOKUSAI-VTE cancer. The assigned treatment periods were either 6 months (SELECT-D and Caravaggio) or at least 6 months and up to 12 months (HOKUSAI-VTE Cancer). SELECT-D was designed as a pilot study and included 406 patients while the HOKUSAI-VTE Cancer and Caravaggio studies had over 1000 patients each. No similar such randomized trials assessing the use of dabigatran in CAT that have been published.
# Recurrent VTE:
Generally, the anti-Xa inhibitors were found to have similar to and potentially lower rates of recurrent VTE when compared with LMWH, with rates between 4% -8% with the anti-Xa inhibitors. Hazard ratios (HR) varied from 0.43 to 0.72 with statistical significance being found only with rivaroxaban (3.9% versus 8.9%, HR, 0.43 [0.19-0.99]).
# Bleeding:
The rates of major bleeding with the anti-Xa inhibitors varied from 4% to 7%. There was more major bleeding with edoxaban as compared with LMWH (HR 1.77), whereas there was no significant difference in major bleeding when rivaroxaban or apixaban were individually compared with LMWH.
In addition, there were more gastrointestinal (GI) bleeds in patients with upper GI cancers in those who were on edoxaban or rivaroxaban, suggesting physicians should be cautious when prescribing these anti-Xa inhibitors in patients with GI malignancies and those at increased risk of GI bleeding. Apixaban had similar rates of GI bleeding compared with LMWH. Risks of intracranial and fatal bleeding were low and similar with the individual anti-Xa inhibitors and LMWH.
The rates of clinically relevant nonmajor bleeding (CRNMB -bleeding that requires medical attention or impairs quality of life) varied from 9% to 15% with the anti-Xa inhibitors. Apixaban and edoxaban had nonsignificantly higher rates of CRNMB compared with LMWH, whereas there was more CRNMB with rivaroxaban compared with LMWH (HR 3.76).
Important study exclusion criteria that may impact bleeding risk included thrombocytopenia (either below 75 x 10 9 /L [apixaban]) or 50 x 10 9 /L [edoxaban]), concomitant ASA use (above 75 mg daily with rivaroxaban or above 165 mg daily with apixaban), and presence of intracranial malignancy or leukemia (apixaban).
# Other outcomes:
Similar to the trials that compared LMWH with warfarin in CAT, there was no survival benefit seen with the use of any anti-Xa inhibitor compared with LMWH. Event-free survival (absence of recurrent VTE, major bleeding, or death) was found to be higher with apixaban compared to LMWH (73.3% vs 68.6%; HR 1.36). There was no statistical difference in this outcome with edoxaban compared with LMWH, and this outcome was not reported with rivaroxaban.
# Dosing:
Apixaban: Initial LMWH is not required. Dosing is as usual at 10 mg twice daily for 1 week followed by 5 mg twice daily. For further information on dosing and drug interactions, see Clinical Guide: Apixaban (Eliquis®). Dose reduction to 2.5 mg twice daily after initial therapy has not been studied in this population.
Edoxaban: After an initial 5-day treatment with therapeutic LMWH, edoxaban 60 mg once daily is given. The dose is reduced to 30 mg once daily in those who have creatinine clearance between 30 and 50 mL/min, weigh 60 kg or less, or are taking potent P-glycoprotein inhibitors (such as erythromycin, cyclosporine, dronedarone, quinidine, or ketoconazole). For further information on dosing and drug interactions, see Clinical Guide: Edoxaban (Lixiana®).
Rivaroxaban: Initial LMWH is not required. Dosing is as usual at 15 mg twice daily for 3 weeks followed by a daily dose of 20 mg. For further information on dosing and drug interactions, see Clinical Guide: Rivaroxaban (Xarelto®). Dose reduction to 10 mg once daily after initial therapy has not been studied in this patient population.
# DURATION OF THERAPY:
Optimal duration has not been studied. Patients should receive anticoagulation for a minimum of 3 to 6 months. At that time, continued anticoagulation is recommended if the patient: 1) is receiving systemic chemotherapy; 2) has metastatic disease; 3) has progressive or relapsed disease; or 4) has other ongoing risk factors that increase the risk of recurrent thrombosis (e.g. central venous catheter). Thereafter, reassessment should be done every 3 -6 months.
Even after 6 months of treatment, the risk of recurrent thrombosis remains high at ~0.5 -0.7%/month while on LMWH therapy (so the risk is expected to be much higher if no anticoagulation was used).
Bleeding risk also remains increased throughout anticoagulation. These risks must be considered along with patient preference, quality of life, and life expectancy when making a decision about continuation of anticoagulation. Many patients near the end of life may benefit from anticoagulation discontinuation as bleeding risk approaches 10% in this population.
# MONITORING:
Patient weight, CBC, and renal function should be checked at least every 3 months. Drug-drug interactions should be reviewed with any change in medication if patient is receiving a DOAC. Whether drug-drug interactions are clinically significant is difficult to determine in some cases. Drugs that are potent inhibitors or inducers of P-glycoprotein 1 and CYP3A4 pathways can increase or reduce the serum levels of DOACs, respectively, and are absolutely contraindicated when relevant DOACs are used.
Laboratory monitoring with anti-Xa levels is not routinely required for patients receiving LMWH and is not recommended for those prescribed the anti-factor Xa DOACs. Heparin-induced thrombocytopenia is uncommon, occurring in <0.5% of patients who are receiving long-term, full-dose LMWH.
# SPECIAL CONSIDERATIONS:
Injection site hematoma and bruising: Injection site bruising and hematomas can be minimized by applying firm pressure to the injection site for 2-5 minutes after an injection and injecting very slowly.
Applying ice to the injection area before and/or after an injection may also reduce bruising and discomfort. Switching to smaller gauge needles (e.g., 30-gauge insulin syringes) and using multi-dose vials (instead of prefilled syringes) will help to reduce bruising.
Perioperative management: Cancer patients are at higher risk for developing post-operative VTE.
Stopping anticoagulants is unnecessary for procedures associated with a very low risk of bleeding, such as skin biopsy. For major surgery or other procedures associated with an increased bleeding risk, the last injection of therapeutic-dose LMWH should NOT be given within 24 hours of the procedure. Provided that hemostasis is achieved, a prophylactic dose of LMWH can be restarted 12-24 hours after the procedure. If there is no bleeding, then the dose can be escalated towards the therapeutic dose over the next 24-72 hours. For procedures or surgeries associated with a very high risk of bleeding (e.g. transurethral resection of the prostate), it is important to be conservative when reintroducing full-dose anticoagulation to avoid causing serious bleeding that will lead to prolonged withholding of anticoagulation. For perioperative management of DOAC therapy, see the Clinical Guide: NOACs/DOACs -Perioperative Management.
Medication Absorption: A potential benefit of LMWH is parenteral administration. This would be the preferred anticoagulant in those with significant nausea and vomiting as it may affect oral medication absorption. In addition, DOACs should be avoided in those who do not have an intact upper GI tract, as absorption is unpredictable and may be subtherapeutic.
# Recurrent thrombosis despite anticoagulation:
Insertion of a vena cava filter is not recommended for recurrent thrombosis in patients receiving therapeutic anticoagulation, as this has been shown to increase the risk of DVT while offering no reduction in PE or survival benefit. If heparin-induced thrombocytopenia has been excluded and adherence has been confirmed, increasing the dose of LMWH by approximately 25% is suggested by experts. Those who develop recurrence on warfarin or DOAC should switch to LMWH. Consultation with a hematologist or thrombosis expert is recommended for further management guidance.
# Thrombocytopenia:
In patients who develop thrombocytopenia, full-dose anticoagulation can generally be continued unless the platelet count is <50 x 10 9 /L. Data are available to support dose modification for more severe thrombocytopenia for LMWH but not for the DOACs. Half-dose LMWH is recommended for patients with a platelet count between 20 and 50 x 10 9 /L. For patients with a platelet count <20 x10 9 /L, anticoagulants are usually withheld until the platelet count increases.
During the first month of therapy when the risk of recurrent thrombosis is highest, platelet transfusions can be considered to maintain the platelet count above 50 x 10 9 /L to allow full-dose administration of LMWH if the thrombotic load is large or threatens hemodynamics. Consultation with a hematologist or thrombosis expert is recommended.
Active bleeding: Hold anticoagulant therapy until the bleeding source is treated or bleeding stops. If bleeding was not in a critical site or came from a local lesion that has been treated, then anticoagulant therapy can be reintroduced once bleeding stops. Avoid insertion of an IVC filter if bleeding is expected to be transient.
# Catheter-related thrombosis:
Anticoagulant therapy generally involves the same regimen as for lower extremity DVT/PE, and LMWH therapy is preferred. Warfarin is an option for patients who cannot tolerate long-term subcutaneous injections. In a pilot study using rivaroxaban for 12 weeks, there was one case of fatal PE and the risk of clinically relevant bleeding was a higher than anticipated at 12.9%. These results suggest that further studies are required prior to recommending routine use of Incidental thrombosis: Incidental thrombosis is common during imaging of the chest or abdomen to assess for cancer recurrence or response to cancer treatment. Patients may or may not have symptoms consistent with thrombosis.
• Pulmonary embolism: involvement of segmental or more proximal pulmonary arteries warrants anticoagulant therapy with the same treatment regimen as for symptomatic thrombosis. This generally also applies to patients with cancer associated isolated subsegmental PE but there may be exceptions when anticoagulation may not be warranted. A preference to treat most cancer associated isolated subsegmental PE is supported by a meta-analysis showing that patients with cancer and subsegmental PE have a risk of recurrent venous thromboembolism comparable to that of patients with more proximal clots). • Portal or splenic vein thrombosis: Differing from the recommendations in the non-cancer population, anticoagulant therapy for most asymptomatic cancer associated portal or splenic vein thrombosis is suggested. Anticoagulation may not be required when the thrombus is localized or there are signs that it is chronic (e.g. cavernous transformation). Acute symptomatic portal vein thrombosis warrants anticoagulant therapy using a standard treatment regimen.
• Mesenteric, renal, cerebral vein thrombosis: such thrombi warrant anticoagulant therapy with the same treatment regimen as for symptomatic thrombosis given the high risk of end organ damage.
Primary prevention of thrombosis in ambulatory cancer patients: Randomized trials and metaanalyses have shown that LMWH reduces the occurrence of symptomatic venous thromboembolism (VTE) in ambulatory cancer patients; however, this intervention is not routinely used or even recommended because of the cost and inconvenience associated with injections, as well as the difficulty in selecting patients most likely to benefit. A meta-analysis of two studies that utilized the Khorana score to select patients at higher risk of VTE who might benefit from prophylaxis with a DOAC (e.g., rivaroxaban and apixaban) showed that while low dose DOAC therapy reduces the overall risk of VTE, it may also increase the risk of major bleeding. Therefore, clinicians need to assess the risk-benefit ratio of prophylaxis on a case-by-case basis to select patients most likely to benefit from a low dose DOAC; this will depend on calculated VTE risk, whether or not the patient has a high risk lesion for bleeding (e.g., gastrointestinal, genitourinary or gynecologic), cost to the patient (and healthcare system), as well as patient values and preferences.
# Cancer-associated thrombosis in children:
Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism. When this is not possible, a combination of a neonatologist/pediatrician and an adult or pediatric hematologist is recommended.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of Version: 27Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
0c936e44ec098d4aadc62048f7396306542f04e2 | cma | None | This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to www.cfp.ca and click on the Mainpro+ link. La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro d'octobre 2020 à la page e264. We encourage readers to share some of their practice experience: the neat little tricks that solve difficult clinical situations. Praxis articles can be submitted online at or through the CFP website (www.cfp.ca) under "Authors and Reviewers.#
T ype 2 diabetes is one of the most common chronic conditions managed in primary care. But how primary care teams provide care and support to people with diabetes needs to change because of new risks posed by the coronavirus disease 2019 (COVID-19) pandemic.
Before the COVID-19 pandemic, usual practice was to see patients with diabetes in the office every 3 to 6 months to review bloodwork results, conduct a focused physical examination, and provide treatment and self-management advice. Primary care clinicians supported patients to reduce their risk of diabetes-related complications through glycemic and blood pressure control, lipid management, smoking cessation, diet, exercise, and timely screening for renal, foot, and retinopathy complications-evidence-based interventions recommended by the Diabetes Canada clinical practice guidelines. 1 But the benefits of an in-person visit now need to be balanced with the risk of patients acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when traveling to and attending a clinic visit. This risk is particularly relevant given that some studies suggest people with diabetes have a higher risk of COVID-19-related complications and death. 2 Primary care clinicians need a new approach to delivering diabetes care-one that continues to support evidence-based interventions but does so in a way that balances the risks and benefits of in-person and virtual visits. To address this need, we have developed virtual-first recommendations to support family physicians and other primary care professionals in managing their patients with type 2 diabetes during COVID-19 (page 1 appears in Figure 1; the full tool is available from CFPlus or ).- This guidance was developed by a group of practising family physicians and endocrinologists in collaboration with the Centre for Effective Practice, using the 2018 clinical practice guidelines from Diabetes Canada as a foundation. We used and cited available evidence when possible, but given the circumstances felt compelled to provide consensus-based recommendations when evidence was lacking. We suggest continuing to use the ABCDESSS (hemoglobin A 1c , blood pressure control, cholesterol, drugs, exercise and eating, self-management , screening, and stop smoking) framework to guide visits and have added 2 additional S's-safety and shots (details on safety are presented on page 3 of the tool). We summarize the common aspects of diabetes care that should remain the same, those that should be changed, and those that can be deferred during the COVID-19 pandemic.
# Most care can be delivered virtually
In a virtual-first approach to diabetes care during COVID-19, virtual assessments (by telephone or video) should be done every 3 to 6 months and can address most aspects of care. More frequent virtual touchpoints might be needed for complex issues or if guiding the patient through change. In-person visits should still occur at least annually. In-person assessments should be more frequent if a patient's risk factor control is suboptimal or his or her capacity to engage in virtual care is limited.
# Support self-assessment
Where feasible, patients should be encouraged to assess their blood pressure, weight, and feet at home. Supporting patient self-assessment makes virtual visits more effective and in-person visits more efficient and thereby safer. Hypertension Canada provides a list of reputable home blood pressure monitors (/ bpdevices) and offers practical advice for patients on how to take their blood pressure at home (https:// hypertension.ca/hypertension-and-you/managinghypertension/measuring-blood-pressure). Blood pressure targets need to be adjusted for home monitoring (eg, an office target of < 130/80 mm Hg means a home target of < 125/75 mm Hg). 3 Patients, together with a caregiver, can perform foot screening for neuropathy using the Touch the Toes Test, a method promoted by Diabetes UK (/ complications/feet/touch-the-toes). 4 Additionally, clinicians can assess feet visually using video or photos and provide virtual counseling on foot care.
# Some investigations can be deferred
Some investigations can be deferred during the COVID-19 pandemic based on individual patient characteristics and risk. For example, patients can have their cholesterol levels checked every 3 years rather than annually if they are taking a stable statin dose with low-density lipoprotein levels at target and have good medication adherence. 5 If the last hemoglobin A 1c level measured within 3 months was less than 8%, testing can likely be extended to a 6-to 9-month interval, with PRAXIS self-monitoring of blood glucose used as a proxy in the interim. Retinopathy screening can be done at a 3-year interval for those with no previous eye disease and a hemoglobin A 1c level of less than 8%. 6 Cardiac screening for asymptomatic individuals using electrocardiography can be deferred. Whenever possible, laboratory tests should be clustered to avoid repeat in-person visits.
# In-person care should be focused and efficient
In-person care should focus on blood pressure measurement (and home machine calibration), foot assessment, immunizations, and review of a blood glucose log if relevant. Even with in-person visits, relevant information can be collected virtually before the appointment to minimize the time in clinic. For example, an electronic survey can be completed by patients and automatically populated into their electronic medical records (https:// ocean.cognisantmd.com/questionnaires/preview/ QuestionnairePreview.html?ref=diabetes is an example).
# Self-management is more important than ever
Supporting self-management has always been a core tenet of good diabetes care and is even more critical during the COVID-19 pandemic. Patients can be referred to a free virtual diabetes educator through Diabetes Canada by calling 800 BANTING (800 226-8464). Providers can gauge medication adherence by asking, "How many doses have you missed in the past week?" Assessing adherence is particularly important because of a potential decrease in the frequency of "objective" measurement (eg, hemoglobin A 1c level, blood pressure, cholesterol level).
Digital health apps can be helpful for some patients, although most apps in Canada focus on glycemic control alone and require paid upgrades for data sharing with a primary care provider. Many glucometers have specific apps; other popular apps to support glycemic control include Health2Sync and mySugr. Additionally, popular exercise tracking apps (eg, MyFitnessPal) might support patients to maintain a healthy lifestyle during the pandemic.
Finally, it is important to recognize that people with diabetes might be experiencing increased socioeconomic challenges and worsening mental health and addictions because of COVID-19. We encourage proactive screening and referral to relevant supports. For example, Wellness Together Canada () is a relatively new national hub providing free mental health and addiction support to patients. The recently developed COVID-19 Social Care Guidance tool 7 provides tips on screening for social issues and practical resources to help patients.
# Conclusion
The COVID-19 pandemic has forced primary care teams to consider a new normal in health care delivery, including chronic disease management for conditions such as type 2 diabetes. Our consensus-based guidance document provides practical recommendations for primary care professionals to help them reduce the risk to patients of acquiring COVID-19 while providing evidence-based care to prevent complications from diabetes.
# Competing interests
Dr Bajaj has received honoraria and research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. Dr Kim has received grant support, honoraria, or consulting fees from Abbott, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, and Sanofi. Dr Ivers is a member of the advisory board of Novo Nordisk, has done evaluation consulting for the Centre for Effective Practice and Merck, and is Past Co-Chair of the Diabetes Canada Guideline Dissemination and Implementation Committee. | This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to www.cfp.ca and click on the Mainpro+ link. La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro d'octobre 2020 à la page e264. We encourage readers to share some of their practice experience: the neat little tricks that solve difficult clinical situations. Praxis articles can be submitted online at http://mc.manuscriptcentral.com/cfp or through the CFP website (www.cfp.ca) under "Authors and Reviewers.#
T ype 2 diabetes is one of the most common chronic conditions managed in primary care. But how primary care teams provide care and support to people with diabetes needs to change because of new risks posed by the coronavirus disease 2019 (COVID-19) pandemic.
Before the COVID-19 pandemic, usual practice was to see patients with diabetes in the office every 3 to 6 months to review bloodwork results, conduct a focused physical examination, and provide treatment and self-management advice. Primary care clinicians supported patients to reduce their risk of diabetes-related complications through glycemic and blood pressure control, lipid management, smoking cessation, diet, exercise, and timely screening for renal, foot, and retinopathy complications-evidence-based interventions recommended by the Diabetes Canada clinical practice guidelines. 1 But the benefits of an in-person visit now need to be balanced with the risk of patients acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when traveling to and attending a clinic visit. This risk is particularly relevant given that some studies suggest people with diabetes have a higher risk of COVID-19-related complications and death. 2 Primary care clinicians need a new approach to delivering diabetes care-one that continues to support evidence-based interventions but does so in a way that balances the risks and benefits of in-person and virtual visits. To address this need, we have developed virtual-first recommendations to support family physicians and other primary care professionals in managing their patients with type 2 diabetes during COVID-19 (page 1 appears in Figure 1; the full tool is available from CFPlus or https://cep.health/tool/download/109).* This guidance was developed by a group of practising family physicians and endocrinologists in collaboration with the Centre for Effective Practice, using the 2018 clinical practice guidelines from Diabetes Canada as a foundation. We used and cited available evidence when possible, but given the circumstances felt compelled to provide consensus-based recommendations when evidence was lacking. We suggest continuing to use the ABCDESSS (hemoglobin A 1c , blood pressure control, cholesterol, drugs, exercise and eating, self-management , screening, and stop smoking) framework to guide visits and have added 2 additional S's-safety and shots (details on safety are presented on page 3 of the tool). We summarize the common aspects of diabetes care that should remain the same, those that should be changed, and those that can be deferred during the COVID-19 pandemic.
# Most care can be delivered virtually
In a virtual-first approach to diabetes care during COVID-19, virtual assessments (by telephone or video) should be done every 3 to 6 months and can address most aspects of care. More frequent virtual touchpoints might be needed for complex issues or if guiding the patient through change. In-person visits should still occur at least annually. In-person assessments should be more frequent if a patient's risk factor control is suboptimal or his or her capacity to engage in virtual care is limited.
# Support self-assessment
Where feasible, patients should be encouraged to assess their blood pressure, weight, and feet at home. Supporting patient self-assessment makes virtual visits more effective and in-person visits more efficient and thereby safer. Hypertension Canada provides a list of reputable home blood pressure monitors (https://hypertension.ca/ bpdevices) and offers practical advice for patients on how to take their blood pressure at home (https:// hypertension.ca/hypertension-and-you/managinghypertension/measuring-blood-pressure). Blood pressure targets need to be adjusted for home monitoring (eg, an office target of < 130/80 mm Hg means a home target of < 125/75 mm Hg). 3 Patients, together with a caregiver, can perform foot screening for neuropathy using the Touch the Toes Test, a method promoted by Diabetes UK (https://www.diabetes.org.uk/guide-to-diabetes/ complications/feet/touch-the-toes). 4 Additionally, clinicians can assess feet visually using video or photos and provide virtual counseling on foot care.
# Some investigations can be deferred
Some investigations can be deferred during the COVID-19 pandemic based on individual patient characteristics and risk. For example, patients can have their cholesterol levels checked every 3 years rather than annually if they are taking a stable statin dose with low-density lipoprotein levels at target and have good medication adherence. 5 If the last hemoglobin A 1c level measured within 3 months was less than 8%, testing can likely be extended to a 6-to 9-month interval, with PRAXIS self-monitoring of blood glucose used as a proxy in the interim. Retinopathy screening can be done at a 3-year interval for those with no previous eye disease and a hemoglobin A 1c level of less than 8%. 6 Cardiac screening for asymptomatic individuals using electrocardiography can be deferred. Whenever possible, laboratory tests should be clustered to avoid repeat in-person visits.
# In-person care should be focused and efficient
In-person care should focus on blood pressure measurement (and home machine calibration), foot assessment, immunizations, and review of a blood glucose log if relevant. Even with in-person visits, relevant information can be collected virtually before the appointment to minimize the time in clinic. For example, an electronic survey can be completed by patients and automatically populated into their electronic medical records (https:// ocean.cognisantmd.com/questionnaires/preview/ QuestionnairePreview.html?ref=diabetes is an example).
# Self-management is more important than ever
Supporting self-management has always been a core tenet of good diabetes care and is even more critical during the COVID-19 pandemic. Patients can be referred to a free virtual diabetes educator through Diabetes Canada by calling 800 BANTING (800 226-8464). Providers can gauge medication adherence by asking, "How many doses have you missed in the past week?" Assessing adherence is particularly important because of a potential decrease in the frequency of "objective" measurement (eg, hemoglobin A 1c level, blood pressure, cholesterol level).
Digital health apps can be helpful for some patients, although most apps in Canada focus on glycemic control alone and require paid upgrades for data sharing with a primary care provider. Many glucometers have specific apps; other popular apps to support glycemic control include Health2Sync and mySugr. Additionally, popular exercise tracking apps (eg, MyFitnessPal) might support patients to maintain a healthy lifestyle during the pandemic.
Finally, it is important to recognize that people with diabetes might be experiencing increased socioeconomic challenges and worsening mental health and addictions because of COVID-19. We encourage proactive screening and referral to relevant supports. For example, Wellness Together Canada (https://ca.portal.gs) is a relatively new national hub providing free mental health and addiction support to patients. The recently developed COVID-19 Social Care Guidance tool 7 provides tips on screening for social issues and practical resources to help patients.
# Conclusion
The COVID-19 pandemic has forced primary care teams to consider a new normal in health care delivery, including chronic disease management for conditions such as type 2 diabetes. Our consensus-based guidance document provides practical recommendations for primary care professionals to help them reduce the risk to patients of acquiring COVID-19 while providing evidence-based care to prevent complications from diabetes.
# Competing interests
Dr Bajaj has received honoraria and research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. Dr Kim has received grant support, honoraria, or consulting fees from Abbott, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, and Sanofi. Dr Ivers is a member of the advisory board of Novo Nordisk, has done evaluation consulting for the Centre for Effective Practice and Merck, and is Past Co-Chair of the Diabetes Canada Guideline Dissemination and Implementation Committee. | None | None |
5e7971c6b66f025a5afd3703b7e136aaae0a1a12 | cma | None | High-risk based on: 1) potential for serious consequences from COVID-19, influenza, and pneumococcal disease, and 2) potential for clinical deterioration of underlying chronic condition due to the direct or indirect consequences of the COVID-19 pandemic.# BC Care Bundle for Supporting High-Risk- Patients During COVID-19 Pandemic and Influenza Season ENHANCE IMMUNIZATION
Assess influenza and pneumococcal immunization status of high-risk patients 2 and ensure immunizations are up to date. Where possible, provide/recommend immunizations to occur at the time of an existing medical visit or health care encounter 3 . Discuss the importance of ensuring close contacts are also immunized.
# CONFIRM ACTION PLAN
With the patient and care provider, review self-preparedness 6 and action plan for intercurrent illness and potential for underlying disease decompensation, including: adequate food & medication supply, social supports/buddy system, disease-specific triggers, symptoms, escalation pathways, and appropriate emergency contacts (i.e., conditionspecific clinic, emergency room).
# EMOTIONAL WELL-BEING?
Isolation, economic hardship, and disruptions of daily routine can have an impact on psychological and emotional well-being 12 . Consider a discussion with patient and caregiver regarding coping mechanisms and review access to additional support services.
# IDENTIFY PATIENTS
Review current patient roster and identify patients deemed to be high risk 1 for complications from COVID-19, influenza, and pneumococcal disease.
# REVIEW GOALS OF CARE
Review goals of care and advanced care directives with patient and family. Where relevant, identify alternate decision-makers. Ensure patients have access to palliative care supports as required 5 .
# REVIEW MEDICATIONS
With the patient and caregiver, discuss current medications (especially those associated with respiratory illness) and review current supply levels, individual sick-day rules 10 , and the benefits of medication adherence 11 .
# PREPARE FOR INFLUENZA
Monitor local influenza rates 4 . Consider antiviral prescription (e.g. oseltamvir) within 12 hours of onset of symptoms if clinically indicated based on local influenza rates and clinically-compatible symptoms or severity.
# FLU/COVID-19 SYMPTOMS?
Determine need for in-person assessment and care management plan based on underlying condition and as clinically appropriate. Consider initiating influenza antiviral 7 and send for COVID-19 testing 8 . If COVID-19 positive, suggest stopping antiviral in accordance with current BC-CDC guidance 9 .
# DISCUSS DIET & EXERCISE
Diet and physical activity can be impacted by pandemic restrictions and/or intercurrent illness 13 . Patients may find value in discussions regarding self-management approaches for diet and exercise.
# Context
Chronic diseases may increase a person's risk of infection or increase a person's risk of more severe disease should infection occur. Individuals with chronic disease are at higher risk of COVID-19, influenza, invasive pneumococcal disease (IPD), and related complications. Influenza and COVID-19 can present with similar symptoms, and can mimic many other illnesses such as the common cold or exacerbation of underlying respiratory conditions. To protect this high risk patient population and to conserve health system capacity during the COVID-19 pandemic, maximizing immunization uptake and optimizing management of patients with chronic conditions need to be an integral component of current care planning.
# References and Resources | High-risk based on: 1) potential for serious consequences from COVID-19, influenza, and pneumococcal disease, and 2) potential for clinical deterioration of underlying chronic condition due to the direct or indirect consequences of the COVID-19 pandemic.# BC Care Bundle for Supporting High-Risk* Patients During COVID-19 Pandemic and Influenza Season ENHANCE IMMUNIZATION
Assess influenza and pneumococcal immunization status of high-risk patients 2 and ensure immunizations are up to date. Where possible, provide/recommend immunizations to occur at the time of an existing medical visit or health care encounter 3 . Discuss the importance of ensuring close contacts are also immunized.
# CONFIRM ACTION PLAN
With the patient and care provider, review self-preparedness 6 and action plan for intercurrent illness and potential for underlying disease decompensation, including: adequate food & medication supply, social supports/buddy system, disease-specific triggers, symptoms, escalation pathways, and appropriate emergency contacts (i.e., conditionspecific clinic, emergency room).
# EMOTIONAL WELL-BEING?
Isolation, economic hardship, and disruptions of daily routine can have an impact on psychological and emotional well-being 12 . Consider a discussion with patient and caregiver regarding coping mechanisms and review access to additional support services.
# IDENTIFY PATIENTS
Review current patient roster and identify patients deemed to be high risk 1 for complications from COVID-19, influenza, and pneumococcal disease.
# REVIEW GOALS OF CARE
Review goals of care and advanced care directives with patient and family. Where relevant, identify alternate decision-makers. Ensure patients have access to palliative care supports as required 5 .
# REVIEW MEDICATIONS
With the patient and caregiver, discuss current medications (especially those associated with respiratory illness) and review current supply levels, individual sick-day rules 10 , and the benefits of medication adherence 11 .
# PREPARE FOR INFLUENZA
Monitor local influenza rates 4 . Consider antiviral prescription (e.g. oseltamvir) within 12 hours of onset of symptoms if clinically indicated based on local influenza rates and clinically-compatible symptoms or severity.
# FLU/COVID-19 SYMPTOMS?
Determine need for in-person assessment and care management plan based on underlying condition and as clinically appropriate. Consider initiating influenza antiviral 7 and send for COVID-19 testing 8 . If COVID-19 positive, suggest stopping antiviral in accordance with current BC-CDC guidance 9 .
# DISCUSS DIET & EXERCISE
Diet and physical activity can be impacted by pandemic restrictions and/or intercurrent illness 13 . Patients may find value in discussions regarding self-management approaches for diet and exercise.
# Context
Chronic diseases may increase a person's risk of infection or increase a person's risk of more severe disease should infection occur. Individuals with chronic disease are at higher risk of COVID-19, influenza, invasive pneumococcal disease (IPD), and related complications. Influenza and COVID-19 can present with similar symptoms, and can mimic many other illnesses such as the common cold or exacerbation of underlying respiratory conditions. To protect this high risk patient population and to conserve health system capacity during the COVID-19 pandemic, maximizing immunization uptake and optimizing management of patients with chronic conditions need to be an integral component of current care planning.
# References and Resources
# Acknowledgements:
This document was developed with input and guidance from: Provincial Health Services Authority Clinical Policy, Planning, and Partnerships portfolio, medical leadership of BC chronic disease groups, and a Primary Care Working Group through the BC Ministry of Health.
# High Risk Population
People who are at high risk for severe illness from COVID- | None | None |
4fb0f44d720ce06fd3783eadf7ddf1722d700dfa | cma | None | The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy contin-Le panel principal responsable des lignes directrices 2021 a s electionn e des el ements cliniquement pertinents et a soumis des recommandations actualis ees, bas ees sur de nouvelles d ecouvertes d'importance apparues depuis les lignes directrices de 2016. Ainsi, le traitement par statine reste recommand e pour les patients atteints d'ath eroscl erose clinique, d'an evrisme de l'aorte abdominale, pour la#
ues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents. For all other patients, we emphasize risk assessment linked to lipid/lipoprotein evaluation to optimize clinical decision-making. Lipoprotein(a) measurement is now recommended once in a patient's lifetime, as part of initial lipid screening to assess cardiovascular risk. For any patient with triglycerides ˃ 1.5 mmol/L, either non-high-density lipoprotein cholesterol or apolipoprotein B are the preferred lipid parameter for screening, rather than low-density lipoprotein cholesterol. We provide updated recommendations regarding the role of coronary artery calcium scoring as a clinical decision tool to aid the decision to initiate statin therapy. There are new recommendations on the preventative care of women with hypertensive disorders of pregnancy. Health behaviour modification, including regular exercise and a heart-healthy diet, remain the cornerstone of cardiovascular disease prevention. These guidelines are intended to provide a platform for meaningful conversation and shared-decision making between patient and care provider, so that individual decisions can be made for risk screening, assessment, and treatment. plupart des patients diab etiques ou atteints d'insuffisance r enale chronique, et chez ceux dont le cholest erol a lipoprot eines de basse densit e est ≥ 5 mmol/l. Nous avons introduit la notion de seuils pour le traitement des lipides/lipoprot eines afin d'intensifier le traitement hypolipid emiant avec des agents non-statiniques, et nous avons identifi e les patients en pr evention secondaire distingu es comme ayant tirer le plus grand b en efice de l'intensification du traitement avec ces agents. Pour tous les autres patients, nous mettons l'accent sur l'appr eciation du risque par le biais de l' evaluation des lipides/lipoprot eines afin d'optimiser la prise de d ecision clinique. Le dosage de la lipoprot eine (a) est maintenant recommand e une fois dans la vie d'un patient, dans le cadre du d epistage initial des lipides pour evaluer le risque cardiovasculaire. Pour tout patient pr esentant des taux de triglyc erides ˃ 1,5 mmol/l, l'apolipoprot eine B ou le cholest erol li e aux lipoprot eines autres que celles de haute densit e sont les indices lipidiques a privil egier pour le d epistage, plutôt que le cholest erol a lipoprot eines de basse densit e. Nous proposons des recommandations actualis ees concernant le rôle du score calcique des art eres coronaires en tant qu'outil de d ecision clinique pour aider a la d ecision d'administrer un traitement par statine. Il existe de nouvelles recommandations concernant les soins pr eventifs des femmes souffrant de troubles hypertensifs de la grossesse. Le changement de comportement en mati ere de sant e, incluant l'exercice physique r egulier et une alimentation saine pour le coeur, reste la pierre angulaire de la pr evention des maladies cardiovasculaires. Ces lignes directrices visent a fournir une plateforme pour une discussion constructive et une prise de d ecision partag ee entre le patient et le prestataire de soins, afin que des d ecisions individuelles puissentêtre prises pour le d epistage, l' evaluation et le traitement des risques.
The 2021 Canadian Cardiovascular Society (CCS) dyslipidemia guidelines have been updated to reflect new clinical trial and epidemiologic evidence published since the previous guidelines in 2016. 1 The primary panel posed a number of population, intervention, comparator, and outcomes (PICO) questions to develop recommendations and inform clinical practice on the basis of a detailed literature review. The PICO format is a common standard used for guidelines development, to aid clinicians in determining whether the recommendations apply to their own patients with outcomes relevant to their practice. Initially, 13 different PICO questions were posed and then rated on the basis of the availability and significance of new evidence and importance to be included in the updated guidelines. The primary panel members voted on the initial 13 PICO questions formulated (see Supplemental Appendix S1 Supplemental Appendix S1, S2, S3 etc. Please check throughout.?>), resulting in the identification of 6 key PICO questions, which are included in this update. Using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards, individual studies and composite literature were reviewed for each PICO question with regard to the quality of the available evidence and the presence of publication or interpretive bias. We have included the updated recommendations within this update, and the results of voting on each recommendation are shown in Supplemental Appendix S2. For recommendations to go forward a two-thirds voting majority was required. Individuals with conflicts of interest were recused from voting on relevant recommendations.
We have introduced the concept of "treatment thresholds" for intensifying lipid-lowering therapy with nonstatin lipid-lowering agents on the basis of new evidence with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and icosapent ethyl (IPE). Because of the increased focus on apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (HDL-C) in this update, values for ApoB and non-HDL-C have been modified (from previous versions of these guidelines) to accurately represent the same percentile equivalents as low-density lipoprotein (LDL) cholesterol (LDL-C) for all recommended thresholds (see Supplemental Appendix S3). The goal of the process was to produce an objective, nonbiased document on the basis of the best available evidence to allow clinicians and patients to make collaborative treatment decisions. These guidelines are not absolute, but are to be used in the context of oneon-one discussion between practitioner and patient and consideration of the patient's values and preferences. Dyslipidemia is an important risk factor for atherosclerotic cardiovascular (CV) disease (ASCVD), and these guidelines inform risk assessment, treatment, and surveillance options for at-risk populations. These guidelines were undertaken under the auspices of the Guideline Committee of the CCS without any support or involvement from outside groups, including industry.
# Definitions
ASCVD refers to all clinical conditions of atherosclerotic origin, including acute coronary syndrome (ACS), myocardial infarction (MI), stable or unstable angina, coronary artery disease documented using angiography, coronary or other arterial revascularization (coronary artery bypass graft surgery, femoral popliteal bypass graft surgery, etc), stroke, transient ischemic attack, documented carotid disease, peripheral artery disease, and abdominal aortic aneurysm.
Statin-indicated condition refers to any condition for which pharmacotherapy with statins is indicated, and consists of all documented ASCVD conditions, as well as other highrisk primary prevention conditions in the absence of ASCVD, such as most patients with diabetes, those with chronic kidney disease (CKD), and those with an LDL-C ≥ 5.0 mmol/L or a diagnosis of familial hypercholesterolemia (FH). This concept was first introduced in the 2016 guidelines and continues to be used in this update.
Primary prevention refers to all efforts aimed at either populations or individuals to prevent or delay the onset of ASCVD.
Secondary prevention refers to the efforts to treat known, clinically significant ASCVD, and to prevent or delay the onset of disease manifestations.
# Overview of the Management of Dyslipidemia in Primary Prevention
# Screening
We determined that there was insufficient new evidence to recommend major changes to the approach of risk assessment in primary prevention. We continue to recommend lipid/lipoprotein screening (in either fasting or nonfasting state) for men and women older than 40 years of age or at any age with one of the specific conditions listed in Table 1. The nonfasting state is recommended (except for individuals with known triglycerides > 4.5 mmol/L) because it leads to minimal changes in relevant lipid levels and has no effect on apolipoprotein levels compared with the fasting state. 1 Table 2 provides a summary of the recommendations for how to screen patients. We maintain the recommendation for regular CV risk assessments using a validated risk model in Canada (either the Framingham Risk Score or the Cardiovascular Life Expectancy Model ) every 5 years for men and women aged 40-75 years to guide preventive care through shared decision-making with the patient. Among individuals 30-59 years of age without diabetes, the presence of a history of premature CV disease (CVD) in a firstdegree relative (ie, 55 years or younger in male relatives and 65 years or younger in female relatives) increases an individual's calculated FRS percent risk by approximately twofold. 1
# Health behaviour interventions
Health behaviour modifications remain the cornerstone of chronic disease prevention, including CVD. Data from the INTERHEART study indicate that, in addition to the traditional risk factors (abnormal lipid levels, hypertension, smoking, and diabetes), abdominal obesity, dietary patterns, alcohol consumption, physical inactivity, and psychosocial factors are modifiable risk factors for MI worldwide in both sexes and at all ages. 2 Evidence from other large prospective cohort studies have also shown that combining low-risk health behaviours that include achieving and maintaining a healthy body weight, consuming a healthy diet, engaging in regular physical activity, smoking cessation, limiting alcohol consumption to no more than moderate, and ensuring a sufficient duration of sleep are associated with benefit for the primary prevention of CVD. 3,4 We continue to recommend a Mediterranean dietary pattern, which has evidence of CV outcome benefit in systematic reviews and meta-analyses. Additionally, other dietary patterns that share important features such as the Portfolio dietary pattern, 5 Dietary Approaches to Stop Hypertension (DASH) dietary pattern, 6 low-glycemic index/glycemic load dietary pattern, 7 and plantbased dietary pattern, 8 as well as dietary patterns high in nuts, 9,10 legumes, 10 olive oil, 9 fruits and vegetables, 11 total fibre, 12 and whole grains. 13 Dietary therapy using these means can be considered to augment drug therapy with statins; however, their benefits have been shown in terms of surrogate CV measures such as blood pressure and lipoproteins.
We also continue to recommend that all adults should accumulate at least 150 minutes of moderate to vigorous aerobic activity per week. It might also be beneficial to add muscle-and bone-strengthening activities at least 2 days per week. Regular exercise has beneficial effects on diabetes risk, hypertension, and hypertriglyceridemia, and improves plasma levels of HDL-C. 14 A summary table of the expected CV outcomes and/or lipid benefits from various health behaviour changes is presented in Supplemental Appendix S4.
# Pharmacologic treatment
Studies consistently show a 20%-22% relative risk reduction for each 1 mmol/L reduction in LDL-C. 15 The absolute risk reduction is thus dependent on the baseline risk and the baseline LDL-C, because statin treatment will provide a greater absolute LDL-C lowering in those with higher baseline values. Therefore, we continue to recommend initiation of statin therapy for: (1) all high-risk patients (≥ 20% 10-year risk); or (2) intermediaterisk patients (10%-19.9%) when LDL-C is ≥ 3.5 mmol/L (or ApoB ≥ 1.05 g/L or non-HDL-C ≥ 4.2 mmol/L). In addition, among intermediate-risk individuals with several additional risk factors as evaluated in Heart Outcomes Prevention Evaluation (HOPE) 3 16 (men 50 years of age or older or women 60 years of age or older with 1 additional risk factor including low HDL-C, impaired fasting glucose, increased waist circumference, cigarette smoking, hypertension) the evidence remains in favour of statin initiation to reduce the risk of CV events. The presence of other risk modifiers in intermediate-risk individuals also favours the use of statins (eg, high-sensitivity C-reactive protein ≥ 2.0 mmol/L, family history of premature coronary artery disease, high lipoprotein(a) ≥ 50 mg/dL or coronary artery calcium score > 0 Agatston units ).
For most low-risk subjects (FRS 0 AU) because the proportional benefit from statin therapy will be similar to that in other treatment groups. Treatment of this group would follow the intermediate risk approach. The treatment approach recommended for primary prevention patients is outlined in Figure 1. Finally, evidence continues to show the benefits of maintaining low levels of atherogenic lipoproteins throughout life and at any age and any level of risk. Even among primary prevention individuals at low 10-year risk, the benefit of lipid-lowering can be substantial, especially when LDL-C ≥ 3.5 mmol/L. 17 In addition, accumulating evidence suggests continued benefits of lipid-lowering for primary prevention in older adults (older than 75 years). 18
# Other statin-indicated conditions
We continue to recommend statin initiation for the following high-risk conditions (ie, "statin-indicated" conditions, even in the absence of a previous CV event: (1) CKD (except for patients receiving chronic dialysis) defined as patients with an estimated glomerular filtration rate 3.0 cm or previous aortic aneurysm surgery. 1 Established ASCVD is also a statinindicated condition, which is discussed in more detail later in these guidelines. The treatment approach for patients with a statin-indicated condition is summarized in Figure 2.
All of the recommendations from the previous dyslipidemia guidelines that remain unchanged are provided in Supplemental Appendix S5.
# New areas of focus
The review of literature and evidence assessment identified several areas for new and/or updated recommendations for primary prevention, specifically in: (1) the preventive care of women with hypertensive disorders of pregnancy; (2) the importance of lipoprotein measurement including non-HDL-C, ApoB, and Lp(a) in assessing CV risk; (3) the role of CAC as a clinical decision-making tool for determining the need to initiate statin treatment; (4) the CV benefit of IPE in patients with triglycerides ≥ 1.5-5.6 mmol/L and a previous CV event or with diabetes and additional risk factors; and (5) the lack of CV benefit of omega-3 fatty acids from dietary sources or other formulations/supplements.
# Overview of the Management of Dyslipidemia in Secondary Prevention
# Health behaviour interventions
We continue to recommend health behaviour interventions to optimize CV health in all patients with a previous ASCVD event (refer to the Health behaviour interventions in the section on Overview of the Management of Dyslipidemia in Primary Prevention). In secondary prevention, limiting sedentary behaviour can be additive to regular physical activity with respect to the reduction of ASCVD events. A certified exercise physiologist might be of value to provide advice and followup. Cardiac rehabilitation has been clearly shown to be of benefit in this patient population and remains a cornerstone of management. 19 Relevant recommendations from the previous dyslipidemia guidelines that remain unchanged are provided in Supplemental Appendix S5.
# New areas of focus
Several areas were reviewed by our group that directly affect the care and management of patients with previous ASCVD events and have led to new or updated recommendations, specifically: (1) the role of nonstatin therapies to reduce ASCVD events; (2) the most appropriate lipid/lipoprotein threshold for the intensification of therapy in the management of dyslipidemia; and (3) the lack of CV benefit of omega-3 fatty acids from dietary sources or other formulations/supplements. Treatment approach for primary prevention patients (without a statin-indicated condition*). Statin-indicated conditions consist of all documented ASCVD conditions, as well as other high-risk primary prevention conditions in the absence of ASCVD, such as most patients with diabetes, those with chronic kidney disease, and those with an LDL-C ≥ 5.0 mmol/L. Screening should be repeated every 5 years for men and women aged 40-75 years using the modified FRS or Cardiovascular Life Expectancy Model (CLEM) to guide therapy to reduce major CV events. A risk assessment might also be completed whenever a patient's expected risk status changes. ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; AU, Agatston units; BAS, bile acid sequestrant; CAC, coronary artery calcium; CAD, coronary artery disease; CV, cardiovascular; FHx, family history; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; HTN, hypertension; FRS, Framingham Risk Score; IFG, impaired fasting glucose; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); mins, minutes; Rx, treatment; yrs, years. - Calculate risk using the FRS-refer to the iCCS available on the App Store or on Google Play. PICO Questions, Evidence Review, and New Recommendations PICO 1: Do pregnancy-related conditions (hypertensive disorders of pregnancy and other related complications) identify women at increased risk of premature CVD warranting lipid screening?
Pregnancy complications such as preeclampsia and related hypertensive disorders of pregnancy, gestational diabetes, placental abruption, preterm delivery, stillbirth, and delivery of a low birth weight infant are associated with a higher lifetime risk of developing CV risk factors (hypertension; type 2 diabetes mellitus; dyslipidemia, especially hypertriglyceridemia and low HDL-C; metabolic syndrome; and subclinical atherosclerosis) and overt ASCVD. 20,21 The strongest and most abundant evidence linking pregnancy events and ASCVD is for preeclampsia, in which there is a twofold relative risk of developing premenopausal ASCVD, with onset at 10-15 years after delivery 20 compared with women who had uncomplicated pregnancies. This risk is highest if preeclampsia is recurrent (ie, 28% lifetime risk of ASCVD, or within 25 years after delivery 22 ), or if associated with preterm delivery (before 37 weeks' gestation) and other adverse conditions (chest pain, dyspnea, low platelet count, elevated liver enzymes, intrauterine growth restriction) or severe complications (eclampsia, stroke, myocardial ischemia, hepatic rupture, acute kidney injury with need for hemodialysis). 23 ASCVD risk is partly mediated by the development of chronic hypertension and metabolic syndrome. 24 There is often silent and subclinical endothelial dysfunction after hypertensive disorders of pregnancy suggesting accelerated vascular aging. 25,26 National CV societies, 1,27 including the CCS, 1 have recommended performing lipid and metabolic screening in postpartum women who have had these complications, although whether specific thresholds warranting pharmacotherapy differ from those typically used in the general population is not known. Although it is true that these women have a low absolute risk of ASCVD over the short term, the postpartum period might represent "a teachable moment" to engage young women in CV prevention and might result in long-term benefits through health behaviour interventions with or without pharmacological intervention. Treatment decisions should be guided on the basis of lifetime risk in conjunction with patient values and preferences. 28
# RECOMMENDATION
- Among women who have had a pregnancy complication such as hypertensive disorders of pregnancy, gestational diabetes, preterm birth, stillbirth, low birth weight infant, or placental abruption, we recommend screening with a complete lipid panel in the late postpartum period, because these women have a higher risk of premature CVD and stroke with onset 10-15 years after index delivery (Strong Recommendation; Moderate-Quality Evidence). 2. We recommend counselling women who have any of these pregnancy-related complications of the increased lifetime risk of ASCVD, and reinforcing the importance of healthy behaviours (ie, maintaining a healthy body weight, 150 weekly minutes of moderate intensity aerobic physical activity, avoiding tobacco consumption, no more than moderate alcohol consumption, stress management, and adopting a healthy dietary pattern, such as the Mediterranean diet (Strong Recommendation; Low-Quality Evidence). 3. To assist with decisions about lipid-lowering pharmacotherapy in this patient population, we recommend favouring CV age, over 10-year risk calculators (Strong Recommendation; Low-Quality Evidence).
Values and preferences. Although much of this observed risk among women who have had a pregnancyrelated complication might be due to conventional ASCVD risk factors, complications such as preeclampsia might lead to ASCVD through accelerated vascular aging or other pathways warranting additional future research.
There is insufficient evidence to guide decisions about use of lipid-lowering therapy in women on the basis of pregnancy factors alone. The American Heart Association 2019 CV prevention guidelines 27 consider preeclampsia a risk enhancer warranting early screening, healthy behaviour interventions, and possibly shifting of risk category from borderline to intermediate risk (ie, eligible for statin or other lipid-lowering therapy).
We suggest individual discussions about statin or other lipid-lowering pharmacotherapy, considering each patient's lifetime risk/individual risk factors along with severity and recurrence of pregnancy complications (in particular preterm preeclampsia with adverse conditions), balanced against the potential side effects and harms of long-term therapy. Although statins were previously considered teratogenic on the basis of earlier animal studies, this has not been consistently shown in recent human studies. 29,30 A part of the observed increase in risk of congenital malformations might be due to underlying medical conditions rather than treatment with statin therapy itself. 29 Furthermore, there appears to be a differential effect on the basis of the type of compound, with most cases of congenital malformations being seen among infants whose mothers took lipophilic compounds (eg, atorvastatin, lovastatin, simvastatin) as opposed to hydrophilic compounds (eg, pravastatin, rosuvastatin). 31,32 Therefore, in women who are reproductive age and who are eligible and considering statin therapy for ASCVD risk reduction on the basis of CV age or lifetime risk of ASCVD, we suggest the use of hydrophilic compounds over lipophilic compounds because of easier passage through the placenta with the latter molecules. It should be noted that for most reproductive women who take statin therapy for primary prevention of ASCVD, an effective birth control method is recommended with interruption of therapy before a planned pregnancy or at the time of an unplanned positive pregnancy test. These treatments can be resumed after delivery, when breastfeeding is completed. Referral to a specialist in obstetrical medicine or in fetal-maternal medicine should also be considered in the management of statin and nonstatin therapies in pregnant women or in women planning pregnancy.
PICO 2a: Is there evidence to promote non-HDL-C over ApoB or ApoB over non-HDL-C for screening and treatment purposes? Previous versions of these guidelines have used LDL-C as the primary laboratory measurement for considering initiation of statin treatment and as a treatment target in low-, intermediate-, and high-risk individuals. Beginning with the 2012 guidelines, it has been recommended that non-HDL-C and ApoB could be used as alternate targets to LDL-C in any individual with triglyceride level > 1.5 mmol/L. 1,33 The rationale for this is that above this level of triglyceride, some cholesterol in LDL particles is replaced by triglyceride, which promotes production of more atherogenic small dense LDL particles, 34 and makes the amount of cholesterol in LDL-C an unreliable reflection of LDL particle number. 35 In addition, other particles, such as remnants of chylomicrons and very LDL-C, as well as Lp(a), all accumulate in the artery wall and contribute to atherogenesis, whereas HDL-C does not. Therefore, estimation of the concentration of all atherogenic particles requires a broader focus than a measurement of LDL-C. Non-HDL-C (indirectly) and ApoB (directly) provide a more accurate assessment of the total concentration of atherogenic particles than LDL-C. Non-HDL-C and ApoB are, for this reason, both better predictors of CV event risk and benefit of lipid-lowering therapy compared with LDL-C. 36,37 On the basis of these previous recommendations, non-HDL-C is now routinely reported across Canada at no additional cost, on the basis of the simple calculation of total cholesterol minus HDL-C. ApoB is also available as an insured laboratory test in all provinces except Ontario. Levels of non-HDL-C and ApoB are not significantly changed in the postprandial state in individuals with triglycerides < 4.5 mmol/L, whereas LDL-C can be lowered by up to 10% because of triglyceride enrichment of LDL-C. 38,39 After the guideline recommendation that was introduced in 2016 allowing for nonfasting collections for screening and follow-up lipid testing, 1 it is now generally preferable to follow non-HDL-C or ApoB levels over LDL-C when interpreting lipid results, particularly when triglyceride levels are ≥ 1.5 mmol/L. A recent survey conducted by the Canadian Association of Medical Biochemists and the Canadian Society of Clinical Chemistry indicates that patients across Canada can now present to laboratories nonfasting and receive a complete lipid profile.
# Non-HDL-C or ApoB for predicting CVD risk
In population studies, non-HDL-C and ApoB can be considered as equivalent markers of total atherogenic lipoproteins and lipid-related CV risk and this applies to most individuals. 40 Publications since the 2016 update of these guidelines indicate a subgroup of individuals, estimated at between 8% and 23%, have discordance between ApoB and non-HDL-C levels in whom ApoB might be the better predictor of risk for coronary calcification 40 and ASCVD events. 41 Analysis of CV events in the large United Kingdom Biobank, 41 and metaanalysis of 110 prospective cohort registries of patients with or at risk for ASCVD, 42 however, showed an overall similar ability of non-HDL-C and ApoB to predict risk, but confirmed both of these measures to be superior to LDL-C. Recent consensus statements have concluded that non-HDL-C is currently a more practical choice because it incurs no additional expense to the patient or health care system. 43,44 In Canada, the approach has been to allow clinicians to use either non-HDL-C or ApoB as their preferred parameter for assessment of risk and achievement of treatment targets, depending on their comfort level with the two measurements, availability of ApoB testing in their region, and when there might be a concern about discordance between the two measurements, as indicated previously. In the current guidelines, we are continuing this recommendation, while strongly urging the routine use of either non-HDL-C or ApoB instead of LDL-C as the lipid level of interest in initial lipid screening and as a treatment target in all patients with triglyceride level > 1.5 mmol/L. RECOMMENDATION 4. We recommend that for any patient with triglycerides > 1.5 mmol/L, non-HDL-C or ApoB be used instead of LDL-C as the preferred lipid parameter for screening (Strong Recommendation, High-Quality Evidence).
PICO 2b: Is there evidence to support measurement of Lp (a) to improve risk stratification and dyslipidemia management in patients with and without previous CV events?
Lp(a) is an LDL-like particle in which ApoB is covalently bound to a plasminogen-like molecule called apolipoprotein (a). 45 Plasma concentrations of Lp(a) are not influenced by age, sex, fasting state, inflammation, or lifestyle factors, but are largely controlled by a single gene locus, LPA on chromosome 6, and are highly (> 90%) heritable. 46 Individual values are generally stable throughout life, thus, repeat measures are not required for risk assessment.
Mendelian randomization studies have clearly shown that genetic variants in the LPA locus uniquely regulating Lp(a) levels are robustly associated with coronary heart disease risk, thereby strongly suggesting a causal association between Lp(a) and CVD. 47,48 The risk of ASCVD increases with increasing Lp(a) levels > 30 mg/dL in a dose-dependent fashion. Among 7524 subjects in the Copenhagen Heart Study followed for 17 years, subjects with an Lp(a) concentration between 30 and 76 mg/dL had a 1.7-fold hazard ratio (HR) for MI and those with an Lp(a) level > 117 mg/dL had an adjusted HR of 2.7. 48 Among 6086 patients with a first MI and 6857 control participants from the INTERHEART study who were stratified according to ethnicity and adjusted for age and sex, Lp(a) concentrations > 50 mg/dL were associated with an increased risk of MI (odds ratio, 1.48; 95% confidence interval , 1.43-1.67), independent of established CVD risk factors including diabetes mellitus, smoking, and high blood pressure. 51 Higher Lp(a) concentrations carried a particularly high population burden in South Asian and Latin American individuals. 51 An Lp(a) level > 50 mg/dL (> 100 nmol/L) is found in approximately 20% of individuals of European and South Asian descent, 40% of African American individuals, and fewer than 10% of East Asian individuals. 51,52 Individuals with extreme elevations in Lp(a) have been shown to be at markedly high risk, with an event rate similar to that for other genetic dyslipidemias for which family screening is recommended (ie, heterozygous FH). As such, Lp(a) is a common but as yet not routinely measured ASCVD risk marker.
Elevated Lp(a) level also increases the risk of recurrent ASCVD in a dose-dependent manner. 50,53 Among 58,527 subjects from the Copenhagen General Population Study, 2527 subjects aged 20-79 years with a history of ASCVD and elevated Lp(a) were followed over a median of 5 years. 54 The adjusted major adverse CV events (MACE) incidence rate ratios were 1.28 (95% CI, 1.03-1.58) for subjects with an Lp(a) level of 10-49 mg/dL (18-104 nmol/L), 1.44 (95% CI, 1.12-1.85) for 50-99 mg/dL (105-213 nmol/L), and 2.14 (95% CI, 1.57-2.92) for those with Lp(a) ≥ 100 mg/dL (≥ 214 nmol/L). 54 In the randomized, controlled Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOUR-IER) and Study to Evaluate the Effect of Alirocumab on the Occurrence of Cardiovascular Events in Patients Who Have Experienced an Acute Coronary Syndrome (ODYS-SEY OUTCOMES) trials, high levels of Lp(a) were associated with an increased risk of recurrent CVD events in patients with established CVD irrespective of LDL cholesterol. 53,54 Furthermore, alirocumab-associated reductions in Lp(a) reduced MACE in patients with a recent ACS independent of LDL-C. 54 Although these new data support the potential role of Lp (a) as a target of treatment in the future, there remains no evidence from RCTs that specifically lowering Lp(a) level leads to reductions in CV outcomes. It should also be noted that commonly used lipid-lowering therapies (ie, statins and ezetimibe) do not appreciably lower Lp(a) levels. The only available lipid-lowering therapies that lead to substantial lowering of Lp(a) include PCSK9 inhibitors, niacin, and apheresis, but relatively limited evidence exists for their use in patients with a high Lp(a) level. Newer investigational agents, such as antisense oligonucleotides and small interfering RNAs are currently being evaluated for CVD risk reduction in this patient population. Accordingly, Lp(a) is not currently considered a treatment target and repeat measures are therefore not indicated.
Lp(a) testing is available across Canada, and is currently an insured laboratory test in most provinces, with the exception of Ontario and Manitoba. Values and preferences. There is a large body of evidence supporting the potential causal association between Lp(a) and future ASCVD. 50,51, The high prevalence of elevated Lp(a) level, the strength of association with incident and recurrent ASCVD events, and the potential to improve CV risk stratification, strongly justify universal screening to identify individuals with very high levels. Identification of high levels of Lp(a) is a useful consideration for shared decision-making in subjects across all ASCVD risk categories, but especially in younger patients, particularly those who have a very strong family history of premature ASCVD. Although further evidence that directly lowering Lp(a) level reduces ASCVD risk is pending, the finding of high Lp(a) should alert primary care practitioners to more actively pursue an overall ASCVD event risk assessment, including careful discussion of current health behaviours, consideration of age-appropriate vascular imaging studies for detecting early evidence of subclinical atherosclerosis in select individuals (eg, CAC score), and earlier introduction of statin or other lipid-lowering therapy, especially in intermediate-risk individuals and/or low-risk individuals with moderate elevations of LDL-C between 3.5 and 5 mmol/L.
In the setting of secondary prevention, the presence of a high Lp(a) level is strongly predictive of recurrent events, and suggests the need for intensification of LDL-lowering therapy, including use of PCSK9 inhibitors. Furthermore, preliminary evidence suggests that treatment with PCSK9 inhibitors post ACS in patients with high Lp(a) reduces MACE independent of LDL-C lowering. 54 When clinicians are uncertain of the implications of elevated Lp(a), consultation with a lipid specialist might be considered. For primary prevention, most guidelines are on the basis of the concept of ASCVD risk assessment to help determine appropriateness and intensity of ASCVD risk factor modification. The primary prevention RCTs on which the recommendations are based, however, use clinical descriptors to identify patients eligible for study and, as a result, the patients eligible for the proven therapy. None of the algorithms available, including the FRS used in Canada, have been used to determine eligibility for any of the successful, primary prevention lipid-lowering trials. Even so, there is evidence to suggest that use of such algorithms is effective on a population level, more so than identification of patients on the basis of trial eligibility criteria. 59,60 Despite this clinical utility, it has been repeatedly shown that typical ASCVD event risk algorithms can lead to substantial over-or underestimation of ASCVD event risk, 61 and consequently, inappropriate risk factor management. Additionally, the value of these algorithms for predicting the presence and burden of atheroma is poor. 62,63 Atheroma burden, the substrate that portends CV events, directly predicts ASCVD event risk in a graded fashion. This has been shown over decades with invasive angiography and more recently with coronary computed tomography, including noncontrast CAC scoring, the latter being highly applicable for assessment of patients who are asymptomatic, and possible candidates for primary prevention. 64,65 Accordingly, the literature is replete with clinical studies reinforcing the concept that directly assessing the presence of atheroma, through CAC scoring, significantly improves the appropriate selection of patients who are likely to benefit from lipid modifying therapy. 66 Noncontrast CAC measurements are sensitive, reproducible, and can be performed rapidly with an average radiation dose of 0.89 mSv (compared with background annual radiation exposure of approximately 3.0 mSv). Evidence for improved C-statistic/net reclassification index after adjustment for standard risk factors (FRS) has been shown in multiple studies. 67,69 The clinical decision-making utility of CAC measurements is best shown in middle-aged, intermediaterisk populations in whom the presence or absence of coronary artery calcification results in reclassification into higher or lower risk populations. A CAC measurement > 0 AU confirms the presence of atherosclerotic plaque. Increasing scores are directly proportional to increased ASCVD event risk. A CAC measurement > 100 AU is associated with a high risk (> 2% annual risk) of an ASCVD event within 2-5 years and is generally an indication for intensive CV risk factor modification, including treatment of LDL-C. CAC > 300 AU places the patient in a very high risk category with a 10-year risk of MI/CV death of approximately 28%. 73 A CAC measurement of 0 AU, however, has a very high negative predictive value for ASCVD events in asymptomatic, low-risk adults within 2-5 years (negative predictive value, 95%-99%). 74 Importantly, although a CAC of 0 AU is indicative of a low event rate (1.5% per 10 years; 0.32-0.43 per 1000 person-years; 1.3-5.6 per 11.1 years), 70, it is not indicative of a 0 event rate. This is likely because noncalcified soft plaque might be present; not all ASCVD events are mediated by vascular atheroma and atheromas might also progress in an unpredictable fashion. The variability in the development of clinical ASCVD with a CAC score of 0 AU is particularly evident in persons younger than 50 years of age, those with a strong family history of premature CVD events, or in the setting of severe CVD risk factors such as smoking, diabetes, poorly controlled hypertension, and in those with lifelong, genetic dyslipidemias (FH or elevated Lp). These are patient categories that in general would warrant aggressive ASCVD risk factor modification, even if CAC = 0 AU, to enhance the likelihood of maintaining as low an atheroma burden as possible over a lifetime. Conversely, if such high-risk patients do have CAC > 0 AU, this might provide a strong rationale for adherence to aggressive CVD risk factor modification, 82,83 including lipidlowering therapy or treatment intensification. 84,85 The effects of statins on the progression of atherosclerosis cannot be assessed through serial CAC scores alone because it does not assess the status of noncalcific plaque. Therapy does not reduce and might even increase CAC scores despite regression of noncalcific plaque components. 86 Accordingly, repeat CAC scanning is not recommended unless risk factor modification has been deferred through patient-physician shared decisionmaking.
Although CAC provides direct evidence of atherosclerotic plaque and a quantitative assessment of risk of attendant ASCVD events, controversy exists because of a paucity of large placebo-controlled RCTs and its cost-effectiveness for identification of patients suitable for statin therapy is uncertain, 87 even when applied only to the intermediate-risk group identified using risk algorithms. Importantly, at present, CAC scoring is not uniformly available or uniformly funded in Canada, and there are no cost-effectiveness analyses that represent the Canadian context. Values and preferences. Patients with modifiable ASCVD risk factors should be counselled with respect to the potential merit of preventing atherosclerosis itself, the substrate for clinical ASCVD events in the long term, through comprehensive ASCVD risk factor management. As outlined elsewhere, RCTs show the ASCVD risk reduction value of statin therapy in patients with intermediate risk and additional ASCVD risk factors (eg, HOPE 3, 16 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin 88 ) in the absence of CAC testing or any testing to identify preclinical atherosclerosis. Accordingly, the patient-physician decision often does not require CAC scoring but might be strongly influenced by these other factors, including family history of premature ASCVD, other features suggesting genetic causes of dyslipidemia, or side effects of statin therapy. In some low-to intermediate-risk subjects, it might be reasonable to withhold statin therapy for CAC = 0 AU because of a favourable intermediateterm outcome. Exceptions would include cigarette smokers, patients with diabetes, those with poorly controlled hypertension, genetic dyslipidemias such as FH or elevated Lp(a) level, and patients with strong family history of premature ASCVD events. If available, a CAC > 100 AU is an indication for statin therapy regardless of FRS. For those with a CAC of 1-99 AU, individual decision-making is required because risk will not be reclassified and would remain intermediate. If a decision is made to withhold statin or lipid-modifying therapy on the basis of CAC = 0, this decision should be reevaluated during follow-up or if clinical circumstances change. CAC scoring should rarely be performed sooner than within 5 years to aid in this reevaluation. Finally, this section is restricted to application in patients who are at least 40 years of age for whom the traditional FRS assessment applies. Prevalence of calcification is a sequential aspect of the atherosclerotic process and might be absent in the early phases. Although CAC has been studied extensively for ASCVD risk prediction, the prevalence of CAC is lower in young patients compared with middle-aged and older patients and also in women vs men younger than 50 years of age. The totality of evidence from observational, pathophysiological, epidemiological, and Mendelian randomization studies and RCTs of lipid-lowering therapies indicate a causal relationship between LDL-C (as well as non-HDL-C and ApoB) and ASCVD and show that lower concentrations of plasma LDL-C levels are associated with a lower risk of ASCVD events extending to very low LDL-C concentrations (< 0.5 mmol/L). 15, In RCTs, however, the absolute benefits of therapy were higher in subsets of patients with higher pretreatment LDL-C and/or additional ASCVD event risk enhancers who were at higher absolute risk.
To date, no clear target to which LDL-C or non HDL-C or ApoB levels should be lowered is clearly identified in RCTs, because such trials have generally used thresholds of LDL-C (or non-HDL-C or ApoB) levels for initiation or intensification of lipid-lowering therapies and fixed-dose lipid-lowering drugs (this pertains to statin RCTs and to RCTs that have used the additional use of nonstatin lipid-lowering agents, such as ezetimibe and PCSK9 inhibitors). Exceptions are the Scandinavian Simvastatin Survival Study (4S) trial in which the statin dose was up-or down-titrated aiming for within-trial total cholesterol levels of 3.0-5.2 mmol/L, 97 the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), which allowed for uptitration of simvastatin to 80 mg daily for in-trial LDL-C levels > 2.0 mmol/L, 98 and the ODYSSEY OUTCOMES trial in patients with a recent ACS, which allowed up-and downtitration of alirocumab aiming for an LDL-C target of 0.65-1.3 mmol/L; however, in these trials no randomized comparison with alternate lipid targets was performed. 90 Additionally, a number of trials comparing different intensities of statin treatment (lower vs higher statin dose) in secondary ASCVD prevention showed benefits for more intensive statin therapy; however, these trials did not explore targets of LDL-C lowering. 99,100 One RCT conducted in patients with a recent ischemic stroke showed reductions in major ASCVD events in patients allocated to a strategy of lower LDL-C (< 1.8 mmol/ L) vs higher targets (2.3-2.8 mmol/L). 101 Nevertheless, the lower LDL-C target in this trial is similar to the threshold for intensification of lipid-lowering therapy used in other recent trials and recommended in this guideline document. 89,102 A number of studies have shown improved ASCVD outcomes in secondary prevention patients reaching lower in-trial LDL-C levels, but these trials are observational and did not test targets of therapy. 103,104 Therefore, we recommend the use of thresholds for intensification of lipid therapy in secondary prevention. Most recent large RCTs have used an LDL-C threshold of 1.8 mmol/L for intensification of lipid-lowering therapy with nonstatin drugs in secondary ASCVD prevention patients receiving a maximally tolerated statin dose. Using this threshold, it is expected that most patients will achieve low and very low LDL-C levels, similar to those reached in clinical trials. 90,91 The IMPROVE-IT trial showed benefit of ezetimibe when used in addition to statin therapy in patients with a recent ACS. 98 The threshold for the additional use of ezetimibe was an LDL-C of 1.3 mmol/L, although in IMPROVE-IT most patients had a higher baseline LDL-C (average 2.45 mmol/L), statin therapy was restricted to only simvastatin (more potent statins were not used) and the modest 6% relative risk reduction was attained only after a long period of treatment (median 6 years). Therefore, we recommend the more robust LDL-C threshold of ≥ 1.8 mmol/L (or percentile equivalent non-HDL-C of ≥ 2.4 mmol/L or ApoB of ≥ 0.7 g/L).
Recent analyses of the large PCSK9 inhibitor trials (FOURIER 89 and ODYSSEY OUTCOMES 90 ) have identified subsets of patients with established CVD who are at very high risk and who derived the largest absolute benefit for intensification of lipid-lowering therapy with evolocumab and alirocumab, respectively. This includes patients with recent ACS and those with ASCVD and additional CV risk enhancers including diabetes mellitus, metabolic syndrome, polyvascular disease (vascular disease in ≥ 2 arterial beds), symptomatic peripheral artery disease, history of MI, MI in the past 2 years, previous coronary artery bypass graft surgery, LDL ≥ 2.6 mmol/L, heterozygous FH and Lp(a) ≥ 60 mg/dL. 90, Intensification of lipid-lowering therapy with PCSK9 inhibitors is especially recommended in these subsets of very high risk patients (see Table 3), with or without the additional use of ezetimibe, which was used in only a small number of patients in these trials. Use of PCSK9 inhibitor therapy in these subsets of patients was shown to result in rapid and large reductions in LDL-C and in significant CVD event reduction. In most other secondary prevention patients, the use of ezetimibe followed by PCSK9 inhibitor therapy is recommended when the LDL-C ≥ 1.8 mmol/L.
The previous 2016 CCS dyslipidemia guidelines did not emphasize the role of plasma triglyceride levels as a threshold or target for lipid-lowering therapy aimed at reducing CVD risk. 1 However, the recent Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed a CV risk reduction (including reduction in CV death) in patients with ASCVD (as well as in those 50 years old or older with type 2 diabetes requiring medication treatment and at least 1 additional CVD risk factor) receiving moderate and high-intensity statin therapy with triglyceride levels of 1.5-5.6 mmol/L and LDL-C levels of 1.1-2.6 mmol/L. 114
# RECOMMENDATION
- We recommend use of high-intensity statin therapy in addition to appropriate health behaviour modifications for all secondary prevention CVD patients. For patients who do not tolerate a high-intensity statins, we recommend the maximally tolerated statin dose (Strong Recommendation; High-Quality Evidence).
- We recommend intensification of lipid-lowering therapy with a PCSK9 inhibitor (evolocumab or alirocumab)-with or without the additional use of ezetimibe-for secondary CV prevention patients shown to derive the largest benefit from PCSK9 inhibitor therapy in whom LDL-C remains ≥ 1.8 mmol/L (or non-HDL-C ≥ 2.4 mmol/L or ApoB ≥ 0.7 g/L) while receiving the maximally tolerated statin dose (Fig. 3; Strong Recommendation; Moderate-Quality Evidence). Secondary prevention patients shown to derive the largest benefit from intensification of statin therapy with PCSK9 inhibitor therapy are defined in Table 3.
- We recommend intensification of lipid-lowering therapy with ezetimibe and/or PCSK9 inhibitor therapy for all secondary prevention CVD patients in whom LDL-C remains ≥ 1. It should be noted that one recommendation on the basis of the evidence review of PICO question 4 were overlapping with a recommendation for PICO question 5 and appear as part of that later section (Recommendation 15).
Values and preferences. On the basis of strong evidence for the benefit of intensive LDL-C lowering in secondary prevention, additional lipid-lowering therapy with ezetimibe and PCSK9 inhibitors might also be considered for ASCVD patients with an LDL-C < 1.8 mmol/L, especially for patients considered to be at high risk for recurrent ASCVD events. When initiating intensified lipidlowering therapy with nonstatin drugs, cost, and access to such therapies should be considered.
There is no evidence to suggest any CV or other risks associated with low and very low LDL-C levels in trials with moderate duration of follow-up. 104,115,116 Therefore, if intensified lipid-lowering therapy initiated for the previously listed thresholds result in low and very low LDL-C levels, lipid-lowering therapy does generally not require down-titration dose adjustment.
Practical tip. Although there is very good evidence supporting the use of PCSK9 inhibitors in patients with ASCVD (especially those listed in Table 3), access might be limited by provincial drug plan coverage in many jurisdictions. Patients with or without private drug plan coverage might need to pay some portion of the cost of these expensive medications. Patient support programs for these medications could be investigated to assist. Clinicians should discuss the indication and potential benefits of a PCSK9 inhibitor with the patient, along with the coverage issues and the potential costs to them. Shared decisionmaking remains key. Ezetimibe. Ezetimibe is a cholesterol absorption inhibitor that lowers LDL-C by approximately 20% in addition to a statin regimen or up to 15% as monotherapy. Only in 1 double-blind, RCT has the efficacy of ezetimibe been assessed in reducing CV risk. The IMPROVE-IT showed that ezetimibe 10 mg daily, compared with placebo and used in addition to statin therapy, showed a modest reduction in CV events in 18,144 patients with an ACS within the preceding 10 days. 98 The primary composite outcome of death from CV causes, major coronary events, and nonfatal stroke was 2% lower with ezetimibe (32.7 vs 34.7%; HR, 0.94; 95% CI, 0.89-0.99) for a number need to treat of 50 over 7 years. There were no significant differences between groups in the prespecified safety end points. This evidence informed the 2016 guideline recommendation for ezetimibe as second-line therapy to reduce CV risk in patients with ASCVD if their LDL-C targets were not reached with maximally tolerated statin therapy. 1 Subsequently, in the Heart Institute of Japan-Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome (HIJ-PROPER) trial open-label pitavastatin with ezetimibe (target LDL-C < 1.8 mmol/L) was compared with pitavastatin monotherapy (target LDL-C 2.3-2.6 mmol/L) in 1734 Japanese patients with an ACS. Over 3.9 years, the primary composite outcome of allcause death, nonfatal MI, nonfatal stroke, unstable angina, and ischemia-driven revascularization was not significantly different between groups (32.8 vs 36.9%; HR 0.89; 95% CI, 0.76-1.04). 117 PCSK9 inhibitors. Inhibitors of PCSK9 are recently available monoclonal antibodies that lower LDL-C between 50% and 70% when used in addition to statin therapy or as monotherapy. 118 Currently, two PCSK9 inhibitors are approved for use in Canada: alirocumab and evolocumab. Both are approved for the treatment of FH or ASCVD in patients as an adjunct to diet and maximally tolerated statin therapy (with or without ezetimibe) who require additional lowering of LDL-C.
The FOURIER trial enrolled 27,564 patients with clinical ASCVD and additional CVD risk factors whose LDL-C remained ≥ 1.8 mmol/L despite maximally tolerated statin therapy. Patients were randomized to receive evolocumab (140 mg subcutaneously (SC) every 2 weeks or 420 mg SC monthly) or placebo. 89 Baseline LDL-C was 2.4 mmol/L, which after 48 weeks was reduced to a median of 0.8 mmol/L (interquartile range, 0.5-1.2 mmol/L) in the evolocumab group. After 2.2 years of follow-up, the primary outcome of CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, and coronary revascularization was lower with evolocumab (9.8% vs 11.3%; HR, 0.85; 95% CI, 0.79-0.92) for a number needed to treat of 67. Evolocumab also reduced the secondary end point of CV death, nonfatal MI, and nonfatal stroke (5.9% vs 7.4%; HR, 0.80; 95% CI, 0.73-0.88). There was no significant difference in CV or all-cause death. Serious adverse events were similar between groups, although injection site reactions were higher with evolocumab (2.1% vs 1.6%; P < 0.001).
In the ODYSSEY OUTCOMES trial alirocumab was evaluated in 18,924 patients with a recent (1-12 months) ACS whose LDL-C was ≥ 1.8 mmol/L despite maximally tolerated statin therapy. 90 Participants were randomized to alirocumab (75 mg SC every 2 weeks to achieve an LDL-C of 0.6-1.3 mmol/L) or placebo. The dose of alirocumab was increased to 150 mg SC every 2 weeks if a participant's LDL-C level remained > 1.3 mmol/L or decreased or discontinued if their LDL-C level was < 0.6 mmol/L. The primary outcome of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization was lower with alirocumab (9.5% vs 11.1%; HR 0.85; 95% CI, 0.78-0.93) for a number needed to treat of 63 over 2 years. All-cause mortality was numerically lower with alirocumab (3.5% vs 4.1%), but on the basis of the authors' prespecified hierarchical testing, it is debatable whether this can be considered statistically significant. There was no significant difference in CV death between groups. There was no significant difference in serious adverse events, but injection site reactions were more common with alirocumab (3.8% vs 2.1%; P < 0.001).
A recent meta-analysis of 23 trials (including FOURIER and ODYSSEY OUTCOMES) compared PCSK9 inhibitors with control in 60,723 patients. 119 There was a significant reduction in MACE (6.2% vs 8.2%; risk ratio, 0.83; 95% CI, 0.78-0.88) with no significant difference in all-cause mortality (risk ratio 0.93; 95% CI, 0.85-1.02) or safety outcomes. Of note, these trials had short follow-up (median of 2.8 years) and therefore might not have been of sufficient duration to observe a mortality benefit.
Although ezetimibe or a PCSK9 inhibitor are reasonable options as monotherapy in patients with complete statin intolerance for LDL-C lowering, there is limited evidence to support either class as an alternative to statin therapy for ASCVD risk reduction. The Study of Alirocumab (REGN727/SAR236553) in Patients With Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular (CV) Risk, Who Are Intolerant to Statins (ODYSSEY ALTERNATIVE) trial enrolled 314 patients with statin intolerance who were randomized to alirocumab 75 mg SC every 2 weeks, ezetimibe 10 mg daily, or atorvastatin 20 mg daily. 120 At 24 weeks, alirocumab reduced LDL-C by a mean difference of 30% compared with ezetimibe. Skeletal muscle-related adverse effects were high overall, but significantly lower with alirocumab (33%) vs atorvastatin (46%) and similar to ezetimibe (41%). The Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3) trial included 218 patients considered to have previous statin intolerance who were randomized to evolocumab 420 mg SC monthly or ezetimibe 10 mg orally daily. 121 Evolocumab showed a significantly greater reduction in LDL-C compared with ezetimibe (mean difference, 36%) at 24 weeks. The incidence of muscle symptoms was relatively high in both groups, but the difference was not statistically significant (21% vs 29%; P = 0.17).
Clinical trials have shown that PCSK9 inhibitors are effective at lowering LDL-C in patients with heterozygous FH 102,120 and in certain patients with homozygous FH, 91 but there is currently a paucity of ASCVD outcome data in these populations.
# Primary prevention
There are currently no RCT data supporting the use of PCSK9 inhibitors to reduce CV events in patients who do not have established ASCVD (ie, primary CV prevention) or FH.
# IPE.
Until recently, contemporary trials of omega-3 fatty acid supplements have not shown a CV benefit in patients with or without CVD. 123,124 Previously, the Japan EPA Lipid Intervention Study (JELIS) showed a reduction in CV events with 1800 mg daily of eicosapentaenoic acid (EPA) combined with a statin, compared with statin monotherapy, in Japanese patients with a total cholesterol ≥ 6.5 mmol/L; however, it was an openlabel trial and the primary outcome was driven by a minor reduction in unstable angina. 125 The REDUCE-IT assessed the effect of a pharmaceutical formulation of purified ethyl EPA (IPE), which was recently approved by Health Canada. 114 In total, 8179 patients were included with established ASCVD (or diabetes and ≥ 1 ASCVD risk factor) who were receiving statin therapy but had an elevated fasting triglyceride level of 1.5-5.6 mmol/L (baseline 2.4 mmol/L). Most patients (71%) were in the secondary prevention cohort. Participants were randomized to 2000 mg of IPE orally twice daily (4 g total per day) or mineral oil as placebo. At 1 year, participants' triglyceride level in the IPE group was modestly reduced by 0.4 mmol/L (approximately 18%) from baseline. IPE reduced the primary outcome of CV death, nonfatal MI, nonfatal stroke, unstable angina, or CV revascularization (17.2% vs 22.0%; HR, 0.75; 95% CI, 0.68-0.83) for a number needed to treat of 21 over 4.9 years. IPE also significantly reduced the composite of CV death, nonfatal MI, and nonfatal stroke (11.2% vs 14.8%; HR, 0.74; 95% CI, 0.65-0.83), as well as CV death (4.3% vs 5.2%; HR, 0.80; 95% CI, 0.66-0.98), but not all-cause death. Atrial fibrillation and peripheral edema were significantly higher with IPE. Because IPE is a purified form of ethyl EPA, the results of REDUCE-IT cannot be extrapolated to other nonprescription omega-3 fatty acids, which typically contain a mixture of EPA and docosahexaenoic acid (DHA).
The Outcomes Study to Assess Statin Residual Risk Reduction With Epanova in High CV Risk Patients With Hypertriglyceridemia (STRENGTH) trial aimed to evaluate a pharmaceutical carboxylic acid formulation of EPA and DHA (referred to as omega-3 CA) to prevent MACE in 13,078 patients with hypertriglyceridemia (2.0-5.6 mmol/L), low HDL-C (< 1.2 mmol/L for women and < 1.1 mmol/L for men) who were receiving statin therapy, and were at increased risk of CVD. 128 Patients were randomized to receive 4 g/d of omega-3 CA or corn oil placebo. The trial was discontinued prematurely after a median follow-up of 3.5 years for futility. The primary end point of CV death, nonfatal MI, nonfatal stroke, unstable angina requiring hospitalization, and coronary revascularization was not significantly different between groups (12.0% vs 12.2%; HR, 0.99; 95% CI, 0.90-1.09). Patient-reported gastrointestinal disorders were more common in patients in the omega-3 CA group (24.7% vs 14.7%).
Other therapies. There are no new recommendations regarding the use of fibrates, niacin, and bile acid sequestrants since the 2016 guidelines. 1
# Ongoing trials
There are a number of ongoing trials of nonstatin therapy. -4) is evaluating whether this LDL-C reduction with inclisiran translates to a reduction in MACE among patients with CVD. 130 The Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS (dal-GenE) study aims to assess the effect of dalcetrapib, a cholesteryl ester transfer protein inhibitor (not approved by Health Canada), in patients with a recent ACS and specific genotype. 131 The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial is evaluating the effect of bempedoic acid, a novel adenosine triphosphate (ATP) citrate lyase inhibitor not approved in Canada, in patients with, or at high risk for, ASCVD who are statinintolerant. 132 It should be noted that 2 recommendations on the basis of the evidence review of PICO question 5 were overlapping with recommendations made for PICO question 4 and appear as part of that earlier section (Recommendations 1 and 2).
Values and preferences. None of these agents have been evaluated in RCTs against each other. Therefore, it is difficult to assess the relative benefit of each therapy. Also, to date these agents have primarily been evaluated in patients with preexisting ASCVD (ie, secondary prevention). The choice of agent should be on the basis of individual patient factors, their values and preferences, and practical considerations, such as access, cost, and adherence. Because ezetimibe lowers LDL-C level by approximately 20% when used in addition to a statin, if a patient's LDL-C is well above the threshold for therapy intensification (ie, > 2.2 mmol/L or > 20% above threshold), it might be preferable to consider a PCSK9 inhibitor as second-line therapy. However, because of cost considerations, some insurance providers might require a trial of ezetimibe before approving the use of a PCSK9 inhibitor. IPE should be preferentially reserved for patients aged ≥ 45 years of age (or ≥ 50 years of age with ≥ 1 CVD risk factor) who are receiving maximally tolerated statin therapy but have a residual elevated triglyceride level (1.5-5.6 mmol/L). Because IPE is a purified form of ethyl EPA, it should not be inferred that the same CV benefits could be derived from the consumption of omega-3 polyunsaturated fatty acid (PUFA) formulations that include EPA alone, EPA and DHA mixtures, or fish oils from supplements or dietary sources.
The recommendation for treatment of patients with FH is on the basis of the 2018 update to the CCS position statement on FH. 134 The recommendation for PCSK9 inhibitors to lower LDL-C level is on the basis of highquality evidence; however, there is a relative paucity of RCT evidence to support any agent to reduce the risk of CV events in FH patients.
Practical tip. Unlike the use of PCSK9 inhibitors in patients with ASCVD, access to these medications is covered by most provincial drug plans for patients with heterozygous FH (with or without ASCVD) with LDL-C level above the threshold. Although the evidence for IPE to decrease the risk of CV events in patients with ASCVD, or with diabetes and ≥ 1 CVD risk factors is good, it is relatively new and most provincial drug plans do not yet cover this expensive medication. Private plans might cover this drug for patients on the basis of specific criteria and there is a manufacturer patient assistance program that might facilitate access. As part of shared decision-making, clinicians should discuss the indication and potential benefits of IPE, as well as the coverage issues and the potential patient costs. PICO 6: In primary and secondary prevention, what is the evidence for CV benefit of omega-3 from (1) dietary sources; and/or (2) over-the-counter formulations/ supplements?
Despite the success of the REDUCE-IT trial in showing a purified prescription IPE at 4 g/d reduces major CVD events in statin-treated patients with elevated triglyceride levels who have established CVD or diabetes and at least 1 CVD risk factor, 114 supplementation with overthe-counter long-chain omega-3 PUFAs marketed as natural health products in Canada that include EPA alone, EPA and DHA mixtures, or fish oils from supplements or dietary sources does not offer any clear advantages for CVD event risk reduction. We updated a systematic review and meta-analysis of RCTs with data from 2 subsequently completed RCTs, A Study of Cardiovascular Events in Diabetes (ASCEND) 135 and Vitamin D and Omega-3 Trial (VITAL), 136 which failed to show a clear CV benefit of supplementation with long chain omega-3 PUFAs in more than 130,000 randomized participants. 137 Another large CVD outcomes trial of a pharmaceutical drug of mixed long-chain omega-3 (largely EPA and DHA) carboxylic acids (omega-3 CA) at 4 g/d with similar entry criteria to the REDUCE-IT trial was also discontinued early by the data safety monitoring board for futility with the drug unlikely to show a benefit to patients. 126 Pooled evidence from RCTs and individual large RCTs, 141 however, have shown consistent triglyceride-lowering effects at high doses (2-4 g/d) of omega-3 PUFAs, independent of CVD event risk reduction. RECOMMENDATION 16. We do not recommend the use of over-the-counter omega-3 polyunsaturated fatty acid supplements (marketed as natural health products in Canada) to reduce CVD risk (Strong Recommendation; High-Quality Evidence).
Values and preferences. Although there is no apparent overall CVD event risk benefit, patients might choose to use these supplements for other indications including the management of high triglycerides, for which very high doses are required (4 g/d), and for which fibrates are generally more effective. Individuals should be aware that, in addition to marine sources, there are different preparations of long-chain omega-3 PUFAs high in DHA and EPA from algal and yeast sources, both of which are suitable for vegans. There is also alpha-linolenic acid from plant sources that do not contain DHA or EPA including flax seeds, chia seeds, and some oils such as canola and soybean oil, which have little or no effect on triglycerides.
# Conclusions
In this focused revision of the CCS guidelines for the management of dyslipidemia, the committee has distilled several years of new research in CV risk assessment (especially as it pertains to women), lipoprotein biomarkers, and coronary artery calcium scanning. The committee also reviewed several major landmark RCTs of novel therapies to treat dyslipidemia. On the basis of the best available evidence to date, we have developed several new recommendations for clinicians to more accurately assess their patients' CV risk and optimally manage their lipid disorders. We acknowledge that the science surrounding CV risk and dyslipidemia management is evolving and therefore these recommendations can only be viewed as the best practices on the basis of the currently available evidence. Nonetheless, the objective of any guideline is to provide clinicians with the most up-to-date knowledge and tools to help them make informed decisions with their patients. Appendix 1 provides an at-a-glance, step-wise summary of the management of adult patients with dyslipidemia for the prevention of cardiovascular disease, based on the 2021 CCS dyslipidemia guidelines.
The past few years has realized significant progress in the management of dyslipidemia, with several new therapies currently available and more in development. With continued efforts to prioritize healthy lifestyles and the use of new pharmacotherapeutic options available to treat eligible patients, we hope to realize further reductions in morbidity and mortality from ASCVD in Canada. | The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy contin-Le panel principal responsable des lignes directrices 2021 a s electionn e des el ements cliniquement pertinents et a soumis des recommandations actualis ees, bas ees sur de nouvelles d ecouvertes d'importance apparues depuis les lignes directrices de 2016. Ainsi, le traitement par statine reste recommand e pour les patients atteints d'ath eroscl erose clinique, d'an evrisme de l'aorte abdominale, pour la#
ues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents. For all other patients, we emphasize risk assessment linked to lipid/lipoprotein evaluation to optimize clinical decision-making. Lipoprotein(a) measurement is now recommended once in a patient's lifetime, as part of initial lipid screening to assess cardiovascular risk. For any patient with triglycerides ˃ 1.5 mmol/L, either non-high-density lipoprotein cholesterol or apolipoprotein B are the preferred lipid parameter for screening, rather than low-density lipoprotein cholesterol. We provide updated recommendations regarding the role of coronary artery calcium scoring as a clinical decision tool to aid the decision to initiate statin therapy. There are new recommendations on the preventative care of women with hypertensive disorders of pregnancy. Health behaviour modification, including regular exercise and a heart-healthy diet, remain the cornerstone of cardiovascular disease prevention. These guidelines are intended to provide a platform for meaningful conversation and shared-decision making between patient and care provider, so that individual decisions can be made for risk screening, assessment, and treatment. plupart des patients diab etiques ou atteints d'insuffisance r enale chronique, et chez ceux dont le cholest erol a lipoprot eines de basse densit e est ≥ 5 mmol/l. Nous avons introduit la notion de seuils pour le traitement des lipides/lipoprot eines afin d'intensifier le traitement hypolipid emiant avec des agents non-statiniques, et nous avons identifi e les patients en pr evention secondaire distingu es comme ayant tirer le plus grand b en efice de l'intensification du traitement avec ces agents. Pour tous les autres patients, nous mettons l'accent sur l'appr eciation du risque par le biais de l' evaluation des lipides/lipoprot eines afin d'optimiser la prise de d ecision clinique. Le dosage de la lipoprot eine (a) est maintenant recommand e une fois dans la vie d'un patient, dans le cadre du d epistage initial des lipides pour evaluer le risque cardiovasculaire. Pour tout patient pr esentant des taux de triglyc erides ˃ 1,5 mmol/l, l'apolipoprot eine B ou le cholest erol li e aux lipoprot eines autres que celles de haute densit e sont les indices lipidiques a privil egier pour le d epistage, plutôt que le cholest erol a lipoprot eines de basse densit e. Nous proposons des recommandations actualis ees concernant le rôle du score calcique des art eres coronaires en tant qu'outil de d ecision clinique pour aider a la d ecision d'administrer un traitement par statine. Il existe de nouvelles recommandations concernant les soins pr eventifs des femmes souffrant de troubles hypertensifs de la grossesse. Le changement de comportement en mati ere de sant e, incluant l'exercice physique r egulier et une alimentation saine pour le coeur, reste la pierre angulaire de la pr evention des maladies cardiovasculaires. Ces lignes directrices visent a fournir une plateforme pour une discussion constructive et une prise de d ecision partag ee entre le patient et le prestataire de soins, afin que des d ecisions individuelles puissentêtre prises pour le d epistage, l' evaluation et le traitement des risques.
The 2021 Canadian Cardiovascular Society (CCS) dyslipidemia guidelines have been updated to reflect new clinical trial and epidemiologic evidence published since the previous guidelines in 2016. 1 The primary panel posed a number of population, intervention, comparator, and outcomes (PICO) questions to develop recommendations and inform clinical practice on the basis of a detailed literature review. The PICO format is a common standard used for guidelines development, to aid clinicians in determining whether the recommendations apply to their own patients with outcomes relevant to their practice. Initially, 13 different PICO questions were posed and then rated on the basis of the availability and significance of new evidence and importance to be included in the updated guidelines. The primary panel members voted on the initial 13 PICO questions formulated (see Supplemental Appendix S1 Supplemental Appendix S1, S2, S3 etc. Please check throughout.?>), resulting in the identification of 6 key PICO questions, which are included in this update. Using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards, individual studies and composite literature were reviewed for each PICO question with regard to the quality of the available evidence and the presence of publication or interpretive bias. We have included the updated recommendations within this update, and the results of voting on each recommendation are shown in Supplemental Appendix S2. For recommendations to go forward a two-thirds voting majority was required. Individuals with conflicts of interest were recused from voting on relevant recommendations.
We have introduced the concept of "treatment thresholds" for intensifying lipid-lowering therapy with nonstatin lipid-lowering agents on the basis of new evidence with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and icosapent ethyl (IPE). Because of the increased focus on apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (HDL-C) in this update, values for ApoB and non-HDL-C have been modified (from previous versions of these guidelines) to accurately represent the same percentile equivalents as low-density lipoprotein (LDL) cholesterol (LDL-C) for all recommended thresholds (see Supplemental Appendix S3). The goal of the process was to produce an objective, nonbiased document on the basis of the best available evidence to allow clinicians and patients to make collaborative treatment decisions. These guidelines are not absolute, but are to be used in the context of oneon-one discussion between practitioner and patient and consideration of the patient's values and preferences. Dyslipidemia is an important risk factor for atherosclerotic cardiovascular (CV) disease (ASCVD), and these guidelines inform risk assessment, treatment, and surveillance options for at-risk populations. These guidelines were undertaken under the auspices of the Guideline Committee of the CCS without any support or involvement from outside groups, including industry.
# Definitions
ASCVD refers to all clinical conditions of atherosclerotic origin, including acute coronary syndrome (ACS), myocardial infarction (MI), stable or unstable angina, coronary artery disease documented using angiography, coronary or other arterial revascularization (coronary artery bypass graft surgery, femoral popliteal bypass graft surgery, etc), stroke, transient ischemic attack, documented carotid disease, peripheral artery disease, and abdominal aortic aneurysm.
Statin-indicated condition refers to any condition for which pharmacotherapy with statins is indicated, and consists of all documented ASCVD conditions, as well as other highrisk primary prevention conditions in the absence of ASCVD, such as most patients with diabetes, those with chronic kidney disease (CKD), and those with an LDL-C ≥ 5.0 mmol/L or a diagnosis of familial hypercholesterolemia (FH). This concept was first introduced in the 2016 guidelines and continues to be used in this update.
Primary prevention refers to all efforts aimed at either populations or individuals to prevent or delay the onset of ASCVD.
Secondary prevention refers to the efforts to treat known, clinically significant ASCVD, and to prevent or delay the onset of disease manifestations.
# Overview of the Management of Dyslipidemia in Primary Prevention
# Screening
We determined that there was insufficient new evidence to recommend major changes to the approach of risk assessment in primary prevention. We continue to recommend lipid/lipoprotein screening (in either fasting or nonfasting state) for men and women older than 40 years of age or at any age with one of the specific conditions listed in Table 1. The nonfasting state is recommended (except for individuals with known triglycerides > 4.5 mmol/L) because it leads to minimal changes in relevant lipid levels and has no effect on apolipoprotein levels compared with the fasting state. 1 Table 2 provides a summary of the recommendations for how to screen patients. We maintain the recommendation for regular CV risk assessments using a validated risk model in Canada (either the Framingham Risk Score [FRS] or the Cardiovascular Life Expectancy Model [CLEM]) every 5 years for men and women aged 40-75 years to guide preventive care through shared decision-making with the patient. Among individuals 30-59 years of age without diabetes, the presence of a history of premature CV disease (CVD) in a firstdegree relative (ie, 55 years or younger in male relatives and 65 years or younger in female relatives) increases an individual's calculated FRS percent risk by approximately twofold. 1
# Health behaviour interventions
Health behaviour modifications remain the cornerstone of chronic disease prevention, including CVD. Data from the INTERHEART study indicate that, in addition to the traditional risk factors (abnormal lipid levels, hypertension, smoking, and diabetes), abdominal obesity, dietary patterns, alcohol consumption, physical inactivity, and psychosocial factors are modifiable risk factors for MI worldwide in both sexes and at all ages. 2 Evidence from other large prospective cohort studies have also shown that combining low-risk health behaviours that include achieving and maintaining a healthy body weight, consuming a healthy diet, engaging in regular physical activity, smoking cessation, limiting alcohol consumption to no more than moderate, and ensuring a sufficient duration of sleep are associated with benefit for the primary prevention of CVD. 3,4 We continue to recommend a Mediterranean dietary pattern, which has evidence of CV outcome benefit in systematic reviews and meta-analyses. Additionally, other dietary patterns that share important features such as the Portfolio dietary pattern, 5 Dietary Approaches to Stop Hypertension (DASH) dietary pattern, 6 low-glycemic index/glycemic load dietary pattern, 7 and plantbased dietary pattern, 8 as well as dietary patterns high in nuts, 9,10 legumes, 10 olive oil, 9 fruits and vegetables, 11 total fibre, 12 and whole grains. 13 Dietary therapy using these means can be considered to augment drug therapy with statins; however, their benefits have been shown in terms of surrogate CV measures such as blood pressure and lipoproteins.
We also continue to recommend that all adults should accumulate at least 150 minutes of moderate to vigorous aerobic activity per week. It might also be beneficial to add muscle-and bone-strengthening activities at least 2 days per week. Regular exercise has beneficial effects on diabetes risk, hypertension, and hypertriglyceridemia, and improves plasma levels of HDL-C. 14 A summary table of the expected CV outcomes and/or lipid benefits from various health behaviour changes is presented in Supplemental Appendix S4.
# Pharmacologic treatment
Studies consistently show a 20%-22% relative risk reduction for each 1 mmol/L reduction in LDL-C. 15 The absolute risk reduction is thus dependent on the baseline risk and the baseline LDL-C, because statin treatment will provide a greater absolute LDL-C lowering in those with higher baseline values. Therefore, we continue to recommend initiation of statin therapy for: (1) all high-risk patients (≥ 20% 10-year risk); or (2) intermediaterisk patients (10%-19.9%) when LDL-C is ≥ 3.5 mmol/L (or ApoB ≥ 1.05 g/L or non-HDL-C ≥ 4.2 mmol/L). In addition, among intermediate-risk individuals with several additional risk factors as evaluated in Heart Outcomes Prevention Evaluation (HOPE) 3 16 (men 50 years of age or older or women 60 years of age or older with 1 additional risk factor including low HDL-C, impaired fasting glucose, increased waist circumference, cigarette smoking, hypertension) the evidence remains in favour of statin initiation to reduce the risk of CV events. The presence of other risk modifiers in intermediate-risk individuals also favours the use of statins (eg, high-sensitivity C-reactive protein ≥ 2.0 mmol/L, family history of premature coronary artery disease, high lipoprotein(a) [Lp(a)] ≥ 50 mg/dL [≥100 nmol/L] or coronary artery calcium score [CAC] > 0 Agatston units [AU]).
For most low-risk subjects (FRS < 10%), health behaviour modification without pharmacotherapy is still recommended; however, the exceptions would be: (1) low-risk individuals with an LDL-C ≥ 5.0 mmol/L (or ApoB ≥ 1.45 g/L or non-HDL-C ≥ 5.8 mmol/L) who have a statin-indicated condition (likely a genetic dyslipidemia such as FH); or (2) individuals with an FRS of 5%-9% with an LDL-C ≥ 3.5 mmol/L (or ApoB ≥ 1.05 g/L or non-HDL-C ≥ 4.2 mmol/L), especially with other CV risk modifiers (eg, family history of premature coronary artery disease, Lp(a) ≥ 50 mg/dL [or ≥ 100 nmol/L] or CAC > 0 AU) because the proportional benefit from statin therapy will be similar to that in other treatment groups. Treatment of this group would follow the intermediate risk approach. The treatment approach recommended for primary prevention patients is outlined in Figure 1. Finally, evidence continues to show the benefits of maintaining low levels of atherogenic lipoproteins throughout life and at any age and any level of risk. Even among primary prevention individuals at low 10-year risk, the benefit of lipid-lowering can be substantial, especially when LDL-C ≥ 3.5 mmol/L. 17 In addition, accumulating evidence suggests continued benefits of lipid-lowering for primary prevention in older adults (older than 75 years). 18
# Other statin-indicated conditions
We continue to recommend statin initiation for the following high-risk conditions (ie, "statin-indicated" conditions, even in the absence of a previous CV event: (1) CKD (except for patients receiving chronic dialysis) defined as patients with an estimated glomerular filtration rate < 60 mL/min/1.73 m 2 and those with preserved estimated glomerular filtration rate in whom CKD is on the basis of an increased urinary albumin to creatinine ratio (≥ 3 mg/mmol) for at least 3 months' duration; (2) diabetes mellitus in patients 40 years of age or older or 30 years of age or older with 15 or more years' duration of diabetes, or the presence of microvascular complications; (3) abdominal aortic aneurysm > 3.0 cm or previous aortic aneurysm surgery. 1 Established ASCVD is also a statinindicated condition, which is discussed in more detail later in these guidelines. The treatment approach for patients with a statin-indicated condition is summarized in Figure 2.
All of the recommendations from the previous dyslipidemia guidelines that remain unchanged are provided in Supplemental Appendix S5.
# New areas of focus
The review of literature and evidence assessment identified several areas for new and/or updated recommendations for primary prevention, specifically in: (1) the preventive care of women with hypertensive disorders of pregnancy; (2) the importance of lipoprotein measurement including non-HDL-C, ApoB, and Lp(a) in assessing CV risk; (3) the role of CAC as a clinical decision-making tool for determining the need to initiate statin treatment; (4) the CV benefit of IPE in patients with triglycerides ≥ 1.5-5.6 mmol/L and a previous CV event or with diabetes and additional risk factors; and (5) the lack of CV benefit of omega-3 fatty acids from dietary sources or other formulations/supplements.
# Overview of the Management of Dyslipidemia in Secondary Prevention
# Health behaviour interventions
We continue to recommend health behaviour interventions to optimize CV health in all patients with a previous ASCVD event (refer to the Health behaviour interventions in the section on Overview of the Management of Dyslipidemia in Primary Prevention). In secondary prevention, limiting sedentary behaviour can be additive to regular physical activity with respect to the reduction of ASCVD events. A certified exercise physiologist might be of value to provide advice and followup. Cardiac rehabilitation has been clearly shown to be of benefit in this patient population and remains a cornerstone of management. 19 Relevant recommendations from the previous dyslipidemia guidelines that remain unchanged are provided in Supplemental Appendix S5.
# New areas of focus
Several areas were reviewed by our group that directly affect the care and management of patients with previous ASCVD events and have led to new or updated recommendations, specifically: (1) the role of nonstatin therapies to reduce ASCVD events; (2) the most appropriate lipid/lipoprotein threshold for the intensification of therapy in the management of dyslipidemia; and (3) the lack of CV benefit of omega-3 fatty acids from dietary sources or other formulations/supplements. Treatment approach for primary prevention patients (without a statin-indicated condition*). Statin-indicated conditions consist of all documented ASCVD conditions, as well as other high-risk primary prevention conditions in the absence of ASCVD, such as most patients with diabetes, those with chronic kidney disease, and those with an LDL-C ≥ 5.0 mmol/L. Screening should be repeated every 5 years for men and women aged 40-75 years using the modified FRS or Cardiovascular Life Expectancy Model (CLEM) to guide therapy to reduce major CV events. A risk assessment might also be completed whenever a patient's expected risk status changes. ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; AU, Agatston units; BAS, bile acid sequestrant; CAC, coronary artery calcium; CAD, coronary artery disease; CV, cardiovascular; FHx, family history; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; HTN, hypertension; FRS, Framingham Risk Score; IFG, impaired fasting glucose; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); mins, minutes; Rx, treatment; yrs, years. * Calculate risk using the FRS-refer to the iCCS available on the App Store or on Google Play. PICO Questions, Evidence Review, and New Recommendations PICO 1: Do pregnancy-related conditions (hypertensive disorders of pregnancy and other related complications) identify women at increased risk of premature CVD warranting lipid screening?
Pregnancy complications such as preeclampsia and related hypertensive disorders of pregnancy, gestational diabetes, placental abruption, preterm delivery, stillbirth, and delivery of a low birth weight infant are associated with a higher lifetime risk of developing CV risk factors (hypertension; type 2 diabetes mellitus; dyslipidemia, especially hypertriglyceridemia and low HDL-C; metabolic syndrome; and subclinical atherosclerosis) and overt ASCVD. 20,21 The strongest and most abundant evidence linking pregnancy events and ASCVD is for preeclampsia, in which there is a twofold relative risk of developing premenopausal ASCVD, with onset at 10-15 years after delivery 20 compared with women who had uncomplicated pregnancies. This risk is highest if preeclampsia is recurrent (ie, 28% lifetime risk of ASCVD, or within 25 years after delivery 22 ), or if associated with preterm delivery (before 37 weeks' gestation) and other adverse conditions (chest pain, dyspnea, low platelet count, elevated liver enzymes, intrauterine growth restriction) or severe complications (eclampsia, stroke, myocardial ischemia, hepatic rupture, acute kidney injury with need for hemodialysis). 23 ASCVD risk is partly mediated by the development of chronic hypertension and metabolic syndrome. 24 There is often silent and subclinical endothelial dysfunction after hypertensive disorders of pregnancy suggesting accelerated vascular aging. 25,26 National CV societies, 1,27 including the CCS, 1 have recommended performing lipid and metabolic screening in postpartum women who have had these complications, although whether specific thresholds warranting pharmacotherapy differ from those typically used in the general population is not known. Although it is true that these women have a low absolute risk of ASCVD over the short term, the postpartum period might represent "a teachable moment" to engage young women in CV prevention and might result in long-term benefits through health behaviour interventions with or without pharmacological intervention. Treatment decisions should be guided on the basis of lifetime risk in conjunction with patient values and preferences. 28
# RECOMMENDATION
1. Among women who have had a pregnancy complication such as hypertensive disorders of pregnancy, gestational diabetes, preterm birth, stillbirth, low birth weight infant, or placental abruption, we recommend screening with a complete lipid panel in the late postpartum period, because these women have a higher risk of premature CVD and stroke with onset 10-15 years after index delivery (Strong Recommendation; Moderate-Quality Evidence). 2. We recommend counselling women who have any of these pregnancy-related complications of the increased lifetime risk of ASCVD, and reinforcing the importance of healthy behaviours (ie, maintaining a healthy body weight, 150 weekly minutes of moderate intensity aerobic physical activity, avoiding tobacco consumption, no more than moderate alcohol consumption, stress management, and adopting a healthy dietary pattern, such as the Mediterranean diet (Strong Recommendation; Low-Quality Evidence). 3. To assist with decisions about lipid-lowering pharmacotherapy in this patient population, we recommend favouring CV age, over 10-year risk calculators (Strong Recommendation; Low-Quality Evidence).
Values and preferences. Although much of this observed risk among women who have had a pregnancyrelated complication might be due to conventional ASCVD risk factors, complications such as preeclampsia might lead to ASCVD through accelerated vascular aging or other pathways warranting additional future research.
There is insufficient evidence to guide decisions about use of lipid-lowering therapy in women on the basis of pregnancy factors alone. The American Heart Association 2019 CV prevention guidelines 27 consider preeclampsia a risk enhancer warranting early screening, healthy behaviour interventions, and possibly shifting of risk category from borderline to intermediate risk (ie, eligible for statin or other lipid-lowering therapy).
We suggest individual discussions about statin or other lipid-lowering pharmacotherapy, considering each patient's lifetime risk/individual risk factors along with severity and recurrence of pregnancy complications (in particular preterm preeclampsia with adverse conditions), balanced against the potential side effects and harms of long-term therapy. Although statins were previously considered teratogenic on the basis of earlier animal studies, this has not been consistently shown in recent human studies. 29,30 A part of the observed increase in risk of congenital malformations might be due to underlying medical conditions rather than treatment with statin therapy itself. 29 Furthermore, there appears to be a differential effect on the basis of the type of compound, with most cases of congenital malformations being seen among infants whose mothers took lipophilic compounds (eg, atorvastatin, lovastatin, simvastatin) as opposed to hydrophilic compounds (eg, pravastatin, rosuvastatin). 31,32 Therefore, in women who are reproductive age and who are eligible and considering statin therapy for ASCVD risk reduction on the basis of CV age or lifetime risk of ASCVD, we suggest the use of hydrophilic compounds over lipophilic compounds because of easier passage through the placenta with the latter molecules. It should be noted that for most reproductive women who take statin therapy for primary prevention of ASCVD, an effective birth control method is recommended with interruption of therapy before a planned pregnancy or at the time of an unplanned positive pregnancy test. These treatments can be resumed after delivery, when breastfeeding is completed. Referral to a specialist in obstetrical medicine or in fetal-maternal medicine should also be considered in the management of statin and nonstatin therapies in pregnant women or in women planning pregnancy.
PICO 2a: Is there evidence to promote non-HDL-C over ApoB or ApoB over non-HDL-C for screening and treatment purposes? Previous versions of these guidelines have used LDL-C as the primary laboratory measurement for considering initiation of statin treatment and as a treatment target in low-, intermediate-, and high-risk individuals. Beginning with the 2012 guidelines, it has been recommended that non-HDL-C and ApoB could be used as alternate targets to LDL-C in any individual with triglyceride level > 1.5 mmol/L. 1,33 The rationale for this is that above this level of triglyceride, some cholesterol in LDL particles is replaced by triglyceride, which promotes production of more atherogenic small dense LDL particles, 34 and makes the amount of cholesterol in LDL-C an unreliable reflection of LDL particle number. 35 In addition, other particles, such as remnants of chylomicrons and very LDL-C, as well as Lp(a), all accumulate in the artery wall and contribute to atherogenesis, whereas HDL-C does not. Therefore, estimation of the concentration of all atherogenic particles requires a broader focus than a measurement of LDL-C. Non-HDL-C (indirectly) and ApoB (directly) provide a more accurate assessment of the total concentration of atherogenic particles than LDL-C. Non-HDL-C and ApoB are, for this reason, both better predictors of CV event risk and benefit of lipid-lowering therapy compared with LDL-C. 36,37 On the basis of these previous recommendations, non-HDL-C is now routinely reported across Canada at no additional cost, on the basis of the simple calculation of total cholesterol minus HDL-C. ApoB is also available as an insured laboratory test in all provinces except Ontario. Levels of non-HDL-C and ApoB are not significantly changed in the postprandial state in individuals with triglycerides < 4.5 mmol/L, whereas LDL-C can be lowered by up to 10% because of triglyceride enrichment of LDL-C. 38,39 After the guideline recommendation that was introduced in 2016 allowing for nonfasting collections for screening and follow-up lipid testing, 1 it is now generally preferable to follow non-HDL-C or ApoB levels over LDL-C when interpreting lipid results, particularly when triglyceride levels are ≥ 1.5 mmol/L. A recent survey conducted by the Canadian Association of Medical Biochemists and the Canadian Society of Clinical Chemistry indicates that patients across Canada can now present to laboratories nonfasting and receive a complete lipid profile.
# Non-HDL-C or ApoB for predicting CVD risk
In population studies, non-HDL-C and ApoB can be considered as equivalent markers of total atherogenic lipoproteins and lipid-related CV risk and this applies to most individuals. 40 Publications since the 2016 update of these guidelines indicate a subgroup of individuals, estimated at between 8% and 23%, have discordance between ApoB and non-HDL-C levels in whom ApoB might be the better predictor of risk for coronary calcification 40 and ASCVD events. 41 Analysis of CV events in the large United Kingdom Biobank, 41 and metaanalysis of 110 prospective cohort registries of patients with or at risk for ASCVD, 42 however, showed an overall similar ability of non-HDL-C and ApoB to predict risk, but confirmed both of these measures to be superior to LDL-C. Recent consensus statements have concluded that non-HDL-C is currently a more practical choice because it incurs no additional expense to the patient or health care system. 43,44 In Canada, the approach has been to allow clinicians to use either non-HDL-C or ApoB as their preferred parameter for assessment of risk and achievement of treatment targets, depending on their comfort level with the two measurements, availability of ApoB testing in their region, and when there might be a concern about discordance between the two measurements, as indicated previously. In the current guidelines, we are continuing this recommendation, while strongly urging the routine use of either non-HDL-C or ApoB instead of LDL-C as the lipid level of interest in initial lipid screening and as a treatment target in all patients with triglyceride level > 1.5 mmol/L. RECOMMENDATION 4. We recommend that for any patient with triglycerides > 1.5 mmol/L, non-HDL-C or ApoB be used instead of LDL-C as the preferred lipid parameter for screening (Strong Recommendation, High-Quality Evidence).
PICO 2b: Is there evidence to support measurement of Lp (a) to improve risk stratification and dyslipidemia management in patients with and without previous CV events?
Lp(a) is an LDL-like particle in which ApoB is covalently bound to a plasminogen-like molecule called apolipoprotein (a). 45 Plasma concentrations of Lp(a) are not influenced by age, sex, fasting state, inflammation, or lifestyle factors, but are largely controlled by a single gene locus, LPA on chromosome 6, and are highly (> 90%) heritable. 46 Individual values are generally stable throughout life, thus, repeat measures are not required for risk assessment.
Mendelian randomization studies have clearly shown that genetic variants in the LPA locus uniquely regulating Lp(a) levels are robustly associated with coronary heart disease risk, thereby strongly suggesting a causal association between Lp(a) and CVD. 47,48 The risk of ASCVD increases with increasing Lp(a) levels > 30 mg/dL in a dose-dependent fashion. [48][49][50] Among 7524 subjects in the Copenhagen Heart Study followed for 17 years, subjects with an Lp(a) concentration between 30 and 76 mg/dL had a 1.7-fold hazard ratio (HR) for MI and those with an Lp(a) level > 117 mg/dL had an adjusted HR of 2.7. 48 Among 6086 patients with a first MI and 6857 control participants from the INTERHEART study who were stratified according to ethnicity and adjusted for age and sex, Lp(a) concentrations > 50 mg/dL were associated with an increased risk of MI (odds ratio, 1.48; 95% confidence interval [CI], 1.43-1.67), independent of established CVD risk factors including diabetes mellitus, smoking, and high blood pressure. 51 Higher Lp(a) concentrations carried a particularly high population burden in South Asian and Latin American individuals. 51 An Lp(a) level > 50 mg/dL (> 100 nmol/L) is found in approximately 20% of individuals of European and South Asian descent, 40% of African American individuals, and fewer than 10% of East Asian individuals. 51,52 Individuals with extreme elevations in Lp(a) have been shown to be at markedly high risk, with an event rate similar to that for other genetic dyslipidemias for which family screening is recommended (ie, heterozygous FH). As such, Lp(a) is a common but as yet not routinely measured ASCVD risk marker.
Elevated Lp(a) level also increases the risk of recurrent ASCVD in a dose-dependent manner. 50,53 Among 58,527 subjects from the Copenhagen General Population Study, 2527 subjects aged 20-79 years with a history of ASCVD and elevated Lp(a) were followed over a median of 5 years. 54 The adjusted major adverse CV events (MACE) incidence rate ratios were 1.28 (95% CI, 1.03-1.58) for subjects with an Lp(a) level of 10-49 mg/dL (18-104 nmol/L), 1.44 (95% CI, 1.12-1.85) for 50-99 mg/dL (105-213 nmol/L), and 2.14 (95% CI, 1.57-2.92) for those with Lp(a) ≥ 100 mg/dL (≥ 214 nmol/L). 54 In the randomized, controlled Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOUR-IER) and Study to Evaluate the Effect of Alirocumab on the Occurrence of Cardiovascular Events in Patients Who Have Experienced an Acute Coronary Syndrome (ODYS-SEY OUTCOMES) trials, high levels of Lp(a) were associated with an increased risk of recurrent CVD events in patients with established CVD irrespective of LDL cholesterol. 53,54 Furthermore, alirocumab-associated reductions in Lp(a) reduced MACE in patients with a recent ACS independent of LDL-C. 54 Although these new data support the potential role of Lp (a) as a target of treatment in the future, there remains no evidence from RCTs that specifically lowering Lp(a) level leads to reductions in CV outcomes. It should also be noted that commonly used lipid-lowering therapies (ie, statins and ezetimibe) do not appreciably lower Lp(a) levels. The only available lipid-lowering therapies that lead to substantial lowering of Lp(a) include PCSK9 inhibitors, niacin, and apheresis, but relatively limited evidence exists for their use in patients with a high Lp(a) level. Newer investigational agents, such as antisense oligonucleotides and small interfering RNAs are currently being evaluated for CVD risk reduction in this patient population. Accordingly, Lp(a) is not currently considered a treatment target and repeat measures are therefore not indicated.
Lp(a) testing is available across Canada, and is currently an insured laboratory test in most provinces, with the exception of Ontario and Manitoba. Values and preferences. There is a large body of evidence supporting the potential causal association between Lp(a) and future ASCVD. 50,51,[55][56][57][58] The high prevalence of elevated Lp(a) level, the strength of association with incident and recurrent ASCVD events, and the potential to improve CV risk stratification, strongly justify universal screening to identify individuals with very high levels. Identification of high levels of Lp(a) is a useful consideration for shared decision-making in subjects across all ASCVD risk categories, but especially in younger patients, particularly those who have a very strong family history of premature ASCVD. Although further evidence that directly lowering Lp(a) level reduces ASCVD risk is pending, the finding of high Lp(a) should alert primary care practitioners to more actively pursue an overall ASCVD event risk assessment, including careful discussion of current health behaviours, consideration of age-appropriate vascular imaging studies for detecting early evidence of subclinical atherosclerosis in select individuals (eg, CAC score), and earlier introduction of statin or other lipid-lowering therapy, especially in intermediate-risk individuals and/or low-risk individuals with moderate elevations of LDL-C between 3.5 and 5 mmol/L.
In the setting of secondary prevention, the presence of a high Lp(a) level is strongly predictive of recurrent events, and suggests the need for intensification of LDL-lowering therapy, including use of PCSK9 inhibitors. Furthermore, preliminary evidence suggests that treatment with PCSK9 inhibitors post ACS in patients with high Lp(a) reduces MACE independent of LDL-C lowering. 54 When clinicians are uncertain of the implications of elevated Lp(a), consultation with a lipid specialist might be considered. For primary prevention, most guidelines are on the basis of the concept of ASCVD risk assessment to help determine appropriateness and intensity of ASCVD risk factor modification. The primary prevention RCTs on which the recommendations are based, however, use clinical descriptors to identify patients eligible for study and, as a result, the patients eligible for the proven therapy. None of the algorithms available, including the FRS used in Canada, have been used to determine eligibility for any of the successful, primary prevention lipid-lowering trials. Even so, there is evidence to suggest that use of such algorithms is effective on a population level, more so than identification of patients on the basis of trial eligibility criteria. 59,60 Despite this clinical utility, it has been repeatedly shown that typical ASCVD event risk algorithms can lead to substantial over-or underestimation of ASCVD event risk, 61 and consequently, inappropriate risk factor management. Additionally, the value of these algorithms for predicting the presence and burden of atheroma is poor. 62,63 Atheroma burden, the substrate that portends CV events, directly predicts ASCVD event risk in a graded fashion. This has been shown over decades with invasive angiography and more recently with coronary computed tomography, including noncontrast CAC scoring, the latter being highly applicable for assessment of patients who are asymptomatic, and possible candidates for primary prevention. 64,65 Accordingly, the literature is replete with clinical studies reinforcing the concept that directly assessing the presence of atheroma, through CAC scoring, significantly improves the appropriate selection of patients who are likely to benefit from lipid modifying therapy. 66 Noncontrast CAC measurements are sensitive, reproducible, and can be performed rapidly with an average radiation dose of 0.89 mSv (compared with background annual radiation exposure of approximately 3.0 mSv). Evidence for improved C-statistic/net reclassification index after adjustment for standard risk factors (FRS) has been shown in multiple studies. 67,69 The clinical decision-making utility of CAC measurements is best shown in middle-aged, intermediaterisk populations in whom the presence or absence of coronary artery calcification results in reclassification into higher or lower risk populations. A CAC measurement > 0 AU confirms the presence of atherosclerotic plaque. Increasing scores are directly proportional to increased ASCVD event risk. [69][70][71][72] A CAC measurement > 100 AU is associated with a high risk (> 2% annual risk) of an ASCVD event within 2-5 years and is generally an indication for intensive CV risk factor modification, including treatment of LDL-C. CAC > 300 AU places the patient in a very high risk category with a 10-year risk of MI/CV death of approximately 28%. 73 A CAC measurement of 0 AU, however, has a very high negative predictive value for ASCVD events in asymptomatic, low-risk adults within 2-5 years (negative predictive value, 95%-99%). 74 Importantly, although a CAC of 0 AU is indicative of a low event rate (1.5% per 10 years; 0.32-0.43 per 1000 person-years; 1.3-5.6 per 11.1 years), 70,[75][76][77] it is not indicative of a 0 event rate. This is likely because noncalcified soft plaque might be present; not all ASCVD events are mediated by vascular atheroma and atheromas might also progress in an unpredictable fashion. The variability in the development of clinical ASCVD with a CAC score of 0 AU is particularly evident in persons younger than 50 years of age, those with a strong family history of premature CVD events, or in the setting of severe CVD risk factors such as smoking, diabetes, poorly controlled hypertension, and in those with lifelong, genetic dyslipidemias (FH or elevated Lp[a]). [78][79][80][81] These are patient categories that in general would warrant aggressive ASCVD risk factor modification, even if CAC = 0 AU, to enhance the likelihood of maintaining as low an atheroma burden as possible over a lifetime. Conversely, if such high-risk patients do have CAC > 0 AU, this might provide a strong rationale for adherence to aggressive CVD risk factor modification, 82,83 including lipidlowering therapy or treatment intensification. 84,85 The effects of statins on the progression of atherosclerosis cannot be assessed through serial CAC scores alone because it does not assess the status of noncalcific plaque. Therapy does not reduce and might even increase CAC scores despite regression of noncalcific plaque components. 86 Accordingly, repeat CAC scanning is not recommended unless risk factor modification has been deferred through patient-physician shared decisionmaking.
Although CAC provides direct evidence of atherosclerotic plaque and a quantitative assessment of risk of attendant ASCVD events, controversy exists because of a paucity of large placebo-controlled RCTs and its cost-effectiveness for identification of patients suitable for statin therapy is uncertain, 87 even when applied only to the intermediate-risk group identified using risk algorithms. Importantly, at present, CAC scoring is not uniformly available or uniformly funded in Canada, and there are no cost-effectiveness analyses that represent the Canadian context. Values and preferences. Patients with modifiable ASCVD risk factors should be counselled with respect to the potential merit of preventing atherosclerosis itself, the substrate for clinical ASCVD events in the long term, through comprehensive ASCVD risk factor management. As outlined elsewhere, RCTs show the ASCVD risk reduction value of statin therapy in patients with intermediate risk and additional ASCVD risk factors (eg, HOPE 3, 16 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin [JUPITER] 88 ) in the absence of CAC testing or any testing to identify preclinical atherosclerosis. Accordingly, the patient-physician decision often does not require CAC scoring but might be strongly influenced by these other factors, including family history of premature ASCVD, other features suggesting genetic causes of dyslipidemia, or side effects of statin therapy. In some low-to intermediate-risk subjects, it might be reasonable to withhold statin therapy for CAC = 0 AU because of a favourable intermediateterm outcome. Exceptions would include cigarette smokers, patients with diabetes, those with poorly controlled hypertension, genetic dyslipidemias such as FH or elevated Lp(a) level, and patients with strong family history of premature ASCVD events. If available, a CAC > 100 AU is an indication for statin therapy regardless of FRS. For those with a CAC of 1-99 AU, individual decision-making is required because risk will not be reclassified and would remain intermediate. If a decision is made to withhold statin or lipid-modifying therapy on the basis of CAC = 0, this decision should be reevaluated during follow-up or if clinical circumstances change. CAC scoring should rarely be performed sooner than within 5 years to aid in this reevaluation. Finally, this section is restricted to application in patients who are at least 40 years of age for whom the traditional FRS assessment applies. Prevalence of calcification is a sequential aspect of the atherosclerotic process and might be absent in the early phases. Although CAC has been studied extensively for ASCVD risk prediction, the prevalence of CAC is lower in young patients compared with middle-aged and older patients and also in women vs men younger than 50 years of age. The totality of evidence from observational, pathophysiological, epidemiological, and Mendelian randomization studies and RCTs of lipid-lowering therapies indicate a causal relationship between LDL-C (as well as non-HDL-C and ApoB) and ASCVD and show that lower concentrations of plasma LDL-C levels are associated with a lower risk of ASCVD events extending to very low LDL-C concentrations (< 0.5 mmol/L). 15,[89][90][91][92][93][94][95][96] In RCTs, however, the absolute benefits of therapy were higher in subsets of patients with higher pretreatment LDL-C and/or additional ASCVD event risk enhancers who were at higher absolute risk.
To date, no clear target to which LDL-C or non HDL-C or ApoB levels should be lowered is clearly identified in RCTs, because such trials have generally used thresholds of LDL-C (or non-HDL-C or ApoB) levels for initiation or intensification of lipid-lowering therapies and fixed-dose lipid-lowering drugs (this pertains to statin RCTs and to RCTs that have used the additional use of nonstatin lipid-lowering agents, such as ezetimibe and PCSK9 inhibitors). Exceptions are the Scandinavian Simvastatin Survival Study (4S) trial in which the statin dose was up-or down-titrated aiming for within-trial total cholesterol levels of 3.0-5.2 mmol/L, 97 the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), which allowed for uptitration of simvastatin to 80 mg daily for in-trial LDL-C levels > 2.0 mmol/L, 98 and the ODYSSEY OUTCOMES trial in patients with a recent ACS, which allowed up-and downtitration of alirocumab aiming for an LDL-C target of 0.65-1.3 mmol/L; however, in these trials no randomized comparison with alternate lipid targets was performed. 90 Additionally, a number of trials comparing different intensities of statin treatment (lower vs higher statin dose) in secondary ASCVD prevention showed benefits for more intensive statin therapy; however, these trials did not explore targets of LDL-C lowering. 99,100 One RCT conducted in patients with a recent ischemic stroke showed reductions in major ASCVD events in patients allocated to a strategy of lower LDL-C (< 1.8 mmol/ L) vs higher targets (2.3-2.8 mmol/L). 101 Nevertheless, the lower LDL-C target in this trial is similar to the threshold for intensification of lipid-lowering therapy used in other recent trials and recommended in this guideline document. 89,102 A number of studies have shown improved ASCVD outcomes in secondary prevention patients reaching lower in-trial LDL-C levels, but these trials are observational and did not test targets of therapy. 103,104 Therefore, we recommend the use of thresholds for intensification of lipid therapy in secondary prevention. Most recent large RCTs have used an LDL-C threshold of 1.8 mmol/L for intensification of lipid-lowering therapy with nonstatin drugs in secondary ASCVD prevention patients receiving a maximally tolerated statin dose. Using this threshold, it is expected that most patients will achieve low and very low LDL-C levels, similar to those reached in clinical trials. 90,91 The IMPROVE-IT trial showed benefit of ezetimibe when used in addition to statin therapy in patients with a recent ACS. 98 The threshold for the additional use of ezetimibe was an LDL-C of 1.3 mmol/L, although in IMPROVE-IT most patients had a higher baseline LDL-C (average 2.45 mmol/L), statin therapy was restricted to only simvastatin (more potent statins were not used) and the modest 6% relative risk reduction was attained only after a long period of treatment (median 6 years). Therefore, we recommend the more robust LDL-C threshold of ≥ 1.8 mmol/L (or percentile equivalent non-HDL-C of ≥ 2.4 mmol/L or ApoB of ≥ 0.7 g/L).
Recent analyses of the large PCSK9 inhibitor trials (FOURIER 89 and ODYSSEY OUTCOMES 90 ) have identified subsets of patients with established CVD who are at very high risk and who derived the largest absolute benefit for intensification of lipid-lowering therapy with evolocumab and alirocumab, respectively. This includes patients with recent ACS and those with ASCVD and additional CV risk enhancers including diabetes mellitus, metabolic syndrome, polyvascular disease (vascular disease in ≥ 2 arterial beds), symptomatic peripheral artery disease, history of MI, MI in the past 2 years, previous coronary artery bypass graft surgery, LDL ≥ 2.6 mmol/L, heterozygous FH and Lp(a) ≥ 60 mg/dL. 90,[105][106][107][108][109][110][111][112][113] Intensification of lipid-lowering therapy with PCSK9 inhibitors is especially recommended in these subsets of very high risk patients (see Table 3), with or without the additional use of ezetimibe, which was used in only a small number of patients in these trials. Use of PCSK9 inhibitor therapy in these subsets of patients was shown to result in rapid and large reductions in LDL-C and in significant CVD event reduction. In most other secondary prevention patients, the use of ezetimibe followed by PCSK9 inhibitor therapy is recommended when the LDL-C ≥ 1.8 mmol/L.
The previous 2016 CCS dyslipidemia guidelines did not emphasize the role of plasma triglyceride levels as a threshold or target for lipid-lowering therapy aimed at reducing CVD risk. 1 However, the recent Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed a CV risk reduction (including reduction in CV death) in patients with ASCVD (as well as in those 50 years old or older with type 2 diabetes requiring medication treatment and at least 1 additional CVD risk factor) receiving moderate and high-intensity statin therapy with triglyceride levels of 1.5-5.6 mmol/L and LDL-C levels of 1.1-2.6 mmol/L. 114
# RECOMMENDATION
10. We recommend use of high-intensity statin therapy in addition to appropriate health behaviour modifications for all secondary prevention CVD patients. For patients who do not tolerate a high-intensity statins, we recommend the maximally tolerated statin dose (Strong Recommendation; High-Quality Evidence).
11. We recommend intensification of lipid-lowering therapy with a PCSK9 inhibitor (evolocumab or alirocumab)-with or without the additional use of ezetimibe-for secondary CV prevention patients shown to derive the largest benefit from PCSK9 inhibitor therapy in whom LDL-C remains ≥ 1.8 mmol/L (or non-HDL-C ≥ 2.4 mmol/L or ApoB ≥ 0.7 g/L) while receiving the maximally tolerated statin dose (Fig. 3; Strong Recommendation; Moderate-Quality Evidence). Secondary prevention patients shown to derive the largest benefit from intensification of statin therapy with PCSK9 inhibitor therapy are defined in Table 3.
12. We recommend intensification of lipid-lowering therapy with ezetimibe and/or PCSK9 inhibitor therapy for all secondary prevention CVD patients in whom LDL-C remains ≥ 1. It should be noted that one recommendation on the basis of the evidence review of PICO question 4 were overlapping with a recommendation for PICO question 5 and appear as part of that later section (Recommendation 15).
Values and preferences. On the basis of strong evidence for the benefit of intensive LDL-C lowering in secondary prevention, additional lipid-lowering therapy with ezetimibe and PCSK9 inhibitors might also be considered for ASCVD patients with an LDL-C < 1.8 mmol/L, especially for patients considered to be at high risk for recurrent ASCVD events. When initiating intensified lipidlowering therapy with nonstatin drugs, cost, and access to such therapies should be considered.
There is no evidence to suggest any CV or other risks associated with low and very low LDL-C levels in trials with moderate duration of follow-up. 104,115,116 Therefore, if intensified lipid-lowering therapy initiated for the previously listed thresholds result in low and very low LDL-C levels, lipid-lowering therapy does generally not require down-titration dose adjustment.
Practical tip. Although there is very good evidence supporting the use of PCSK9 inhibitors in patients with ASCVD (especially those listed in Table 3), access might be limited by provincial drug plan coverage in many jurisdictions. Patients with or without private drug plan coverage might need to pay some portion of the cost of these expensive medications. Patient support programs for these medications could be investigated to assist. Clinicians should discuss the indication and potential benefits of a PCSK9 inhibitor with the patient, along with the coverage issues and the potential costs to them. Shared decisionmaking remains key. Ezetimibe. Ezetimibe is a cholesterol absorption inhibitor that lowers LDL-C by approximately 20% in addition to a statin regimen or up to 15% as monotherapy. Only in 1 double-blind, RCT has the efficacy of ezetimibe been assessed in reducing CV risk. The IMPROVE-IT showed that ezetimibe 10 mg daily, compared with placebo and used in addition to statin therapy, showed a modest reduction in CV events in 18,144 patients with an ACS within the preceding 10 days. 98 The primary composite outcome of death from CV causes, major coronary events, and nonfatal stroke was 2% lower with ezetimibe (32.7 vs 34.7%; HR, 0.94; 95% CI, 0.89-0.99) for a number need to treat of 50 over 7 years. There were no significant differences between groups in the prespecified safety end points. This evidence informed the 2016 guideline recommendation for ezetimibe as second-line therapy to reduce CV risk in patients with ASCVD if their LDL-C targets were not reached with maximally tolerated statin therapy. 1 Subsequently, in the Heart Institute of Japan-Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome (HIJ-PROPER) trial open-label pitavastatin with ezetimibe (target LDL-C < 1.8 mmol/L) was compared with pitavastatin monotherapy (target LDL-C 2.3-2.6 mmol/L) in 1734 Japanese patients with an ACS. Over 3.9 years, the primary composite outcome of allcause death, nonfatal MI, nonfatal stroke, unstable angina, and ischemia-driven revascularization was not significantly different between groups (32.8 vs 36.9%; HR 0.89; 95% CI, 0.76-1.04). 117 PCSK9 inhibitors. Inhibitors of PCSK9 are recently available monoclonal antibodies that lower LDL-C between 50% and 70% when used in addition to statin therapy or as monotherapy. 118 Currently, two PCSK9 inhibitors are approved for use in Canada: alirocumab and evolocumab. Both are approved for the treatment of FH or ASCVD in patients as an adjunct to diet and maximally tolerated statin therapy (with or without ezetimibe) who require additional lowering of LDL-C.
The FOURIER trial enrolled 27,564 patients with clinical ASCVD and additional CVD risk factors whose LDL-C remained ≥ 1.8 mmol/L despite maximally tolerated statin therapy. Patients were randomized to receive evolocumab (140 mg subcutaneously (SC) every 2 weeks or 420 mg SC monthly) or placebo. 89 Baseline LDL-C was 2.4 mmol/L, which after 48 weeks was reduced to a median of 0.8 mmol/L (interquartile range, 0.5-1.2 mmol/L) in the evolocumab group. After 2.2 years of follow-up, the primary outcome of CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, and coronary revascularization was lower with evolocumab (9.8% vs 11.3%; HR, 0.85; 95% CI, 0.79-0.92) for a number needed to treat of 67. Evolocumab also reduced the secondary end point of CV death, nonfatal MI, and nonfatal stroke (5.9% vs 7.4%; HR, 0.80; 95% CI, 0.73-0.88). There was no significant difference in CV or all-cause death. Serious adverse events were similar between groups, although injection site reactions were higher with evolocumab (2.1% vs 1.6%; P < 0.001).
In the ODYSSEY OUTCOMES trial alirocumab was evaluated in 18,924 patients with a recent (1-12 months) ACS whose LDL-C was ≥ 1.8 mmol/L despite maximally tolerated statin therapy. 90 Participants were randomized to alirocumab (75 mg SC every 2 weeks to achieve an LDL-C of 0.6-1.3 mmol/L) or placebo. The dose of alirocumab was increased to 150 mg SC every 2 weeks if a participant's LDL-C level remained > 1.3 mmol/L or decreased or discontinued if their LDL-C level was < 0.6 mmol/L. The primary outcome of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization was lower with alirocumab (9.5% vs 11.1%; HR 0.85; 95% CI, 0.78-0.93) for a number needed to treat of 63 over 2 years. All-cause mortality was numerically lower with alirocumab (3.5% vs 4.1%), but on the basis of the authors' prespecified hierarchical testing, it is debatable whether this can be considered statistically significant. There was no significant difference in CV death between groups. There was no significant difference in serious adverse events, but injection site reactions were more common with alirocumab (3.8% vs 2.1%; P < 0.001).
A recent meta-analysis of 23 trials (including FOURIER and ODYSSEY OUTCOMES) compared PCSK9 inhibitors with control in 60,723 patients. 119 There was a significant reduction in MACE (6.2% vs 8.2%; risk ratio, 0.83; 95% CI, 0.78-0.88) with no significant difference in all-cause mortality (risk ratio 0.93; 95% CI, 0.85-1.02) or safety outcomes. Of note, these trials had short follow-up (median of 2.8 years) and therefore might not have been of sufficient duration to observe a mortality benefit.
Although ezetimibe or a PCSK9 inhibitor are reasonable options as monotherapy in patients with complete statin intolerance for LDL-C lowering, there is limited evidence to support either class as an alternative to statin therapy for ASCVD risk reduction. The Study of Alirocumab (REGN727/SAR236553) in Patients With Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular (CV) Risk, Who Are Intolerant to Statins (ODYSSEY ALTERNATIVE) trial enrolled 314 patients with statin intolerance who were randomized to alirocumab 75 mg SC every 2 weeks, ezetimibe 10 mg daily, or atorvastatin 20 mg daily. 120 At 24 weeks, alirocumab reduced LDL-C by a mean difference of 30% compared with ezetimibe. Skeletal muscle-related adverse effects were high overall, but significantly lower with alirocumab (33%) vs atorvastatin (46%) and similar to ezetimibe (41%). The Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3) trial included 218 patients considered to have previous statin intolerance who were randomized to evolocumab 420 mg SC monthly or ezetimibe 10 mg orally daily. 121 Evolocumab showed a significantly greater reduction in LDL-C compared with ezetimibe (mean difference, 36%) at 24 weeks. The incidence of muscle symptoms was relatively high in both groups, but the difference was not statistically significant (21% vs 29%; P = 0.17).
Clinical trials have shown that PCSK9 inhibitors are effective at lowering LDL-C in patients with heterozygous FH 102,120 and in certain patients with homozygous FH, 91 but there is currently a paucity of ASCVD outcome data in these populations.
# Primary prevention
There are currently no RCT data supporting the use of PCSK9 inhibitors to reduce CV events in patients who do not have established ASCVD (ie, primary CV prevention) or FH.
# IPE.
Until recently, contemporary trials of omega-3 fatty acid supplements have not shown a CV benefit in patients with or without CVD. 123,124 Previously, the Japan EPA Lipid Intervention Study (JELIS) showed a reduction in CV events with 1800 mg daily of eicosapentaenoic acid (EPA) combined with a statin, compared with statin monotherapy, in Japanese patients with a total cholesterol ≥ 6.5 mmol/L; however, it was an openlabel trial and the primary outcome was driven by a minor reduction in unstable angina. 125 The REDUCE-IT assessed the effect of a pharmaceutical formulation of purified ethyl EPA (IPE), which was recently approved by Health Canada. 114 In total, 8179 patients were included with established ASCVD (or diabetes and ≥ 1 ASCVD risk factor) who were receiving statin therapy but had an elevated fasting triglyceride level of 1.5-5.6 mmol/L (baseline 2.4 mmol/L). Most patients (71%) were in the secondary prevention cohort. Participants were randomized to 2000 mg of IPE orally twice daily (4 g total per day) or mineral oil as placebo. At 1 year, participants' triglyceride level in the IPE group was modestly reduced by 0.4 mmol/L (approximately 18%) from baseline. IPE reduced the primary outcome of CV death, nonfatal MI, nonfatal stroke, unstable angina, or CV revascularization (17.2% vs 22.0%; HR, 0.75; 95% CI, 0.68-0.83) for a number needed to treat of 21 over 4.9 years. IPE also significantly reduced the composite of CV death, nonfatal MI, and nonfatal stroke (11.2% vs 14.8%; HR, 0.74; 95% CI, 0.65-0.83), as well as CV death (4.3% vs 5.2%; HR, 0.80; 95% CI, 0.66-0.98), but not all-cause death. Atrial fibrillation and peripheral edema were significantly higher with IPE. Because IPE is a purified form of ethyl EPA, the results of REDUCE-IT cannot be extrapolated to other nonprescription omega-3 fatty acids, which typically contain a mixture of EPA and docosahexaenoic acid (DHA).
The Outcomes Study to Assess Statin Residual Risk Reduction With Epanova in High CV Risk Patients With Hypertriglyceridemia (STRENGTH) trial aimed to evaluate a pharmaceutical carboxylic acid formulation of EPA and DHA (referred to as omega-3 CA) to prevent MACE in 13,078 patients with hypertriglyceridemia (2.0-5.6 mmol/L), low HDL-C (< 1.2 mmol/L for women and < 1.1 mmol/L for men) who were receiving statin therapy, and were at increased risk of CVD. 128 Patients were randomized to receive 4 g/d of omega-3 CA or corn oil placebo. The trial was discontinued prematurely after a median follow-up of 3.5 years for futility. The primary end point of CV death, nonfatal MI, nonfatal stroke, unstable angina requiring hospitalization, and coronary revascularization was not significantly different between groups (12.0% vs 12.2%; HR, 0.99; 95% CI, 0.90-1.09). Patient-reported gastrointestinal disorders were more common in patients in the omega-3 CA group (24.7% vs 14.7%).
Other therapies. There are no new recommendations regarding the use of fibrates, niacin, and bile acid sequestrants since the 2016 guidelines. 1
# Ongoing trials
There are a number of ongoing trials of nonstatin therapy. -4) is evaluating whether this LDL-C reduction with inclisiran translates to a reduction in MACE among patients with CVD. 130 The Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS (dal-GenE) study aims to assess the effect of dalcetrapib, a cholesteryl ester transfer protein inhibitor (not approved by Health Canada), in patients with a recent ACS and specific genotype. 131 The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial is evaluating the effect of bempedoic acid, a novel adenosine triphosphate (ATP) citrate lyase inhibitor not approved in Canada, in patients with, or at high risk for, ASCVD who are statinintolerant. 132 It should be noted that 2 recommendations on the basis of the evidence review of PICO question 5 were overlapping with recommendations made for PICO question 4 and appear as part of that earlier section (Recommendations 1 and 2).
Values and preferences. None of these agents have been evaluated in RCTs against each other. Therefore, it is difficult to assess the relative benefit of each therapy. Also, to date these agents have primarily been evaluated in patients with preexisting ASCVD (ie, secondary prevention). The choice of agent should be on the basis of individual patient factors, their values and preferences, and practical considerations, such as access, cost, and adherence. Because ezetimibe lowers LDL-C level by approximately 20% when used in addition to a statin, if a patient's LDL-C is well above the threshold for therapy intensification (ie, > 2.2 mmol/L or > 20% above threshold), it might be preferable to consider a PCSK9 inhibitor as second-line therapy. However, because of cost considerations, some insurance providers might require a trial of ezetimibe before approving the use of a PCSK9 inhibitor. IPE should be preferentially reserved for patients aged ≥ 45 years of age (or ≥ 50 years of age with ≥ 1 CVD risk factor) who are receiving maximally tolerated statin therapy but have a residual elevated triglyceride level (1.5-5.6 mmol/L). Because IPE is a purified form of ethyl EPA, it should not be inferred that the same CV benefits could be derived from the consumption of omega-3 polyunsaturated fatty acid (PUFA) formulations that include EPA alone, EPA and DHA mixtures, or fish oils from supplements or dietary sources.
The recommendation for treatment of patients with FH is on the basis of the 2018 update to the CCS position statement on FH. 134 The recommendation for PCSK9 inhibitors to lower LDL-C level is on the basis of highquality evidence; however, there is a relative paucity of RCT evidence to support any agent to reduce the risk of CV events in FH patients.
Practical tip. Unlike the use of PCSK9 inhibitors in patients with ASCVD, access to these medications is covered by most provincial drug plans for patients with heterozygous FH (with or without ASCVD) with LDL-C level above the threshold. Although the evidence for IPE to decrease the risk of CV events in patients with ASCVD, or with diabetes and ≥ 1 CVD risk factors is good, it is relatively new and most provincial drug plans do not yet cover this expensive medication. Private plans might cover this drug for patients on the basis of specific criteria and there is a manufacturer patient assistance program that might facilitate access. As part of shared decision-making, clinicians should discuss the indication and potential benefits of IPE, as well as the coverage issues and the potential patient costs. PICO 6: In primary and secondary prevention, what is the evidence for CV benefit of omega-3 from (1) dietary sources; and/or (2) over-the-counter formulations/ supplements?
Despite the success of the REDUCE-IT trial in showing a purified prescription IPE at 4 g/d reduces major CVD events in statin-treated patients with elevated triglyceride levels who have established CVD or diabetes and at least 1 CVD risk factor, 114 supplementation with overthe-counter long-chain omega-3 PUFAs marketed as natural health products in Canada that include EPA alone, EPA and DHA mixtures, or fish oils from supplements or dietary sources does not offer any clear advantages for CVD event risk reduction. We updated a systematic review and meta-analysis of RCTs with data from 2 subsequently completed RCTs, A Study of Cardiovascular Events in Diabetes (ASCEND) 135 and Vitamin D and Omega-3 Trial (VITAL), 136 which failed to show a clear CV benefit of supplementation with long chain omega-3 PUFAs in more than 130,000 randomized participants. 137 Another large CVD outcomes trial of a pharmaceutical drug of mixed long-chain omega-3 (largely EPA and DHA) carboxylic acids (omega-3 CA) at 4 g/d with similar entry criteria to the REDUCE-IT trial was also discontinued early by the data safety monitoring board for futility with the drug unlikely to show a benefit to patients. 126 Pooled evidence from RCTs [138][139][140] and individual large RCTs, 141 however, have shown consistent triglyceride-lowering effects at high doses (2-4 g/d) of omega-3 PUFAs, independent of CVD event risk reduction. RECOMMENDATION 16. We do not recommend the use of over-the-counter omega-3 polyunsaturated fatty acid supplements (marketed as natural health products in Canada) to reduce CVD risk (Strong Recommendation; High-Quality Evidence).
Values and preferences. Although there is no apparent overall CVD event risk benefit, patients might choose to use these supplements for other indications including the management of high triglycerides, for which very high doses are required (4 g/d), and for which fibrates are generally more effective. Individuals should be aware that, in addition to marine sources, there are different preparations of long-chain omega-3 PUFAs high in DHA and EPA from algal and yeast sources, both of which are suitable for vegans. There is also alpha-linolenic acid from plant sources that do not contain DHA or EPA including flax seeds, chia seeds, and some oils such as canola and soybean oil, which have little or no effect on triglycerides.
# Conclusions
In this focused revision of the CCS guidelines for the management of dyslipidemia, the committee has distilled several years of new research in CV risk assessment (especially as it pertains to women), lipoprotein biomarkers, and coronary artery calcium scanning. The committee also reviewed several major landmark RCTs of novel therapies to treat dyslipidemia. On the basis of the best available evidence to date, we have developed several new recommendations for clinicians to more accurately assess their patients' CV risk and optimally manage their lipid disorders. We acknowledge that the science surrounding CV risk and dyslipidemia management is evolving and therefore these recommendations can only be viewed as the best practices on the basis of the currently available evidence. Nonetheless, the objective of any guideline is to provide clinicians with the most up-to-date knowledge and tools to help them make informed decisions with their patients. Appendix 1 provides an at-a-glance, step-wise summary of the management of adult patients with dyslipidemia for the prevention of cardiovascular disease, based on the 2021 CCS dyslipidemia guidelines.
The past few years has realized significant progress in the management of dyslipidemia, with several new therapies currently available and more in development. With continued efforts to prioritize healthy lifestyles and the use of new pharmacotherapeutic options available to treat eligible patients, we hope to realize further reductions in morbidity and mortality from ASCVD in Canada.
# Acknowledgements
We are grateful to Andrea Quattini (Assistant Librarian, Schulich Library of Physical Sciences, Life Sciences, and Engineering McGill University, Montreal, Quebec) for her assistance in searching the medical literature for evidence to be reviewed and inform the recommendations for PICO question 1. We also thank Andre Mattman, MD, St Paul's Hospital Medical Biochemistry Laboratory, Vancouver, British
# Supplementary Material
To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at https://doi.org/10.1016/j. cjca.2021.03.016. | None | None |
2fdc04b61b87a981e41c657590d6c7042f594714 | cma | None | These guidelines are not binding on nurses, other health providers, or the organizations that employ them. The use of these guidelines should be flexible and based on individual needs and local circumstances. They constitute neither a liability nor discharge from liability. While every effort has been made to ensure the accuracy of the contents at the time of publication, neither the authors nor the Registered Nurses' Association of Ontario (RNAO) gives any guarantee as to the accuracy of the information contained in them or accepts any liability with respect to loss, damage, injury, or expense arising from any such errors or omission in the contents of this work.With the exception of those portions of this document for which a specific prohibition or limitation against copying appears, the balance of this document may be produced, reproduced, and published in its entirety, without modification, in any form, including in electronic form, for educational or non-commercial purposes. Should any adaptation of the material be required for any reason, written permission must be obtained from RNAO. Appropriate credit or citation must appear on all copied materials as follows: Registered Nurses' Association of Ontario. Supporting adults who anticipate or live with an ostomy. 2nd ed. Toronto (ON): Registered Nurses' Association of Ontario; 2019.Declarations of competing interest that might be construed as constituting an actual, potential, or apparent conflict were made by all members of the RNAO expert panel, and members were asked to update their disclosures throughout the guideline development process. Information was requested about financial, intellectual, personal, and other interests and documented for future reference. No limiting conflicts were identified. Details regarding disclosures are available at .# Table of Contents
# Table of Contents
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Purpose and Scope Purpose RNAO's BPGs are systematically developed, evidence-based documents that include recommendations on specific clinical, healthy work environment, and health system topics that are intended for nurses, members of the interprofessional team, educators, leaders, policy-makers, researchers and persons and families with lived experience. BPGs promote consistency and excellence in clinical care, education, and administrative practices and policies with the aim of achieving optimal health outcomes for people, communities, and the health system as a whole.
This BPG replaces the RNAO BPG Ostomy Care and Management, which was released in 2009. The purpose of this BPG is to provide nurses and the interprofessional team with evidence-based recommendations for the most effective strategies to support adults (18 years and older) who anticipate or live with an ostomy that will (a) promote self-management G , (b) enhance access and delivery of care, and (c) lead to positive health outcomes. For this BPG, persons who anticipate an ostomy are those who are in the preoperative phase and awaiting an ostomy surgery. This BPG recognizes that adults who anticipate or live with an ostomy and their support network G are experts in their health and decision making; collaboration among the interprofessional team, the person anticipating or living with an ostomy, and their support network (if needed) therefore is essential for achieving improved health outcomes.
In October 2017, RNAO convened an expert panel to determine the scope of this revised BPG and to develop recommendation questions to inform the systematic reviews G . The RNAO expert panel included persons with lived experience and was interprofessional in composition, comprising of individuals with knowledge and experience in clinical practice, education, research, and policy across a range of health service organizations, practice areas, and sectors. These experts shared their insights on supporting and caring for adults who anticipate or live with an ostomy across the continuum of care (e.g., acute care, rehabilitation, community, and primary care). A systematic and comprehensive analysis was completed by the RNAO Best Practice Guideline Development and Research Team and the RNAO expert panel to determine the scope of this BPG and to prioritize recommendation questions for its development (see Appendix D).
# Scope
To determine the scope of this BPG, the RNAO development team conducted the following steps:
Reviewed the previous RNAO BPG, Ostomy Care and Management (2009). Conducted a guideline search and gap analysis.
Undertook a scoping review G of the literature to determine the depth of peer-reviewed studies in the area of pediatric populations (younger than 18 years) living with an ostomy.
Conducted six key informant interviews.
Held two virtual focus groups with experts in the field, including front-line health providers G , researchers, and persons with lived experience.
The analysis informed the scope of this BPG. This BPG will focus on adults (18 years and older) who live with or anticipate an ostomy. The scoping review identified a lack of peer-reviewed studies addressing pediatric populations living with an ostomy. It was thus concluded that a separate search for evidence and approach to guideline development was warranted to address this population.
Regulated health provider: In Ontario, the Regulated Health Professional Act, 1991 (RHPA) provides a framework for regulating 23 health professions, outlining the scope of practice and the profession-specific controlled or authorized acts that each regulated professional is authorized to perform when providing health care and services (5).
Unregulated health provider: Unregulated health providers fulfill a variety of roles in areas that are not subject to the RHPA. They are accountable to their employers but not to an external regulating professional body (e.g., College of Nurses of Ontario). Unregulated health providers fulfill a variety of roles and perform tasks that are determined by their employer and employment setting. Unregulated health providers only have the authority to perform a controlled act as set out in the RHPA if the procedure falls under one of the exemptions set out in the Act (6).
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Ostomy care program: An organization-level approach to standardize care for persons who anticipate or live with an ostomy. The ostomy care program includes structured treatment, management, and follow-up strategies developed by an interprofessional team, which may consist of NSWOCs, nurses, surgeons, physicians, social workers, dieticians, and pharmacists (among others).
Parastomal hernia: Occurs when one or more loops of the bowel protrude through the abdominal wall, creating a bulge around the peristomal skin G (7).
Topics Outside the Scope of this Best Practice Guideline
The following conditions and topics are not covered within the scope of this BPG:
Pharmaceutical interventions for the prevention and management of ostomy-related complications.
Surgical procedures in the creation of a stoma.
Surgical interventions for the prevention and management of ostomy-related complications.
Pediatric populations anticipating or living with an ostomy.
# Recommendation Questions
Within the determined scope defined above, the following priority recommendation questions and outcomes were developed by the RNAO expert panel and informed the development of this BPG:
Outcomes: Psychological health status and self-identity.
Note: These priority recommendation questions are condensed versions of the more comprehensive PICO G (population, intervention, comparison, outcomes) research questions developed by the RNAO expert panel to guide the systematic reviews and development of this BPG. For the PICO research questions and the detailed process of how the RNAO expert panel determined these priority questions and outcomes, see Appendix D.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Recommendations
Recommendations in this BPG address access to the appropriate specialist to support comprehensive care (i.e., NSWOCs G ), the need for a standardized ostomy care program within health service organizations, guidance on the prevention of parastomal hernias, and quality of life assessments in adults who anticipate or live with an ostomy. The evidence-based recommendations in this BPG are applicable to all practice settings where adults who anticipate or live with an ostomy are accessing services (such as, but not limited to, acute care, long-term care, community settings, and rehabilitation settings).
In this BPG, no recommendation questions were identified that addressed the core education and training strategies required for curricula, ongoing education, and professional development of nurses or the interprofessional team in order to support adults living with or anticipating an ostomy. Please refer to Appendix C for education statements G that educators, managers, administrators, and academic and professional institutions can use to support the uptake of this BPG.
Note: Recommendations in this BPG were developed for adults who anticipate or live with an ostomy, but in some cases, recommendations also may be applicable to adults with continent diversions G (bowel or urinary).
# RNAO Guidelines and Resources that Align with this Best Practice Guideline
Other RNAO guidelines and other resources may support implementation of this BPG. See Appendix B for RNAO guidelines and other resources on the following related topics:
Client centred learning.
Culturally sensitive care.
Implementation science, implementation frameworks, and resources.
Interprofessional collaboration.
Person-and family-centred care.
Self-management of chronic conditions.
Therapeutic relationships.
For more information on the guideline development process, systematic reviews, and search strategy for this BPG, see Appendix D.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Interpretation of Evidence and Recommendation Statements
RNAO Guidelines are developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) G and Confidence in the Evidence from Reviews of Qualitative Research (CERQual) G methods. For more information about the guideline development process, including the use of GRADE and GRADE-CERQual methods, refer to Appendix D.
# Certainty of Evidence
The certainty of evidence (i.e., the level of confidence we have that an estimate of effect is true) for quantitative research is determined using GRADE methods (8). After synthesizing the evidence for each prioritized outcome, the certainty of evidence is assessed. The overall certainty of evidence is then determined by considering the certainty of evidence across all prioritized outcomes per recommendation question. GRADE categorizes the overall certainty of evidence as high, moderate, low, or very low. See Table 1 for the definition of these categories.
# Table 1: Certainty of Evidence
# CERTAINTY OF EVIDENCE DEFINITION High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
# Very Low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Confidence in Evidence
The confidence in evidence for qualitative research G (i.e., the extent to which the review finding is a reasonable representation of the phenomenon of interest) is determined using GRADE-CERQual methods (hereafter referred to as CERQual) (9). For qualitative evidence, an overall judgment of the confidence is made per finding in relation to each recommendation statement, as relevant. CERQual categorizes the confidence in evidence as high, moderate, low, or very low. See Table 2 for the definitions of these categories.
# CONFIDENCE IN EVIDENCE DEFINITION High
It is highly likely that the review finding is a reasonable representation of the phenomenon of interest.
# Moderate
It is likely that the review finding is a reasonable representation of the phenomenon of interest.
# Low
It is possible that the review finding is a reasonable representation of the phenomenon of interest.
# Very Low
It is not clear whether the review finding is a reasonable representation of the phenomenon of interest.
Source: Reprinted from Lewin S, Booth A, Glenton C, et al. Applying GRADE-CERQual to qualitative evidence synthesis findings: introduction to the series. Implement Sci. 2018;13(Suppl 1):1-10. Table 3, Description of level of confidence in a review finding in the CERQual approach; p. 6. Reprinted with permission.
Note: The assigned certainty and/or confidence in evidence can be found directly below each recommendation statement. For more information on the process of determining the certainty and/or confidence in the evidence and the documented decisions made by RNAO Guideline Development Methodologists, see Appendix D.
# Strength of Recommendations
Recommendations are formulated as strong or conditional by considering the certainty and/or confidence in evidence and the following key criteria (see Discussion of Evidence for definitions):
Balance of benefits and harms.
Values and preferences.
Potential impact on health equity.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Strong Recommendation
"A strong recommendation reflects the expert panel's confidence that the desirable effects of an intervention outweigh its undesirable effects (strong recommendation for an intervention) or that the undesirable effects of an intervention outweigh its desirable effects (strong recommendation against an intervention)" (8). A strong recommendation implies that the majority of persons will be best served by the recommended action (8).
# Conditional Recommendation
"A conditional recommendation reflects the expert panel's confidence that the desirable effects probably outweigh the undesirable effects (conditional recommendation for an intervention) or undesirable effects probably outweigh desirable effects (conditional recommendation against an intervention), but some uncertainty exists" (8). A conditional recommendation implies that not all persons will be best served by the recommended action: "there is a need for more careful consideration of personal circumstances, preferences, and values" (8).
# Note:
The strength of the recommendation statement is detailed directly below each recommendation statement and in the Summary of Recommendations. For more information on the process the expert panel used for determining the strength of each recommendation, please see Appendix D.
# Discussion of Evidence
The Discussion of Evidence that follows each recommendation includes the following main sections:
- Benefits and Harms: Identifies the potential desirable and undesirable outcomes reported in the literature when the recommended practice is used. Content in this section solely includes research from the systematic review.
# Values and Preferences:
Denotes the relative importance or worth of the health outcomes of following a particular clinical action from a person-centered perspective. Content for the Values and Preferences section may include research from the systematic reviews and (when applicable) the RNAO expert panel.
# Health Equity:
Identifies the potential impact that the recommended practice could have on health across different populations. Content for the Health Equity section may include research from the systematic reviews and (when applicable) the RNAO expert panel.
# Expert Panel Justification of Recommendation:
Provides a rationale for why the expert panel made the decision to rate a recommendation as strong or conditional.
Practice Notes: Highlights pragmatic information for nurses and members of the interprofessional team. This section may include supporting evidence from the systematic review and/or from other sources (e.g., the RNAO expert panel).
- Supporting Resources: Includes a list of relevant resources (such as websites, books, organizations, and more) that support recommendations. Content listed in this section was not part of the systematic review and therefore not all content was quality appraised. As such, the list is not exhaustive and the inclusion of a resource in one of these lists does not imply an endorsement from RNAO.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Summary of Recommendations
This Guideline replaces the RNAO BPG Ostomy Care and Management (2009). A summary of how the recommendations in this Guideline compare to the recommendations in the previous Guideline is available at .
# RECOMMENDATIONS STRENGTH OF THE RECOMMENDATION
Recommendation Question #1: Should access to nurses specialized in wound, ostomy, and continence or no access to nurses specialized in wound, ostomy, and continence be recommended?
Outcomes: Peristomal dermatitis, peristomal irritation, ostomy leakage, quality of life, hospital length of stay and readmission rates to hospital .
# Recommendation 1 .1
The expert panel recommends that health service organizations provide access to nurses specialized in wound, ostomy, and continence as essential members of the interprofessional team for all persons who anticipate or live with an ostomy .
# Strong Recommendation 1 .2:
The expert panel recommends that access to nurses specialized in wound, ostomy, and continence includes the following support within the ostomy care continuum: Performing preoperative stoma site marking . Providing perioperative education and counselling . Providing ongoing follow-up consultation and management . Involving persons who anticipate or live with an ostomy and their support network in all steps of care, as appropriate .
# Strong
Recommendation Question #2: Should an ostomy care program or no ostomy care program be recommended?
Outcomes: Patient satisfaction, hospital length of stay, readmission rates to hospital and staff satisfaction.
# Recommendation 2 .1:
The expert panel recommends that health service organizations implement an internal expertguided, standardized ostomy care program that is developed using an interprofessional, teambased approach .
# Strong BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Recommendation 2 .2:
The expert panel recommends that health service organizations include the following interventions within a standardized ostomy care program:
Preoperative education and counselling on ostomy surgery, daily living, and self-care . Postoperative education regarding stoma self-management and potential complications . Discharge planning that is based on a readiness criteria and includes follow-up information . Scheduled home visits and telephone follow-up within the first four weeks . Access to nurses specialized in wound, ostomy, and continence perioperatively and on an ongoing basis, as necessary .
# Strong
Recommendation Question #3:
Should prevention strategies for parastomal hernia development or no prevention strategies for parastomal hernia development be recommended?
Outcomes: Parastomal hernia rates .
# Guideline Evaluation
As you implement the recommendations in this BPG, we ask you to consider how you will monitor and evaluate its implementation and impact.
The Donabedian model informs the development of indicators for evaluating quality health care, which includes three categories: structure, process, and outcome (10).
Structure describes the required attributes of the health system, health service organization or academic institution to ensure quality care. It includes physical resources, human resources, and information and financial resources.
Process examines the health-care activities being provided to, for, and with persons or populations as part of the provision of quality care.
Outcome analyzes the effect of quality care on the health status of persons and populations, health workforce, health service organizations, academic institutions or health systems (10).
For additional information, please refer to the RNAO Toolkit: Implementation of Best Practice Guidelines, Second Edition (2012).
Tables 3, 4, and 5 provide potential structure, process and outcome measures to assess Guideline success. It is important to evaluate evidence-based practice changes when implementing a Guideline. Select the measures most relevant to the practice setting. There are few data repositories/indicator libraries available for ostomy support in Ontario and Canada. The following measures will support quality improvement and evaluation.
Table 3 provides potential structure measures associated with all recommendation statements, to assess attributes related to human resources.
# Stakeholder Acknowledgment
As a component of the guideline development process, feedback was obtained from participants across a wide range of health service organizations, practice areas, and sectors. Participants include nurses and people with lived experience. Stakeholders G representing diverse perspectives were solicited for their feedback (see Appendix D). RNAO wishes to acknowledge the following individuals for their contribution in reviewing this BPG. Stakeholder reviewers have given consent to the publication of their names and relevant information in this BPG.
# Background Context
What is an Ostomy?
An ostomy is a surgically created opening in the abdominal wall that results in the external diversion of feces and urine (1). An ostomy may be permanent or temporary, and the surgery is performed for various etiologies, including (but not limited to) diverticulitis, colorectal cancer, bowel obstruction, inflammatory bowel disease G , or bladder cancer (11). Each procedure results in a stoma, which is the end of the small or large intestine that can be seen protruding through the abdominal wall (2). The most common types of ostomy are the following:
Colostomy: A surgically created opening from the colon to the abdominal wall to allow the elimination of feces (3).
Ileostomy: A surgically created opening from the last part of the small intestine (ileum) to the abdominal wall to allow elimination of small bowel effluent (3).
Urostomy: A surgically created opening to divert the flow of urine by transplanting the ureters into an isolated segment of the ileum, bringing one end through the abdominal wall to create a stoma. Urine flows from the kidney to the ureters, then through the ileal conduit, exiting through the stoma (3).
For some people, it is possible to have a continent bowel or urinary diversion in which an internal reservoir is surgically created using a section of the bowel to collect feces or urine. Continent diversions may or may not result in the creation of a stoma, and they eliminate the necessity for a pouching system G to be worn outside the body (2).
# Prevalence and Impact of Living with an Ostomy
An estimated 1.3 million people around the world have an ostomy, whether it be an ileostomy, colostomy, or urostomy (12). North Americans constitute a large portion of this population, with an estimated 750,000 living with an ostomy (13). In Canada alone, approximately 13,000 new ostomy surgeries are performed every year (13).
The creation of an ostomy is a life-changing event and has implications for various aspects of a person's healthrelated quality of life (11). Living with an ostomy may cause changes to physical and emotional well-being, and it may require lifestyle adjustments. One of the most common physical outcomes of living with an ostomy is the risk for stoma-related complications. Approximately 20 per cent to 71 per cent of persons with an ostomy experience stoma related complications, the most common being ostomy leakage and peristomal skin problems (14). Peristomal skin complications affect one third of persons with a colostomy and two thirds of persons with a urostomy or ileostomy (15).
Another common complication is the incidence of parastomal hernias. A parastomal hernia occurs when one or more loops of the bowel protrude through the abdominal muscle, creating a bulge around the peristomal skin (7).
Living with a parastomal hernia has been associated with impairments in quality of life, stressors related to body image, fatigue, and the physical burden of the hernia (1). The reported incidence of parastomal hernia varies widely within the literature, ranging from 0 per cent to 78 per cent; it is caused by risk factors such as high body mass index and waist circumference (7,16,17). When persons living with an ostomy have access to evidence-based care provided by knowledgeable and skilled health providers, however, many of these complications are preventable and treatable (18,19).
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Living with an ostomy can impact a person's psychological health and affect social functioning (20). For instance, living with an ostomy can negatively impact body image, sexual function, mood, and daily activities, thus impairing a person's overall psychological health (11,21). Lifestyle considerations and adjustments may also be required for aspects of daily life, such as diet, exercise, intimacy, and self-management of the ostomy (13). Despite so many challenges, if the right resources and supports are in place, it is certainly possible for persons to live an active and meaningful life after ostomy surgery.
There currently are no definite statistics determining the costs associated with living with an ostomy. However, maintaining an ostomy through the regular use of supplies can be expensive. In Canada, the type and availability of financial support for adults living with an ostomy varies across provinces, ranging from complete coverage to no coverage at all, resulting in many people having to pay out-of-pocket fees (22). Living with an ostomy, whether it is temporary or permanent, also increases the risk of costly complications (23). Research suggests that costs of care are substantially higher for persons with peristomal skin complications related to an ostomy (24). It is estimated that average treatment costs are $77 CDN greater (including pouching systems and accessories) over a seven-week period of treatment for people with peristomal skin complications versus those without peristomal skin complications (25).
# Streamlining Ostomy Support
In accordance with the Charter of Ostomates Rights (Appendix K), persons living with an ostomy have the right to comprehensive, personalized, and accessible care (26). As the number of persons living with an ostomy increases, the need to provide such care becomes increasingly critical for health service organizations and health systems in order to meet the needs of the persons they serve (23).
The interprofessional team supporting persons living with an ostomy throughout the health continuum includes (but is not limited to) NSWOCs, nurses, surgeons/physicians, social workers, dietitians, and pharmacists. In particular, NSWOCs are designated experts who are highly trained, both in the psychological aspects of care and the care of persons with fecal and urinary diversions (27). "NSWOC" is a protected title and limited to certain jurisdictions, however, its equivalent may be represented in other locations with titles such as stoma nurse, WOC nurse, or ostomy nurse. An NSWOC is deemed certified if they graduate from a WCET®-accredited ostomy education program and pass a national certification exam (4). Ostomy champion roles may assist and support the NSWOC expert in many organizations, but they are not independent subject experts.
Comprehensive ostomy care, which includes access to expert health providers, is related to improved health outcomes. Comprehensive care requires collaboration among the interprofessional team, the person anticipating or living with an ostomy and their support network, along with standardized work processes and care pathways. Furthermore, use of evidence-based practice enables informed decision making at the person, organization, and system levels to ensure improved health outcomes. Consistent use of evidence-based practices related to ostomy care is ultimately enabled by policies and programs that standardize work processes.
# Conclusion
Prevention strategies, timely interventions, knowledgeable providers, and accessible resources are required to facilitate optimal well-being for persons who anticipate or live with an ostomy. This BPG provides evidence-based best practice recommendations that will help health service organizations and the interprofessional team to support adults (18 years and older) anticipating or living with a colostomy, ileostomy, or urostomy to enhance access and care delivery, promote self-management, and lead to positive health outcomes. The expert panel recommends that health service organizations provide access to nurses specialized in wound, ostomy, and continence as essential members of the interprofessional team for all persons who anticipate or live with an ostomy.
# RECOMMENDATIONS
# Strength of recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
Evidence demonstrates that access to a NSWOC may promote positive health outcomes in persons living with or anticipating an ostomy. Studies examined the benefits of one or more of the following interventions: performing preoperative stoma site marking G , providing perioperative G education and counselling, providing ongoing followup consultation and management, and involving persons who anticipate or live with an ostomy and their support network. These interventions were provided by a NSWOC (or a NSWOC as a key member of the interprofessional team) compared to no access to a NSWOC in persons who anticipate or live with an ostomy.
The studies found that regardless of the intervention, access to a NSWOC may reduce the incidence of peristomal dermatitis or skin irritation, readmission rates to hospital, hospital length of stay and the rates of ostomy leakage; access also may improve quality of life in persons anticipating or living with an ostomy across various health settings (community and hospital) (11,(28)(29)(30)(31)(32)(33)(34)(35). The evidence was of low certainty due to limitations in how studies were conducted, use of different tools to measure outcomes across studies and the small number of study participants. In qualitative studies reporting on facets of quality of life, persons living with an ostomy indicated that care provided by NSWOCs could help address their psychosocial concerns and help them resume a normal life (36,37). The qualitative evidence was of low confidence due to limitations in how studies were conducted and the small number of study participants. There were no harms related to the interventions provided by NSWOCs in the literature.
For more detailed information of the impact of the intervention (access to NSWOCs) on each of the prioritized outcomes (peristomal dermatitis, peristomal irritation, ostomy leakage, quality of life, hospital length of stay and readmission rates to hospital), please refer to the evidence profiles available here: .
See Recommendation 1.2 for details on the specific interventions provided by NSWOCs and their associated benefits and harms.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Values and Preferences
The evidence indicates that persons with an ostomy attributed high value to the role of the NSWOC. Persons with an ostomy value the opportunity to speak about their challenges and concerns, and to receive timely follow-up advice from a NSWOC (37).
# Health Equity
The expert panel suggests that availability and timely access to expert assessment and management provided by a NSWOC in all care settings would improve health equity, particularly in rural settings. Literature demonstrates that living in a rural area was associated with a lack of access to expert ostomy assessment and management (38). Group education provided by NSWOCs may be more effective at increasing quality of life for persons living with an ostomy in rural areas, as these persons may be at greater risk for social isolation (32).
# Expert Panel Justification of Recommendation
There were benefits to having access to NSWOCs and no harms were found. However, the certainty in this evidence was low. The expert panel determined that persons would value improvements in outcomes and attributed high value to ensuring that persons who anticipate or live with an ostomy have equitable access to NSWOCs to decrease the risk of complications (peristomal dermatitis, peristomal irritation and ostomy leakage), improve organization-related outcomes (readmission rates to hospital and hospital length of stay) and improve quality of life across populations. Therefore, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
There are no practice notes associated with this recommendation. The expert panel recommends that access to nurses specialized in wound, ostomy, and continence includes the following support within the ostomy care continuum:
Performing preoperative stoma site marking.
Providing perioperative education and counselling.
Providing ongoing follow-up consultation and management.
Involving persons who anticipate or live with an ostomy and their support network in all steps of care, as appropriate.
# Strength of recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
Studies examined one or more of the following interventions: performing preoperative stoma site marking, providing perioperative education and counselling, providing ongoing follow-up consultation and management, and involving persons with an ostomy and their support network in all steps of care, as appropriate. These interventions were provided by a NSWOC (or the NSWOC as a key member of the interprofessional team) compared to no access to an NSWOC. The studies found benefits in outcomes for persons anticipating or living with an ostomy across various health settings (community and hospital) (11,(28)(29)(30)(31)(32)(33)(34)(35). The evidence was of low certainty due to limitations in how studies were conducted, use of different tools to measure outcomes across studies and the small number of study participants. For qualitative studies, the confidence in evidence was also low due to limitations in how studies were conducted and the small number of study participants. There were no harms related to these interventions provided by NSWOCs in the literature.
For more detailed information of the impact of the intervention on each of the prioritized outcomes (peristomal dermatitis, peristomal irritation, ostomy leakage, quality of life, hospital length of stay and readmission rates to hospital), refer to the evidence profiles available here: .
The key interventions provided by the NSWOC throughout the ostomy care continuum and the associated health outcomes are outlined below. Please see Table 6 under Practice Notes for more details on specific components of the interventions.
# Performing Preoperative Stoma Site Marking
The evidence was limited to two studies. The evidence suggests that persons who receive stoma site marking by a NSWOC may experience a reduction in hospital length of stay and peristomal dermatitis (34,35).
# Providing Perioperative Education and Counselling
There is consistent evidence that suggests when NSWOCs provide preoperative and/or postoperative education and counselling, it may reduce hospital length of stay (28,31,33) and rates of peristomal dermatitis/irritation (28,29,31,35). The majority of studies suggest that when NSWOCs provide preoperative and/or postoperative education and counselling, it may improve quality of life (28, 31, 32) and reduce readmission rates to hospital (28,31,33).
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Refer to Appendix J for a sample ostomy teaching record to guide perioperative education and counselling for persons anticipating or living with an ostomy. Refer to Appendix M for nutritional management tips for persons living with an ostomy, which is an important component of perioperative education and counselling.
# Providing Ongoing Follow-up Consultation and Management
There is consistent evidence that suggests when NSWOCs provide ongoing follow-up consultation and management, it may improve quality of life (29,30). The evidence regarding peristomal dermatitis/irritation was limited to one study; it suggests that when NSWOCs provide ongoing follow-up consultation and management, rates of peristomal dermatitis/irritation may be reduced (29).
In findings from qualitative research reporting on quality of life, persons living with an ostomy expressed that ongoing follow-up consultation and management by NSWOCs could help address their psychosocial concerns and help them resume a normal life (36,37).
# Involving Persons Who Anticipate or Live with an Ostomy and Their Support Network in all Steps of Care, as Appropriate
Education provided by NSWOCs for persons who anticipate or live with an ostomy and their support network may have benefits. The evidence regarding the outcome quality of life was limited to one study; it suggested that involving the support network may improve quality of life for persons who anticipate or live with an ostomy (32). Furthermore, the evidence regarding peristomal dermatistis/irritation and ostomy leakage was also limited to one study, which suggested that involving the support network may decrease rates of peristomal dermatitis/irritation and ostomy leakage (28).
# Values and Preferences
See Recommendation 1.1 for the applicable values and preferences. The research suggests that the values and preferences associated with this recommendation are consistent with those outlined in Recommendation 1.1.
# Health Equity
See Recommendation 1.1 for the applicable impact on health equity. The research and the expert panel suggest that the impacts on health equity associated with this recommendation are consistent with those outlined in Recommendation 1.1.
# Expert Panel Justification of Recommendation
There were benefits to the use of the following interventions when conducted by a NSWOC or the NSWOC as a key member of the interprofessional team: preoperative stoma site marking, providing perioperative education and counselling, providing ongoing follow-up consultation and management, and involving persons who anticipate or live with an ostomy and their support network in all steps of care, as appropriate. No harms were found. However, the certainty in this evidence was low.
The expert panel determined that persons would value improvements in outcomes and attributed high value to ensuring that persons who anticipate or live with an ostomy have equitable access to NSWOCs to decrease risks of complications (peristomal dermatitis, peristomal irritation, and ostomy leakage), to improve organization-related outcomes (readmission rates to hospital and hospital length of stay), and to improve quality of life across populations. The expert panel therefore determined the strength of the recommendation to be strong.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Practice Notes
# KEY INTERVENTION DETAILS FROM THE EVIDENCE
# Performing preoperative stoma site marking
No further details from the evidence regarding performing preoperative stoma site marking.
Procedural information can be found within the grey literature, under the Supporting Resources section for this Recommendation.
# Providing perioperative education and counselling
Preoperative education and counselling included the following:
A description of the surgical procedure and what an ostomy is (31,33).
An explanation of preoperative interventions (e.g. stoma site marking) (28,33).
Instruction and practical demonstration of stoma site care (28).
Reviewing ostomy supply needs (28).
Describing in-hospital interventions to expect after surgery (28,31).
Explaining how to manage common complications (28,32,33).
Describing the impact of a stoma on daily life (e.g. sexuality) (31).
Reviewing changes to diet and hydration needs (28,33).
# Postoperative education and counselling included the following:
Directions and hands-on experience on how to change a pouching system and care for the stoma (31,33).
Providing a description of supplies (31,33).
Reviewing changes to diet and hydration (33).
Providing resources for social support (31).
# Educational delivery considerations for preoperative group education:
Encouraging discussion, asking questions, and sharing lived experiences (28,32).
Reinforcing through a video demonstration that a person living with an ostomy can do anything (32).
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# KEY INTERVENTION DETAILS FROM THE EVIDENCE
# Providing ongoing follow-up consultation and management
Follow-up consultation and management included the following:
Conducting a peristomal assessment (29,37).
For resources to aid in conducting a peristomal assessment, please refer to:
Appendix G for ostomy assessment terms.
Appendix H for ostomy assessment parameters and definitions.
Appendix I for a sample assessment and management form for peristomal skin breakdown.
Conducting a pouching system assessment (29).
Evaluating and guiding a person's stoma self-care (36,37).
Helping persons to accept their new condition, and helping them to see that they can continue activities and have control over their lives (36,37).
Answering questions or concerns (36,37).
Providing appropriate referral as needed (in the context of telephone follow-up) (37).
# Involving persons with ostomy and their support network in all steps of care, as appropriate
No further details from the evidence regarding involving persons anticipating or living with an ostomy and their support network in their care. The expert panel recommends that health service organizations implement an internal expertguided, standardized ostomy care program that is developed using an interprofessional, teambased approach.
# Strength of the recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
A standardized ostomy care program is an organization-level approach established within individual health service organizations to standardize care for persons anticipating or living with an ostomy. The ostomy care program includes structured treatment, management, and follow-up strategies developed and implemented by an interprofessional team that is internal to each organization, which may consist of NSWOCs, nurses, surgeons/physicians, social workers, and dietitians (among others).
Findings from quantitative research suggest that implementing an internal expert-guided, standardized ostomy care program within health organizations-compared to not implementing an ostomy care program-may reduce hospital length of stay and 30-day readmission rates to hospital, and improve patient satisfaction for persons anticipating or living with an ostomy (18,19,31,33,(39)(40)(41)(42)(43). The evidence was of low certainty due to limitations in how studies were conducted, use of different tools to measure outcomes across studies and the small number of study participants. There were no harms related to these interventions provided within the ostomy care program in the literature.
For more detailed information of the impact of the intervention (ostomy care program) on each of the specified outcomes (patient satisfaction, hospital length of stay, readmission rates to hospital and staff satisfaction), refer to the evidence profiles available here: .
See Recommendation 2.2 for further details regarding specific interventions included within the ostomy care program and the associated benefits and harms.
Refer to Appendix L for a sample ostomy care program patient checklist that can be used by the person anticipating an ostomy surgery.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Values and Preferences
Evidence suggests that persons living with an ostomy attributed high value to clear postoperative education, such as understanding common post-operative occurrences and how to resolve complications while at home (41). Some persons also requested the opportunity for family involvement so that they are well informed and can ask questions, as well as more information on types of stomas and where to order supplies (44). Persons living with an ostomy prefer having direct access to an assigned NSWOC or health provider compared to an emergent health visit to address complications after discharge (41).
# Health Equity
The expert panel suggests that implementation of an internal, expert-guided, standardized ostomy care program would improve health equity by ensuring the consistency of care delivered across populations. An interprofessional, internal, expert-guided and standardized ostomy care program requires the appropriate health human resources. This may be a challenge in some settings.
# Expert Panel Justification of Recommendation
There were benefits in implementing an internal, expert-guided, standardized ostomy care program and no harms were found. However, this evidence was of low certainty. The expert panel determined that persons would value improvements in outcomes and attributed high value to ensuring that health service organizations implement a standardized ostomy care program to improve patient satisfaction, to improve organization-related outcomes (readmission rates to hospital and hospital length of stay) and to enhance staff satisfaction. Therefore, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
The expert panel attributed high value to having experts in ostomy care (e.g., NSWOCs) within health service organizations to guide the implementation of a standardized ostomy care program. Experts are identified as those with formal knowledge and experience in providing care for persons who anticipate or live with an ostomy. The expert panel emphasized the importance of collaboration among the interprofessional team to support standardization of care across the organization. The expert panel recommends that health service organizations include the following interventions within a standardized ostomy care program:
# RECOMMENDATIONS
Preoperative education and counselling on ostomy surgery, daily living, and self-care.
Postoperative education regarding stoma self-management and potential complications.
Discharge planning that is based on a readiness criteria and includes follow-up information.
Scheduled home visits and telephone follow-up within the first four weeks.
Access to nurses specialized in wound, ostomy, and continence perioperatively and on an ongoing basis, as necessary.
# Strength of the recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
Studies examined one or more of the components of a standardized ostomy care program within health service organizations. All interventions involved collaboration among one or more members of the interprofessional team. When compared to no standardized ostomy care program, the proposed interventions within a standardized ostomy care program displayed benefits in outcomes for persons who anticipate or live with an ostomy (18,19,27,33,(39)(40)(41)(42)(43)45). The evidence was of low certainty due to limitations in how studies were conducted and the use of different tools to measure outcomes across studies. The qualitative evidence was of low confidence due to limitations in how the study was conducted and the small number of study participants. There were no harms in the literature related to these interventions provided within the ostomy care program.
For more detailed information on the components of this intervention on each of the specified outcomes (patient satisfaction, hospital length of stay, readmission rates to hospital and staff satisfaction), refer to the evidence profiles available here: .
The key interventions included within a standardized ostomy care program and the associated health outcomes are outlined below. See Table 7 under Practice Notes for more details on specific interventions.
# Preoperative Education and Counselling on Stoma Surgery, Daily Living, and Self-care
There is consistent evidence that suggests when persons anticipating stoma surgery receive preoperative education and counselling, it may reduce hospital length of stay (19,31,33). The majority of studies also suggest that when persons anticipating stoma surgery receive preoperative education and counselling, it may reduce readmission rates to hospital (19,33,43). The evidence regarding the outcome patient satisfaction is limited to one study and suggests that when persons anticipating stoma surgery receive preoperative education and counselling, it may improve patient satisfaction (27).
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Postoperative Education regarding Stoma Self-management and Potential Complications and Discharge Planning That is Based on a Readiness Criteria and Includes Follow-up Information
There is consistent evidence that suggests when persons receive postoperative education, discharge planning that is based on a readiness criteria and includes follow-up information prior to discharge, it may reduce hospital length of stay (19,31,43) and improve patient satisfaction (27,40,41). The majority of studies suggest that when persons receive postoperative education, discharge planning that is based on a readiness criteria and includes follow-up information prior to discharge, readmission rates to hospital may be reduced (18,19,33,40,42,43).
# Scheduled Home Visits and Telephone Follow-up within the First Four Weeks
There is consistent evidence that suggests when persons receive scheduled home visits and telephone follow-up, it may reduce readmission rates to hospital (33,40,42,43) and it may improve patient satisfaction (27,40,45). In all studies, health providers carrying out the scheduled home visits and telephone follow-up included NSWOCs, colon and rectal surgeons, physicians, nurse practitioners, or visiting registered nurses.
There is consistent qualitative evidence that indicates that persons who receive home visits and/or telephone follow-up calls experience feelings of reassurance, safety, gratitude, and satisfaction with care (40,45). The evidence regarding the outcome staff satisfaction was limited to one qualitative study. In this study, NSWOCs who provided telephone follow-up support expressed finding meaningful worth through recognizing the significant impact they have on the lives of persons who anticipate or live with an ostomy (37).
# Access to Nurses Specialized in Wound, Ostomy, and Continence Perioperatively and on an Ongoing Basis, as Necessary
There is consistent evidence that suggests access to NSWOCs perioperatively and on an ongoing basis may improve patient satisfaction (27,40,41,45) and reduce hospital length of stay (31,33,40). The majority of studies suggest that access to NSWOCs perioperatively and on an ongoing basis may reduce readmission rates to hospital (18,33,40,42).
One qualitative study reported that persons who received telephone follow-up calls from NSWOCs felt excited, comfortable, safe, and reassured, and that they had greater satisfaction with care received (37).
# Values and Preferences
Research suggests that persons living with an ostomy attributed high value to having direct access to (or contact information of) a NSWOC (41). Persons with an ostomy indicated that they wanted clear and consistent postoperative education on stoma management, stoma supplies, potential stoma complications, and courses of actions to resolve issues (41). Persons with an ostomy also preferred receiving follow-up telephone calls from hospital staff, as such calls provided reassurance that no pertinent information related to their treatment and recovery had been missed (37).
In relation to staff satisfaction, NSWOCs who conducted the telephone follow-up calls attributed high value to receiving training related to communication skills and counselling techniques; such training helped them to overcome difficulties, such as language barriers, time limitations, and poor patient moods (37). They also felt that providing psychological support to patients to boost confidence and courage and help them resume normal lives was the most valuable component of the telephone follow-up intervention (37).
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Health Equity
See Recommendation 2.1 for the applicable impact on health equity. The expert panel suggests that the impact on health equity associated with this Recommendation is consistent with what is outlined in Recommendation 2.1.
# Expert Panel Justification of Recommendation
There were benefits of the intervention components included as part of a standardized ostomy care program within health service organizations. No harms were found. However, the certainty in this evidence was low. The expert panel determined that persons would value improvements in outcomes and attributed high value to health organizations implementing a standardized ostomy care program to improve patient satisfaction and organization-related outcomes (readmission rates to hospital and hospital length of stay) and to enhance staff satisfaction. Therefore, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
The expert panel attributed high value to providing persons with an ostomy with direct access to an NSWOC, as needed, during the first four weeks after surgery and on an ongoing basis in order to improve patient satisfaction and decrease readmission rates to hospital.
The expert panel emphasized that scheduled home visits should be conducted by nurses possessing the appropriate knowledge and skills.
The expert panel emphasized that persons who anticipate or live with an ostomy, and who have concerns regarding medications, be directed to their pharmacist.
The expert panel attributed high value to health providers conducting an ostomy assessment immediately postoperatively and throughout the ostomy care program. Refer to Appendices G, H and I for ostomy assessment terms, definitions, parameters and sample assessment form that can be used for persons who live with an ostomy.
The expert panel emphasized that the interventions within the ostomy care program are based on a plan of care promoting self-efficacy that has been established in collaboration with the person, their support network (if needed) and the interprofessional team.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Explaining what an ileostomy is (33).
Demonstrating pouching systems and techniques (33).
Introducing concepts of stoma output management in relation to diet and antidiarrheals (33).
Describing the surgical procedure and showing pictures of stomas (31).
Describing the potential impact of stoma on relationships, sexuality, showering, and other activities of daily life (31).
Explaining postoperative routines (31).
Holding practice sessions to change and manage stomas (31).
Provision of information regarding the purchase of stoma care equipment (31).
# Postoperative education regarding stoma selfmanagement and potential complications
# Discharge planning that is based on a readiness criteria and includes follow-up information
Postoperative education and discharge planning included the following:
Strategies to improve self-management of the ostomy in the hospital (18,33,42).
Using a readiness criteria or checklist to determine when a person can be discharged; for instance, using a person-centred checklist to teach stoma care and evaluate readiness for discharge (18,33,42).
Establishing discharge and follow-up plans that include providing home care support or referral (40)(41)(42)(43).
Providing an overview of signs and symptoms of dehydration and/or other complications (40,41).
Providing instructions on how to document intake and output and monitor for signs and symptoms of dehydration for persons with an ileostomy (33,42).
# Scheduled home visits and telephone followup within the first four weeks.
Scheduled home visits and telephone follow-up included the following:
Providing a telephone consult regarding intake/output and how to avoid dehydration (40).
Home visits by trained nurses after hospital discharge for four continuous weeks to assess for signs of dehydration, pouching issues, stoma output, and infection (42).
Providing appropriate referral for stoma nurse clinic, surgical consultation, or emergency room based on evaluation from the telephone consultation (45). The expert panel suggests that health providers implement the following interventions to prevent parastomal hernias for persons who anticipate or live with an ostomy:
# RECOMMENDATIONS
Conduct a risk factor assessment related to body mass index and waist circumference.
Provide expert advice on weight management, as needed.
Perform stoma site marking preoperatively.
Provide postoperative education related to:
abstinence from heavy lifting postoperatively;
consideration of lightweight support garments; and
abdominal exercises beginning within three months of surgery.
# Strength of the recommendation: Conditional
# Certainty of the evidence of effects: Very Low
Confidence in evidence: Not Applicable
# Discussion of Evidence: Benefits and Harms
Research suggests that six key interventions performed by health providers that support prevention of parastomal hernias may decrease incidence of parastomal hernias in persons who anticipate or live with an ostomy (16). However, two studies by Thompson and Trainer as cited in Bland and Young (1) reported a 17 per cent increase in the incidence of parastomal hernias after implementation of an early hernia prevention program that utilized the six key strategies. The studies concluded that the rise was related to participant non-adherence. The studies also reported a long term reduction in incidence of parastomal hernias among those who adhered to the early hernia prevention program (1). The body of evidence was of very low certainty due to limitations in how studies were conducted and the small number of study participants.
For more detailed information on the impact of the components of hernia prevention strategies on the outcome rates of parastomal hernia, please refer to the evidence profiles available here: .
The hernia prevention strategies and their impact on rates of parastomal hernia in persons who live with an ostomy are summarized on the next page. Specific components of the interventions noted in the literature and identified by the expert panel are outlined under Practice Notes.
# RECOMMENDATIONS
# Perform Stoma Site Marking Preoperatively
The evidence regarding performing stoma site marking preoperatively is limited to one study. According to Person et al. as cited in Bland and Young (1), preoperative stoma site marking by a NSWOC may reduce rates of parastomal hernia in persons living with an ostomy. The rate of parastomal hernia was 3.8 per cent in the group that received stoma site marking compared to 24.5 per cent in the group that did not receive a stoma site marking.
# Provide postoperative education related to: Abstinence from Heavy Lifting Postoperatively; Consideration of Lightweight Support Garments; and Abdominal Exercises Beginning within Three Months of Surgery
According to two studies by Thompson and Trainer as cited in Bland and Young (1) and North (16), persons who anticipate or live with an ostomy-and who receive advice on abstinence from heavy lifting, consideration of lightweight support garments and instructions to begin specific abdominal exercises within three months after surgery as part of a hernia prevention program-may experience a decrease in the rates of parastomal hernias. One research study reported that after implementing the program, the rates of parastomal hernia were 15 per cent in all study participants and 1 per cent among those who were fully compliant (compared to 23 per cent local incidence and 44 per cent overall incidence reported in existing studies) (16). The 2005 and 2007 studies by Thompson and Trainer as cited in Bland and Young (1) indicated that reduction in parastomal hernias was 14 per cent after implementing the hernia prevention program compared to 28 per cent before the program. There was limited and very low certainty of evidence about how long a person with an ostomy needs to abstain from heavy lifting postoperatively. Please refer to Practice Notes for the expert panel consensus time frame on abstaining from heavy lifting postoperatively.
# Values and Preferences
Evidence indicates that only 45 per cent of participants who ordered a support garment utilized it on a regular basis, and only 27 per cent of participants believed that wearing the garment was important to prevent hernia (1).
# Health Equity
The expert panel recognizes that there is limited evidence that supports the benefits of lightweight support garments in prevention of parastomal hernias. In addition, persons of lower socio-economic status may have challenges with access to lightweight support garments due to cost.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Expert Panel Justification of Recommendation
The expert panel determined that there is likely high variability in how much persons living with an ostomy value the outcomes associated with this recommendation. Given the unclear benefits associated with wearing lightweight support garments compared to other factors (such as cost and comfort), persons with an ostomy may choose not to receive the intervention. In addition, the overall evidence for hernia prevention strategies was of very low certainty. Therefore, the expert panel determined the strength of the recommendation to be conditional.
# Practice Notes
# Conducting a risk factor assessment related to body mass index (BMI) and waist circumference
An online calculator to measure BMI is provided in the Supporting Resources section.
A risk factor assessment should be conducted preoperatively, postoperatively and on an as needed basis.
# Providing expert advice on weight management, as needed
Referral to a registered dietician for education regarding nutrition and weight management.
# Advising abstinence from heavy lifting postoperatively
Providing immediate postoperative education on the following:
Heavy lifting.
Weight transfer.
Splinting with coughing, nausea, or vomiting.
Avoiding straining with constipation.
Avoid lifting no more than 10 lbs for the first month after surgery, and then slowly work back up to lifting normal weights.
# Consideration of lightweight support garments before discharge
Providing information on support garments.
# Providing instructions on abdominal exercises to begin within three months of surgery
Surgeons to recommend abdominal exercises with specific instructions on when to begin and how to perform them.
Providing appropriate referral to a physiotherapist to provide education on abdominal exercises and proper body mechanics to perform during the first three months after surgery.
# Additional considerations
Providing education on what a parastomal hernia is.
Having an anti-emetic protocol in place immediately after surgery.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Abdominal exercise
Gently place your hands on your lower tummy. Breathe in through your nose and, as you breathe out, gently pull your tummy button down towards your spine. Feel the muscles tighten, try to hold for a count of 3 and then relax. Breathe in and out normally.
# Pelvic tilting
Place your hands in the hollow of your back. Tighten your tummy muscles (as exercise 1), flatten your lower back onto your hands and tilt your bottom. Breathe normally. Hold for 3 seconds and release gently.
# Knee rolling
Tighten your tummy muscles (as exercise 1) and gently lower both knees to one side as far as is comfortable. Bring them back to the middle and relax. Repeat to the other side. This exercise has the added benefit of releasing trapped wind.
Aim to do each of these exercises five times, three times a day. Do more repetitions as you feel able. In order to guide person-centred care, the expert panel recommends that health providers assess quality of life in persons who anticipate or live with an ostomy. Specific areas of focus should include the following:
Psychological distress (anxiety and depression).
Self-identity (sexuality and body image).
# Strength of the recommendation: Strong
# Certainty of the evidence: Very Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
Systematic review results highlight the lack of literature on the impact of conducting a quality of life assessment for persons who anticipate or live with an ostomy. As a result, literature was examined to understand the relationship between anticipating or living with an ostomy, and quality of life outcomes of psychological distress and selfidentity. Studies demonstrate the impact of living with an ostomy on quality of life through the use of quality of life assessments. The evidence was of very low certainty due to limitations in how studies were conducted, the use of different tools to measure outcomes across studies and the small number of study participants. For qualitative studies, the evidence was of low confidence due to some limitations in how studies were conducted and the small number of study participants.
The creation of an ostomy is a life-changing event and may have implications on various aspects related to quality of life, most notably psychological health and self-identity. Descriptive studies report that 46 per cent to 63 per cent of people expressed feelings of depression following stoma surgery and had lower quality of life scores in the mental health domain compared to the general public (46,47). Conversely, a descriptive study reported no difference between the general public and persons with a stoma in quality of life scores after surveying 2,329 community-dwelling persons with an ostomy (48). However, specific to the mental health domain of the survey, Nichols (48) reported that persons with an ostomy were more likely to indicate feeling "down in the dumps" most or all of the time and downhearted and depressed most or all of time. Furthermore, Knowles et al. (49) reported that results from survey data indicated that nearly 50 per cent of respondents who had Crohn's disease G and were living with an ostomy had scores indicating possible or probable anxiety disorder, while 42 per cent had a depressive symptom score.
A majority of the literature reported that living with an ostomy may have a negative impact on aspects of self-identity, most notably on body image and sexuality. Descriptive studies reported that body image was inferior for persons living with a permanent stoma after rectal cancer surgery compared to those without a stoma, while most persons
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition reported their sexual life was affected negatively after creation of a stoma (50,51). Persons who were diagnosed with rectal cancer and were living with an ostomy were more likely to be fearful of resuming sexual activity or to have problems undressing in front of a partner, interference with personal relationships, decreased ability to be intimate, and less satisfaction with appearance (52). For persons who were sexually active, descriptive studies reported that 33 per cent of them resumed sexual activity after stoma surgery (46,47).
Similarly, qualitative studies found that persons living with an ostomy expressed several changes in sexual function, such as erectile dysfunction, vaginal dryness, and pain during intercourse. Persons also experienced psychological impacts such as fear and anxiety related to sexual competence and/or the potential for pouching system mishaps during intimacy (53,54).
Fewer studies reported that living with an ostomy has no substantial (or a lesser) effect on body image and sexuality (55,56). Furthermore, some persons in two qualitative studies expressed that their self-perceptions about body image did not change, while others described negative self-perceptions about body image (53,54).
# Values and Preferences
In a qualitative study, persons with an ostomy expressed that they valued nurses as a source of practical and psychological support (54). In another qualitative study, persons with an ostomy expressed that they expect sexual counselling from a nurse to help them normalize their sexual lives (53). Persons with an ostomy also expressed the importance of support from family and friends during the adaption stage after ostomy surgery (54).
# Health Equity
No studies were found that directly assessed the impact of conducting a quality of life assessment on health equity. In a study conducted by Knowles et al. (49), 77 per cent of participants reported no current or past professional support to address their mental health concerns, despite a substantial portion of participants who had psychological concerns. These findings highlight the need for improved access to psychological services for persons living with an ostomy (49). Psychological services may include further assessment and management of psychological distress (anxiety and depression) and self-identity (sexuality and body image).
# Expert Panel Justification of Recommendation
The impact of a quality of life assessment was not evident in the literature. Instead, evidence regarding the impact of living with an ostomy on psychological health and self-identity was explored, which was of very low certainty. However, as the majority of literature reported on the negative effects of living with an ostomy on psychological health status and self-identity, the expert panel felt it is necessary to assess quality of life in all persons who anticipate or live with an ostomy as a precaution so that the appropriate follow-up can be completed (if needed). Therefore, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
The How has getting the necessary ostomy supplies been for you?
For those who are in committed relationships:
Some people who have the same surgery as you report feelings of discomfort or anxiety with resuming sexual or intimate activities with their partner. Have you experienced this?
For those who are not in a relationship:
Some people who have the same surgery as you report that becoming involved in an intimate relationship is problematic. Have you been experiencing this since surgery?
The expert panel emphasized the importance of follow-up care after completing a quality of life assessment. Followup care can include the following:
Providing education and counselling on how to mititigate negative feelings.
Providing referrals for further support (e.g., psychotherapists, psychiatrists, and counselors).
Incorporating the person's needs (such as emotional or cultural needs) into the plan of care.
# Research Gaps and Future Implications
The RNAO Best Practice Guideline Development and Research Team and expert panel identified priority areas for future research (outlined in Table 10). Studies conducted in these areas would provide further evidence to support high-quality and equitable support for adults who anticipate or live with an ostomy. The list is not exhaustive; other areas of research may be required. Outcomes: Parastomal hernia rates.
The effectiveness of abdominal exercises in the prevention of parastomal hernias.
The identification of specific abdominal exercises to prevent occurrence of parastomal hernias.
Exploring the benefits of preoperative versus postoperative abdominal exercises to prevent occurrence of parastomal hernias.
The effectiveness of lightweight support garments in the prevention of parastomal hernias.
The identification of specific instructions and considerations related to heavy lifting at any point after stoma surgery.
# Implementation Strategies
Implementing guidelines at the point of care is multi-faceted and challenging. It takes more than awareness and distribution of guidelines for practice to change: guidelines must be adapted for each practice setting in a systematic and participatory way to ensure that recommendations fit the local context (57). The 2012 RNAO Toolkit: Implementation of Best Practice Guidelines, Second Edition provides an evidence-based process for doing this. It can be downloaded at www.RNAO.ca/bpg/resources/toolkit-implementation-best-practice-guidelines-second-edition.
The Toolkit is based on emerging evidence that successful uptake of best practices in health care is more likely when the following occur:
Leaders at all levels are committed to supporting guideline implementation.
Guidelines are selected for implementation through a systematic, participatory process.
Stakeholders for whom the guidelines are relevant are identified and engaged in the implementation.
Environmental readiness for implementing guidelines is assessed.
The guideline is tailored to the local context.
Barriers and facilitators to using the guideline are assessed and addressed.
Interventions to promote use of the guideline are selected.
Use of the guideline is systematically monitored and sustained.
Evaluation of the guideline's impact is embedded in the process.
There are adequate resources to complete all aspects of the implementation.
The Toolkit uses the "Knowledge-to-Action" framework to demonstrate the process steps required for knowledge inquiry and synthesis (58) (see Figure 3). It also guides the adaptation of the new knowledge to the local context and implementation. This framework suggests identifying and using knowledge tools (such as guidelines) to identify gaps and begin the process of tailoring the new knowledge to local settings.
RNAO is committed to widespread deployment and implementation of our BPGs. We use a coordinated approach to dissemination, incorporating a variety of strategies, including the following:
- The Nursing Best Practice Champion Network®, which develops the capacity of individual nurses to foster awareness, engagement, and adoption of BPGs.
- The BPG Order Set TM provide clear, concise, and actionable intervention statements derived from practice recommendations. BPG Order Sets can be readily embedded within electronic records, but they can also be used in paper-based or hybrid environments.
- The Best Practice Spotlight Organization® (BPSO®) designation, which supports implementation at the organization and system levels. BPSOs focus on developing evidence-based cultures with the specific mandate to implement, evaluate, and sustain multiple RNAO BPGs.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
In addition, we offer annual capacity-building learning institutes on specific BPGs and their implementation.
Information about our implementation strategies can be found at:
RNAO
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Crohn's disease: Chronic idiopathic disease that causes inflammation of the lining of the gastrointestinal tract. This condition usually presents with abdominal pain and chronic diarrhea (3).
Diversion: Surgical creation of an alternative route through the abdominal wall to divert feces and urine (2).
# Downgrade:
In GRADE and GRADE-CERQual, when limitations in the individual studies potentially bias the results, the certainty of evidence will decrease (63). For example, a body of quantitative evidence for one priority outcome may begin with high certainty, but due to serious limitations in one or more of the five GRADE criteria, it will be rated down by one or two levels (64).
Education statement: Organizational approaches to the delivery of education in health service organizations and academic institutions to support evidence-based practice. Education statements are based on an analysis of educational recommendations across several BPGs on diverse clinical topics and populations. Education statements can be applicable to all clinical BPGs and can be contextually adapted within health service organizations and academic institutions to support implementation of clinical recommendations.
Effluent: Fecal or urinary discharge from the stoma after ostomy surgery (65).
# Evidence-based nursing practice:
The integration of research evidence with clinical expertise and patient values; unifies research evidence with clinical expertise and encourages the inclusion of patient preferences (66).
# Evidence-to-Decision (EtD) frameworks:
A table that facilitates expert panels to make decisions when moving from evidence to recommendations. The purpose of the EtD framework is to summarize the research evidence, outline important factors that can determine the recommendation, inform panel members about the benefits and harms of each intervention considered, and increase transparency about the decision-making process in the development of recommendations (67).
# GRADE:
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) is a methodological approach to assess the certainty of a body of evidence in a consistent and transparent way, and to develop recommendations in a systematic way. The body of evidence across identified important and/or critical outcomes is evaluated based on risk of bias, consistency of results, relevance of the studies, precision of the estimates, publication bias, large effect, dose response, and opposing confounding (67). cont.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition When using GRADE, five components contribute to the assessment of confidence in the evidence for each outcome. These components are as follows:
- Risk of bias, which focuses on the flaws in the design of a study or problems in its execution. 2. Inconsistency, which looks at a body of evidence and assesses whether the results point in the same direction or are different. 3. Imprecision, which refers to the accuracy of results based on the number of participants and/or events included, and the width of the confidence intervals across a body of evidence. 4. Indirectness, whereby each primary study that supports an outcome is assessed and a decision is made regarding the applicability of the findings to the population, intervention, and outcome outlined in the research question. 5. Publication bias, where a decision is made about whether the body of published literature for an outcome potentially includes only positive or statistically significant results (67).
Health provider: Refers to both regulated (e.g., nurses, physicians, dieticians and social workers) and unregulated (e.g., personal support workers) workers that are part of the interprofessional team.
# Regulated health provider:
In Ontario, the Regulated Health Professional Act, 1991 (RHPA) provides a framework for regulating 23 health professions, outlining the scope of practice and the profession-specific controlled or authorized acts that each regulated professional is authorized to perform when providing health care and services (5).
Unregulated health provider: Unregulated health providers fulfill a variety of roles in areas that are not subject to the RHPA. They are accountable to their employers but not to an external regulating professional body (e.g., College of Nurses of Ontario). Unregulated health providers fulfill a variety of roles and perform tasks that are determined by their employer and employment setting. Unregulated health providers only have the authority to perform a controlled act as set out in the RHPA if the procedure falls under one of the exemptions set out in the Act (6).
# Hernia (parastomal):
A parastomal hernia occurs when one or more loops of the bowel protrude through the abdominal wall, creating a bulge around the peristomal skin (7).
Ileostomy: A surgically created opening from the last part of the small intestine (ileum) to the abdominal wall to allow the elimination of small bowel effluent. An ileostomy can be either temporary or permanent (3).
# Inflammatory bowel disease:
The term refers to a group of chronic, relapsing gastrointestinal tract conditions, with ulcerative colitis and Crohn's disease being two main forms (68).
Interprofessional team: "A team comprised of multiple health providers (regulated and unregulated) who work collaboratively to deliver comprehensive and quality health care and services to people within, between, and across health settings" (60). Key interprofessional team members supporting adults who anticipate or live with an ostomy include NSWOCs, nurses, surgeons, physicians, social workers, dietitians, and pharmacists.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Meta-analysis: A systematic review of randomized controlled trials that uses statistical methods to analyze and summarize the results of the included studies (69).
# See systematic review
Nurse: "Refers to registered nurses, licensed practical nurses (referred to as registered practical nurses in Ontario), registered psychiatric nurses, and nurses in advanced practice roles such as nurse practitioners and clinical nurse specialists" (70).
Nurse specialized in wound, ostomy, and continence (NSWOC): "A registered nurse with advanced and specialized knowledge and clinical skills in wound, ostomy, and continence care who has graduated from a World Council of Enterostomal Therapists (WCET ® ) recognized education program" (4). A NSWOC provides specialized holistic assessment and management as an interprofessional team member to meet the needs to individuals/families with ostomies, acute and chronic wounds, and urinary and fecal continence problems" (4).
The NSWOC equivalent may be represented with other titles around the world, such as (but not limited to): stoma nurse; wound, ostomy, continence nurse (WOC nurse); or ostomy nurse.
Ostomy: Ostomy refers to a surgically created opening in the abdominal wall that results in the external diversion of feces and urine. The most common types of ostomy are colostomy and ileostomy for feces and urostomy for urine (2). A permanent ostomy refers to an ostomy "that will never be closed" (59). In the case of a temporary ostomy, "usually the surgical plan is to reconnect the intestine and to close the ostomy" (59).
Ostomy care program: An ostomy care program is an organization-level approach to standardize care for persons anticipating or living with an ostomy. The ostomy care program includes structured treatment, management, and follow-up strategies developed by an interprofessional team that may consist of NSWOCs, nurses, surgeons, physicians, social workers, dieticians, and pharmacists (among others).
Ostomy leakage: Exudate that seeps out of the stoma.
Outcomes: A dependent variable, or the clinical and/or functional status of a patient or population, that is used to assess if an intervention is successful. In GRADE, outcomes are prioritized based on if they are critical for decision making, important but not critical for decision making, or not important. Use of these outcomes helps literature searches and systematic reviews to be more focused (67).
Perioperative: Something occurring "around the time of surgery. This usually lasts from the time the patient goes into the hospital or doctor's office for surgery until the time the patient goes home" (71).
# Peristomal dermatitis (allergic and irritant):
Peristomal dermatitis (allergic) is skin damage caused by pouching system adhesives, powders, or barriers. Allergic dermatitis occurs at the site where offending agents or adhesives contact the skin (65). Peristomal dermatitis (irritant) is skin damage resulting from contact with fecal or urinary drainage. Irritant contact dermatitis is the most common peristomal skin complication and occurs at the site of effluent leakage (65).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Peristomal irritation: Peristomal irritation is a common complication resulting from moisture-associated skin damage. It may cause the peristomal skin to be inflamed, sore, itchy, and red (72).
Peristomal skin/plane: An area of "3 to 4 inches (10 x 10 cm) of skin surface surrounding an abdominal stoma" (59).
PICO question: A framework to outline a focused question. It specifies four components:
- The patient or population that is being studied.
- The intervention to be investigated.
- The alternative or comparison intervention. 4. The outcome that is of interest (67).
# Pouching systems (ostomy pouching systems):
A system "composed of a skin barrier and a collection device to collect drainage (effluent) and protect the skin. Pouching systems are one-piece or two-piece products. The pouch attaches to the skin barrier, which adheres to the abdomen, and is fitted over and around the stoma to collect stool or urine" (59).
Qualitative research: An approach to research that seeks to convey how human behaviour and experiences can be explained within the contexts of social structures and through the use of an interactive and subjective approach to investigate and describe phenomena (73).
# Quasi-experimental study:
A study that estimates causal effects by observing the exposure of interest, but in which the experiments are not directly controlled by the researcher and lack randomization (i.e., before-andafter designs) (74).
# Randomized controlled trial (RCT):
An experiment in which the investigator assigns one or more interventions to participants who are randomly allocated to either the experimental group (receives intervention) and the comparison (conventional treatment) or control group (no intervention or placebo) (69).
Recommendation: A course of suggested action(s) that directly answers a recommendation question. A recommendation is based on a systematic review of the literature and is made in consideration of its potential benefits and harms, values and preferences from a person-centered perspective, and impact on health equity. All recommendations are given a strength, either strong or conditional through expert panel consensus. It is important to note that recommendations should not be viewed as prescriptive, as recommendations cannot take into account all of the unique features of individual, organizational and clinical circumstances (8).
# Recommendation question:
A priority research area of practice, policy or education identified by expert panel members that requires evidence to answer. The recommendation question may also aim to answer a topic area around which there is ambiguity or controversy. The recommendation question informs the research question, which guides the systematic review.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Scoping review: "Scoping reviews have been described as a process of mapping the existing literature or evidence base. Scoping reviews can be used in a number of ways, for example identifying research gaps and summarizing findings of research. They can also be used to inform systematic reviews" (75).
Self-management: "The tasks that individuals must undertake to live well with one or more chronic conditions. These tasks include having the confidence to deal with medical management, role management, and emotional management of their conditions. The goal of self-management is increased confidence in the ability to change, rather than compliance with the caregiver's advice. The purpose of self-management support is to help persons become informed about their conditions and take an active role in treatment" (76).
Stakeholder: An individual, group, or organization that has a vested interest in the decisions and actions of organizations, and may attempt to influence decisions and actions (77). Stakeholders include all of the individuals and groups who will be directly or indirectly affected by the change or solution to the problem.
Stoma: An opening created on the abdominal wall by ostomy surgery to allow elimination of urine and feces. A stoma is usually dark pink in colour (2).
Stoma site marking: "Selection of the ideal location on the abdomen for a stoma prior to surgery by a trained health professional, usually a NSWOC or surgeon to help prevent future stoma complications and pouching problems" (59).
# Support network:
A term used to refer to those whom the person identifies as significant in his or her life. This can include individuals who are related (biologically, emotionally, or legally) and/or those with close bonds (friendships, commitments, shared household and child-rearing responsibilities, and romantic attachment) (70,78).
# Systematic review:
A comprehensive review of the literature that uses clearly formulated questions and systematic and explicit methods to identify, select, and critically appraise relevant research. A systematic review collects and analyzes data from the included studies and presents them, sometimes using statistical methods (69).
See meta-analysis Urostomy (ileal conduit): A surgical procedure to divert the flow of urine by transplanting the ureters into an isolated segment of the ileum, bringing one end through the abdominal wall to create a stoma. Urine flows from the kidney to the ureters, then through the ileal conduit, exiting through the stoma. A urostomy can be either temporary or permanent (3).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Appendix B: RNAO Guidelines and Resources that Align with this Guideline
The following are topics that align with this Guideline and with suggested RNAO guidelines and resources from other organizations.
# TOPIC RESOURCE(S)
Client centred learning Academic institutions should consider integrating guideline content into theoretical and practice-based courses for nurses and other regulated health providers, including social workers, physiotherapists, occupational therapists, dieticians and pharmacists in pre-licensure and post-licensure programs. Pre-licensure education establishes foundational knowledge that can be strengthened and augmented, as necessary, within health service organizations. Post-licensure education at the graduate level may include preparing nurses and other regulated health providers for advanced practice roles and functions within clinical practice, education, administration, research, and policy (79). As such, the integration of guideline content into curricula will differ in terms of educational content and complexity based on the overall educational objectives of the program. In both cases, integrating guideline content into curricula supports student learning consistent with evidence-based practices, with the ultimate goal of enhancing the health outcomes of persons and families.
To support the integration of evidence-based guidelines into curricula, the following approaches may be utilized: (a) developing multi-level guideline-related learning objectives and (b) designing guideline-related teaching and learning strategies (80). Both approaches are outlined below.
A) Developing multi-level guideline-related learning objectives: Guideline-related learning objectives at multiple levels of a program (pre-licensure and post-licensure) facilitate integration of guideline content into curricula. At the program level, such integration broadens student knowledge, attitude, judgment, and skills.
For instance, a program-level outcome at a graduate level may include student awareness of elements of implementation science to support uptake and sustained use of guidelines in clinical settings (80). At the course level, integration of guideline content supports student learning that is consistent with evidence-based practices within academic and practice settings. For example, course-level outcomes at the undergraduate level may include students being able to gain increased knowledge about guidelines, select guidelines relevant to practice (and provide rationale for their selection), and integrate guideline recommendations into plans of care for persons and families (80).
B) Designing guideline-related teaching and learning strategies: Teaching strategies should be tailored to address the program-level educational objectives and needs of learners, and to equip the learner to improve practice and promote positive outcomes (81). The various guideline-related teaching and learning strategies are outlined below.
Lectures: Educators can use lectures as a means to provide a broad understanding of guidelines, specifically the rigorous process of guideline development and their various recommendations. Lectures can provide students with an understanding of the scope and strength of evidence that inform the recommendations (80).
Interactive classroom activities: Interactive learning activities within the classroom setting can support students to obtain additional information, participate in problem-solving, and articulate knowledge gained. Examples include (a) assigning group work to help students learn how to navigate a guideline and become familiar with its recommendations, (b) using case studies to provide students with opportunities to identify and apply guideline recommendations in care plans, and (c) using videos and role playing to promote skills in articulating the rationale for selecting specific guidelines/recommendations in care plans (80).
Simulation: High-quality digital simulation within skills lab settings can ease the uncertainty of students related to clinical practice; it can also increase skill acquisition, self-confidence, and satisfaction. Faculty trained in pedagogy can use simulation to teach students content related to safe and effective person and family care within a standardized clinical environment (82). Educators can support students to incorporate guideline content into simulated practice sessions when teaching evidence-based practice (80). (80).
# A P P E N D I C E S
Supporting Adults
Access to BPG-related resources: Educators can promote and facilitate access to BPG-related links and resources. For example, providing access to the RNAO Nursing Best Practice Guidelines App (see https:// rnao.ca/bpg/pda/app) enables students to access content from guidelines within classroom and practice settings (80).
Assignments and tests: Students may be asked to incorporate guidelines into their learning plans or write a reflective journal related to a guideline important to their area of practice. Tests or exam questions that demonstrate critical thinking related to guidelines can also be used. Overall, guideline-related assignments and tests can assist students to reflect upon guidelines, understand their application, and critique them (80).
Preceptorship or mentorship in clinical placements: Preceptors within clinical settings play an integral role in teaching practical skills that complement the theoretical learning of students. Preceptors are responsible for providing clinical teaching and supervision, and they perform formal student evaluation (83). Preceptors can support students to integrate guideline content into their learning objectives and clinical activities to promote evidence-based knowledge and practice.
# EDUCATION STATEMENT 2:
Health service organizations use strategies to integrate evidence-based guidelines into education and training of nurses and other health providers.
# Discussion of Literature:
The thematic analysis of the education recommendations in a number of BPGs found the second theme of: "health service organizations use strategies to integrate evidence-based guidelines into education and training of nurses and other health providers, " as foundational to evidence-based practice capacity building. Education and training programs should be based on the principles of adult learning, including the following:
Adults have an awareness of learning needs/goals.
Adults are self-directed and autonomous.
Adults value and utilize prior life experiences.
Adults have readiness to learn.
Adults are motivated to learn.
Adults are presented knowledge and skills in the context of practical, real-life situations (85).
Furthermore, education and training should be appropriate to the health provider's scope of practice and their defined role. Education and training strategies may include the following:
In-service education sessions: In-service education sessions can be planned by clinical experts within practice settings to support the utilization of a specific guideline or recommendations stimulating evidence-based practice among staff. The education may include one-on-one or group sessions and should address the needs of learners. It is recommended that the education sessions are followed with refresher or booster sessions to provide feedback and enhance staff learning (86,87).
Workshops/seminars: Highly interactive workshops/seminars help nurses and health providers maintain practice based on best evidence when they incorporate a variety of teaching-learning strategies, including pre-circulated materials, small group discussions using case studies, and multimedia such as Power Point and videos that integrate relevant guidelines/recommendations. RNAO's Best Practice Champions Workshop and BPG Learning Institutes are examples of programs that provide education on how to implement BPGs within practice settings (88).
Quality improvement: Participating in quality improvement within workplace settings can support nurses and health workers to recognize sentinel events and examine ways to improve care. Meeting accreditation standards is an important quality improvement activity that bridges gaps between current and best practices and supports continued competence. Examples of strategies that nurses and other health providers can use to meet accreditation standards include the following:
Participating in a unit-based guideline implementation process to promote patient safety, reduce risks, and improve care outcomes. Choosing guideline-specific recommendations to facilitate practice change. Sharing knowledge and lessons learned from reviewing guidelines with the accreditation committee (89,90).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# EVALUATION
All educational strategies require evaluation to (a) monitor the adoption of knowledge and (b) measure the impact on clinical outcomes. RNAO has developed the Educator's Resource: Integration of Best Practice Guidelines (2005) to provide strategies for educators within academia and practice settings to introduce BPGs to student nurses, faculty, nurses and other health providers. The resource provides guidance on student evaluation strategies that include self-evaluation peer-evaluation and end-of-course evaluations by the educator.
Furthermore, RNAO has developed the Practice Education in Nursing (2016) BPG to provide evidence-based recommendations that support with the application of knowledge to various practice settings by student nurses. The guideline also assists nurses nurse educators, preceptors and other members of the interprofessional team to understand the effective use of teaching-learning strategies in clinical settings.
The RNAO Toolkit: Implementation of Best Practice Guidelines (2012)- identifies the following strategies for evaluation of provider practice change and health outcomes for persons within health service organizations:
Pre-and post-tests for staff educational sessions.
Staff focus groups/interviews.
Observation of patient-provider encounters.
Chart audits to determine the impact on person and family outcomes.
Person and family satisfaction surveys or interviews.
- The RNAO Toolkit: Implementation of Best Practice Guidelines (2012) is under review and the next edition is expected to be issued in 2020.
Other quality improvement opportunities include participating in incident reporting, patient safety initiatives, and other health initiatives within areas of practice.
Post-licensure mentorship: Post-licensure mentorship involves providing new graduates or less experienced staff with guidance for skill development and support for growth of professional roles.
Research suggests that working with mentors reduces stress and improves satisfaction for new staff during the transition process (91). Mentors can support integration of guideline content while teaching evidencebased practice.
- A guideline search and gap analysis was undertaken. Two Guideline Development Methodologists (one of them being the Guideline Development Lead) searched an established list of websites for guidelines and other relevant content published between January 2007 and August 2017. The resulting list was compiled based on knowledge of evidence-based practice websites and recommendations from the literature. RNAO expert panel members were asked to suggest additional guidelines (see Figure 4 in Appendix E). The purpose of the guideline search and gap analysis was to gain an understanding of existing guidelines regarding ostomy care and support in order to identify opportunities for addressing the purpose and scope of this BPG. Detailed information about the search strategy for existing guidelines, including the list of websites searched and the inclusion criteria used, is available at https:// rnao.ca/bpg/guidelines/ostomy.
The guidelines were reviewed for content, applicability to nursing scope of practice, accessibility, and quality. The two Guideline Development Methodologists appraised three international guidelines using the AGREE II tool and came to consensus on an overall score for each guideline (92). Guidelines with a score of six or seven (on a 7-point Likert scale) were considered to be of high quality. The systematic reviews that answered research questions in high quality guidelines were considered to be beyond the scope of this guideline. The following guidelines were appraised as indicated:
Miller D, Pearsall E, Johnston D, et al. Executive summary: enhanced recovery after surgery: best practice guideline for care of patients with a fecal diversion. J Wound Ostomy Continence Nurs. 2017 Jan/Feb;44(1):74-7. (Score: 4 out of 7. This guideline was used as a supporting resource in this BPG) Ostomy Guidelines Task Force. Management of the patient with a fecal ostomy-best practice guidelines for clinicians. J Wound Ostomy Continence Nurs. 2010 Dec;37(6):596-8. (Score: 3 out of 7. This guideline was not used as a supporting resource in this BPG because the content was not as relevant)
World Council of Enterostomal Therapists (WCET). WCET international ostomy guideline. Perth (Australia): WCET; 2014. (Score: 4 out of 7. This guideline was used as a supporting resource in this BPG)
- A scoping review of the literature was performed to determine the depth of peer-reviewed studies in the area of pediatric populations (younger than 18 years) living with an ostomy.
Six key informant interviews took place with experts in the field including front-line health providers, researchers, and individuals with lived experiences, to understand the needs of nurses, members of the interprofessional health team, and persons with lived experience.
- Two virtual focus groups were convened to understand the needs of nurses, members of the interprofessional health team, and persons with lived experience.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Assembly of the Expert Panel
RNAO aims for diversity in membership of an expert panel in alignment with its Organizational Statement on Diversity and Inclusivity which is part of the RNAO Mission and Values (93). RNAO also aims for persons impacted by guideline recommendations, especially persons with lived experiences and caregivers, to be included as expert panel members.
There are numerous ways in which RNAO finds and selects members of an expert panel, including searching the literature for researchers in the topic area; recommendations from key informant interviews; drawing from established professional networks such as RNAO interest groups, Champions Network © , and BPSO © ; other nursing and health provider associations; topic-relevant technical associations or organizations; and advocacy bodies.
For this Guideline, the RNAO Best Practice Guideline Development and Research Team assembled a panel of experts from nursing practice, administration, research, education and policy, as well as other members of the interprofessional team representing a range of sectors and practice areas, and persons with lived experiences (see the RNAO Expert Panel).
The expert panel engaged in the following activities:
Approved the scope of this BPG.
Determined the recommendation questions and outcomes to be addressed in this BPG.
Participated in a consensus development process to finalize recommendation statements.
Provided feedback on the draft of this BPG.
Participated in the development of evaluation indicators.
Identified appropriate stakeholders to review the draft guideline prior to publication.
The expert panel co-chairs led the following activities:
Monthly co-chair meetings with the Guideline Development Methodologists and Guideline Development Project Coordinator.
Facilitated expert panel meetings.
Provided in-depth guidance on clinical and/or research issues.
Moderated and acted as tiebreakers in voting processes.
# Declarations of Competing Interest
Declarations of competing interest that might be construed as constituting an actual, potential, or apparent conflict were made by all members of the RNAO's expert panel, and members were asked to update their disclosures throughout the guideline development process. Information was requested about financial, intellectual, personal, and other interests and documented for future reference. No limiting conflicts were identified. Declarations of competing interest are posted as a separate document on the RNAO webiste: .
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Identifying Priority Recommendation Questions and Outcomes
In October 2017, the RNAO Best Practice Guideline Development and Research Team convened to determine the priority recommendation questions and outcomes for this Guideline. A comprehensive list of recommendation questions that the Guideline could potentially address was developed at the in-person meeting, informed by the following:
The guideline gap analysis.
The scoping review of the literature.
Key informant interviews and focus groups.
Expert panel discussion at the in-person meeting.
This comprehensive list of potential recommendation questions was presented to the expert panel for a vote. Each expert panel member was allowed four votes for preferred recommendation questions. The four recommendation questions with the most votes were deemed the final recommendation questions. Expert panel co-chairs did not participate in the vote as they functioned as tiebreakers for the fourth recommendation question.
Following this initial vote-and in alignment with GRADE standards for assessing and presenting the evidenceoutcomes were identified and prioritized per recommendation question. A comprehensive list of outcomes per recommendation question was developed at the in-person meeting, informed by the following:
The scoping review of the literature.
Key informant interviews and focus groups.
Expert panel discussion at the in-person meeting.
Based on the comprehensive list of outcomes, the expert panel was asked to rank order the relative importance of each outcome per recommendation question. Each panel member participated in a confidential online rank order vote. It was deemed feasible to have a total of 13 prioritized outcomes across the four recommendation questions. Expert panel co-chairs did not participate in the vote as they functioned as co-facilitators. Voting results were presented to the expert panel. Through a facilitated discussion, priority outcomes were determined per recommendation question. Each recommendation question informed a PICO research question which guided the systematic reviews. The four recommendation questions and their respective PICO research questions are presented below:
Recommendation Question 1: Should access to nurses specialized in wound, ostomy, and continence or no access to nurses specialized in wound, ostomy, and continence be recommended?
# PICO Research Question 1 Population:
Adults anticipating or living with an ostomy. Intervention: Access to nurses specialized in wound, ostomy, and continence. Comparison: No access to nurses specialized in wound, ostomy, and continence.
# Outcomes:
Peristomal skin breakdown*, ostomy leakage, quality of life, hospital length of stay and readmission rates to hospital.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Outcomes:
Quality of life and financial priorities.
Recommendation Question 4: Should the use of standardized assessment tool for quality of life to customize care plan (for education and referral) or no use of standardized assessment tool for quality of life to customize care plan (for education and referral) be recommended?
# PICO Research Question 4 Population:
Adults anticipating or living with an ostomy. Intervention: Use of a standardized assessment tool for quality of life to customize care plan (for education and referral). Comparison: Usual care.
# Outcomes:
Psychological health status and self-identity.
- The peristomal skin breakdown outcome was not found in the literature. As a result, peristomal dermatitis and peristomal irritation were chosen as surrogate outcomes after consultation with expert panel co-chairs. A surrogate outcome is one that is a similar measure to the desired outcome and reflects what would contribute to the desired outcome.
The preoperative stoma site marking outcome was not found in the literature. A surrogate outcome was not chosen in replacement as there deemed to be a sufficient number of outcomes related to Research Question #2.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Literature regarding access to affordable ostomy supplies was not found. As access to affordable supplies was highlighted as a priority topic by the expert panel, RNAO is taking policy initiatives on universal funding for ostomy supplies to promote optimal health outcomes for all adults who anticipate or live with an ostomy.
In consultation with the co-chairs, an alternate priority research question identified by the expert panel was chosen.
The respective priority outcome was also determined by the co-chairs. The revised Recommendation Question #3 is outlined below:
Recommendation Question 3: Should prevention strategies for parastomal hernia development or no prevention strategies for parastomal hernia development be recommended?
# PICO Research Question 3 Population:
Adults living with an ostomy. Intervention: Prevention strategies for parastomal hernias. Comparison: Usual care.
# Outcomes:
Rates of parastomal hernias.
Literature specific to the use of standardized assessment tool for quality of life to customize care plan (for education and referral) was not found. In consultation with the co-chairs, a broader recommendation question was identified that could indirectly inform the need for quality of life assessment in adults who anticipate or live with an ostomy. The revised Recommendation Question #4 is outlined below: and 8). Detailed information on the search strategy for the systematic reviews, including the inclusion and exclusion criteria and search terms, is available at .
Recommendation
All studies were independently assessed for relevance and eligibility by the two Guideline Development Methodologists based on the inclusion and exclusion criteria. Any disagreements were resolved through consensus.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition All included articles were independently assessed for risk of bias by study design using validated and reliable tools.
Randomized controlled trials G were assessed using the Risk of Bias 2.0 tool (94), quasi-experimental studies G and other non-randomized studies were assessed using the ROBINS-I tool (95), systematic reviews were assessed using the AMSTAR 2 tool (96) and qualitative studies were assessed using the CASP qualitative checklist (97). Two reviewers reached consensus on all scores through discussion.
Data extraction was performed simultaneously. Reviewers completed independent data extraction for 75 per cent of the studies. The remaining studies were split between the reviewers and were cross-checked for accuracy. In total, 36 studies were included across all four systematic reviews.
In January 2019, an additional guideline search was conducted in an established list of websites for guidelines published between September 2017 and January 2019 to identity recommended resources. One guideline was found however it was for purchase, and therefore not accessible. Furthermore, searches in all databases were re-run on January 11, 2019 to capture recent research. Studies were screened for relevancy to inform values and preferences and health equity for all recommendations. Findings from one study were incorporated in the discussion of evidence for Recommendation 2.1 and 2.2.
# Determining Certainty and Confidence of Evidence
# Certainty of Evidence
The certainty of quantitative evidence (i.e., the extent to which one can be confident that an estimate of an effect is true) is determined using GRADE methods (8). First, the certainty of the evidence is rated for each prioritized outcome across studies (i.e., for a body of evidence) per research question (8). This process begins with the study design and then requires an examination of five domains-risk of bias, inconsistency, imprecision, indirectness, and publication bias-to potentially downgrade G the certainty of evidence for each outcome. Following the initial consideration for rating down, the following three factors that permit rating up the certainty of evidence are assessed: large magnitude of effect, dose-response gradient, and effect of plausible confounding. See Table 11 for a definition of each of these certainty criteria.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Risk of bias
Limitations in the study design and execution that may bias study results.
Valid and reliable quality appraisal tools are used to assess the risk of bias. First, risk of bias is examined for each individual study and then examined across all studies per defined outcome.
# Inconsistency
Unexplained differences (heterogeneity) of results across studies.
Inconsistency is assessed by exploring the magnitude of difference, and possible explanations, in the direction and size of effects reported across studies for a defined outcome.
# Indirectness
Variability between the research and review question and context within which the recommendations would be applied (applicability). There are four sources of indirectness which are assessed:
Differences in population.
Differences in interventions.
Differences in outcomes measured.
Differences in comparators.
# Imprecision
The degree of uncertainty around the estimate of effect. This is usually related to sample size and number of events. Studies are examined for sample size, number of events, and confidence intervals.
# Publication bias
Selective publication of studies based on study results. If publication bias is strongly suspected, downgrading is considered.
Source: The GRADE Working Group. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach 2013. Available from: #h.svwngs6pm0f2.
Following the initial consideration for rating down the certainty of quantitative evidence, there are three factors assessed that permit rating up the certainty of evidence for observational studies:
- Large magnitude of effect: If the body of evidence has not been rated down for any of the five criteria and a large estimate of the magnitude of intervention effect is present, there is consideration for rating up (8).
- Dose-response gradient: If the body of evidence has not been rated down for any of the five criteria and a doseresponse gradient is present, there is consideration for rating up (8).
# Effect of plausible confounding:
If the body of evidence has not been rated down for any of the five criteria and all residual confounders would result in an underestimation of treatment effect, there is consideration for rating up (8).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
The overall certainty of evidence is the combined rating of the certainty of evidence across all prioritized outcomes per recommendation question. GRADE categorizes the overall certainty of evidence as high, moderate, low, or very low. See Table 12 for the definitions of these categories.
For this Guideline, the five GRADE certainty criteria for potentially rating down and the three GRADE certainty criteria for potentially rating up were independently assessed by the two Guideline Development Methodologists. Any discrepancies were resolved through consensus. An overall certainty of evidence per recommendation question was assigned based on these assessments. Recommendations that were derived from the recommendation questions were accordingly assigned this certainty of evidence.
# High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
# Very Low
We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
# Confidence in Evidence
Similar to GRADE, there are four CERQual criteria G to assess the confidence in qualitative findings related to a phenomenon of interest:
- Methodological limitations.
- Relevance.
- Coherence.
# Adequacy.
See Table 13 for a definition of each of these criteria.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Methodological limitations
The extent to which there are concerns about the design or conduct of the primary studies that contributed evidence to an individual review finding.
# Coherence
An assessment of how clear and cogent the fit is between the data from the primary studies and a review finding that synthesises that data. By "cogent," we mean well supported or compelling.
# Adequacy of data
An overall determination of the degree of richness and quantity of data supporting a review finding.
# Relevance
The extent to which the body of evidence from the primary studies supporting a review finding is applicable to the context (perspective or population, phenomenon of interest, setting) specified in the review question.
Source: Reprinted from Lewin S, Booth A, Glenton C, et al. Applying GRADE-CERQUAL to qualitative evidence synthesis findings: introduction to the series. Implement Sci. 2018;13(Suppl 1):1-10. Table 2, Definitions of the components of the CERQual approach; p. 5. Reprinted with permission.
For qualitative findings related to one of the prioritized outcomes, these four criteria were independently assessed by the two Guideline Development Methodologists. Discrepancies were resolved through consensus. An overall judgment of the confidence in each review finding was made based on these assessments above (see Table 14 for the confidence of evidence judgments). Recommendations that included qualitative evidence were assigned an overall confidence in evidence based on the corresponding review finding.
# High
It is highly likely that the finding is a reasonable representation of the phenomenon of interest.
# Moderate
It is likely that the finding is a reasonable representation of the phenomenon of interest.
# Low
It is possible that the review finding is a reasonable representation of the phenomenon of interest.
# Very Low
It is not clear whether the review finding is a reasonable representation of the phenomenon of interest.
Source: Reprinted from Lewin S, Booth A, Glenton C, et al. Applying GRADE-CERQUAL to qualitative evidence synthesis findings: introduction to the series. Implement Sci. 2018;13(Suppl 1):1-10. Table 3, Description of level of confidence in a review finding in the CERQual approach; p. 6. Reprinted with permission.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Summarizing the Evidence
GRADE and GRADE CERQual evidence profiles are used to present decisions on determining the certainty and confidence of evidence, as well as general information about the body of research evidence, including key statistical or narrative results. Evidence profiles summarize the body of evidence for each systematic review per outcome and are developed by the two Guideline Development Methodologists.
Evidence profiles for the body of quantitative studies present the decisions made by the two reviewers on the five key GRADE certainty domains for rating down and the three GRADE certainty domains for rating up. The evidence profiles present general information about the body of evidence, including a description of the intervention, key results, and transparent judgments about the certainty underlying the evidence for each outcome (8). For this Guideline, meta-analyses G were not performed; results were therefore synthesized in narrative format in the evidence profiles.
CERQual evidence profiles were created for the body of qualitative evidence for each systematic review per outcome. Similar to the GRADE evidence profiles used for quantitative research, the CERQual evidence profiles present the body of evidence supporting each theme related to outcomes for every recommendation question. These evidence profiles presented the decisions made by the two Guideline Development Methodologists on the four key CERQual criteria and transparent judgements about the confidence underlying the evidence for each theme.
The GRADE and CERQual evidence profiles for each systematic review, organized per outcome, can be accessed online at .
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Formulating Recommendations
# Evidence-to-Decision Frameworks
Evidence-to-Decision (EtD) frameworks G outline proposed recommendations and summarize all necessary factors and considerations based on available evidence and expert panel judgement for formulating the recommendation statements. EtD frameworks are used to help ensure that all important factors required to formulate recommendations are considered by an expert panel (8). Both quantitative and qualitative evidence are incorporated into the frameworks. The Guideline Development Methodologists draft the frameworks with available evidence from the systematic reviews.
For this Guideline, the EtD frameworks included the following areas of consideration for each drafted recommendation statement (see Table 15):
Background information on the magnitude of the problem.
Includes the PICO question and general context related to the research question.
The balance of benefits and harms of an intervention.
Certainty and/or confidence of the evidence.
Values and preferences.
Health equity.
# Decision Making: Determining the Direction and Strength of Recommendations
Expert panel members are provided with the EtD frameworks to review prior to a scheduled two-day in-person meeting to determine the direction (i.e., to provide a recommendation for or against an intervention) and the strength of the recommendations in the guideline. Expert panel members also are given access to the complete evidence profiles and full-text articles.
Using the EtD frameworks as a guiding document, the expert panel members participated in an online vote from May 15th to May 30th, 2018. The following questions were posed to all expert panel members for each draft recommendation:
Is there important uncertainty about or variability in how much people value the main outcomes?
Does the balance between desirable and undesirable effects favor the intervention or the comparison?
What would be the impact on health equity?
The Likert scales created by the GRADEpro software were used for voting on each factor (98). There also was the opportunity for expert panel members to provide written comments related to each of the judgement criteria.
The results of the online vote were calculated and presented to the expert panel at the two-day in-person meeting held June 21-22, 2018. The online vote results were used to help guide discussion. The expert panel co-chairs and the Guideline Development Lead facilitated the meeting to allow for adequate discussion for each proposed recommendation.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
The decision on direction and strength of each recommendation statement was determined by discussion and a consensus vote of 70 per cent. The voting process was moderated by the expert panel co-chairs and Guideline Development Lead. In determining the strength of a recommendation statement, the expert panel was asked to consider the following (see Table 15):
The balance of benefits and harms.
Certainty and confidence of the evidence.
Values and preferences.
Potential impact on health equity.
Following the in-person meeting, the final decisions made on all recommendations were summarized and sent to the full expert panel electronically.
# Benefits and harms
Potential desirable and undesirable outcomes reported in the literature when the recommended practice or intervention is used.
"The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a conditional recommendation is warranted" (99).
Includes research exclusively from the systematic review.
# Certainty and confidence of evidence
The extent of confidence that the estimates of an effect are adequate to support a recommendation. The extent of confidence that a review finding is a reasonable representation of the phenomenon of interest (100).
Recommendations are made with different levels of certainty or confidence; the higher the certainty or confidence, the higher the likelihood that a strong recommendation is warranted (99).
Includes research exclusively from the systematic review.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# FACTOR DEFINITION SOURCES
# Values and preferences
The relative importance or worth of the health outcomes of following a particular clinical action from a person-centred perspective.
"The more values and preferences vary or the greater the uncertainty in values and preferences the higher the likelihood that a conditional recommendation is warranted" (99).
Includes evidence from the systematic review (when available) and other sources, such as insights from the expert panel.
# Health equity
Represents the potential impact of the recommended practice or intervention on health outcomes or health quality across different populations.
The greater the potential for increasing health inequity, the higher the likelihood that a conditional recommendation is warranted.
Includes evidence from the systematic review (when available) and other sources, such as insights from the expert panel.
Source: Adapted by the RNAO expert panel from The GRADE Working Group. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach 2013. Available from: #h.svwngs6pm0f2.
# Drafting the Guideline
The Guideline Development Methodologists wrote the draft of this Guideline. The expert panel reviewed the draft and provided written feedback. A teleconference was held October 2nd, 2018, to review panel feedback and incorporate changes, as necessary. The Guideline then proceeded to external stakeholder review.
# Stakeholder Review
RNAO is committed to obtaining feedback from (a) nurses and other health providers from a wide range of practice settings and roles, (b) knowledgeable administrators and funders of health services, and (c) stakeholder associations as part of the guideline development process.
Stakeholder reviewers for RNAO BPGs are identified in two ways. First, stakeholders are recruited through a public call issued on the RNAO website (RNAO.ca/bpg/get-involved/stakeholder). Second, individuals and organizations with expertise in the guideline topic area are identified by the RNAO Best Practice Guidelines Development and Research Team and the expert panel, and are directly invited to participate in the review.
Stakeholder reviewers are individuals with subject matter expertise in the guideline topic or those who may be affected by its implementation. Reviewers may be nurses, members of the interprofessional team, nurse executives, administrators, research experts, educators, nursing students, or persons with lived experience and family members.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
Reviewers are asked to read a full draft of the BPG and participate in the review of it prior to its publication. Stakeholder feedback is submitted online by completing a survey questionnaire. The stakeholders are asked the following questions:
Is the guideline title appropriate?
Is the guideline development process description clear?
In addition, the stakeholders are asked the following questions about each recommendation:
Is this recommendation clear?
Do you agree with this recommendation?
Is the discussion of evidence thorough and does the evidence support the recommendation?
The survey also provides an opportunity to include comments and feedback for each section of the BPG. Survey submissions are compiled and feedback is summarized by the RNAO Best Practice Guidelines Development and Research Team. The survey results are reviewed and discussed with the expert panel. If necessary, the guideline content and recommendations are modified prior to publication to reflect the feedback received.
For this Guideline, the stakeholder review process was completed from October 19th to November 2nd, 2018 and diverse perspectives provided feedback (see Stakeholder Acknowledgment).
# Procedure for Updating the Guideline
The RNAO commits to updating all BPGs, as follows:
- Each BPG will be reviewed by a team of specialists in the topic area every five years following publication of the previous edition.
- RNAO International Affairs and Best Practice Guidelines Centre staff regularly monitor for new systematic reviews, randomized controlled trials, and other relevant literature in the field.
- Based on that monitoring, staff may recommend an earlier revision period for a particular BPG. Appropriate consultation with members of the original expert panel and other specialists and experts in the field will help inform the decision to review and revise the BPG earlier than planned. 5. New editions of BPGs will be disseminated based on established structures and processes.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Os tilted
Opening of bowel is tilted from center of stoma.
# Prolapsed
The telescoping of the bowel through the stoma, making the stoma longer.
# Raised
Stoma is sitting above level of the skin.
# Retracted
Disappearance of the normal stoma opening below skin level.
# Black (necrosis)
Ischemia of the stoma from inadequate blood supply.
# Dusky
Purple to a deep wine-coloured hue from altered blood supply.
# Edematous
Interstitial collection of fluid.
# Friable
Fragile tissue that bleeds easily.
# STOMA APPEARANCE
# Moist
Mucosal tissue is damp.
# Pale
Diminished colour.
# Pink
Pink in colour.
# Red
Red in colour.
# Red (Dark)
Stoma has a deep/dark red hue.
# Slough
Dry or wet, loose or firmly attached, yellow to brown dead tissue.
# Turgor
Ability to change shape and return to normal appearance after lightly touching stoma (elasticity).
# Trauma
Injury to surface of stoma like a cut, abrasion, or bruise.
# Cancerous lesion
Able to visualize cancerous lesion/tumor on or attached to stoma.
# Pseudoverrucous lesions
Wart-like lesions from chronic moisture irritation on or directly around stoma.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# PERIOSTOMY SKIN Macerated
Wet, white.
# Mucosal transplant
Seeding of viable intestinal mucosa along suture line and onto peristomal skin.
# Parastomal hernia
A deficit in the fascia that allows loops of the intestine to protrude in areas of weakness. Can present as abnormal bumps on the abdomen around the stoma.
# Pseudo-verrucous lesions
Wart-like lesions from chronic moisture irritation around stoma.
# Psoriasis
Chronic disease characterized by proliferation of epidermis that often appears as an erythematic, thick, silvery-white, and scaling plaque.
# Pyoderma gangrenosum
Ulcerative inflammatory skin condition of unknown etiology that starts as pustules and break open to form full thickness ulcers often with undermining, ragged edges, and overhanging margins.
# Trauma
Loss of epidermis around stoma.
# Ulceration
Ulcer located around stoma.
# Length & Width
Length: Longest measurement.
Width: Measured at widest area perpendicular to length.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition STOMA COLOUR: Stoma colour is usually pink or red but may vary depending on blood supply.
# Pink/red
Pink or red: ealthy with normal/adequate blood supply.
# Dusky
Bluish hue due to altered blood supply.
# Necrotic
Purple to a deep wine coloured hue due to ischemia of the stoma. The stomal tissue may turn to yellow slough and can progress to black dry tissue (eschar).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition STOMA TISSUE: Stoma tissue is usually moist and damp. The tissue can vary depending on blood supply, damage, trauma, etc.
# Moist
Mucosal tissue is damp.
# Edematous
Shiny, swollen, translucent, smooth appearance; due to interstitial collection of fluid.
# Slough
Soft, moist, devitalized tissue; may be white, yellow, tan or green. May be loose or firmly adherent.
# Friable (no image available)
Stoma tissue is fragile and bleeds easily with minimal contact.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition STOMA HEIGHT: An elevation above skin level of approximately 2cm is ideally for a good fit of the appliance. Due to surgical complication of body habitus, stomas can be either retracted or prolapsed.
# Protruding
Stoma protrudes above level of the skin by approximately 2cms.
# Flush
Stoma sits at the same level of the skin.
# Retracted
The stoma is pulled down below the level of the skin.
# Prolapsed
A prolapsed sttoma is a stoma that develops a length longer than what was created at the time of surgery. The prolapse is created by the outward telescoping of the bowel. The length of the prolapse can vary.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition PERISTOMAL SKIN: the skin surrounding the stoma.
# Intact
Unbroken skin.
# Excoriated
Superficial loss of tissue that presents irregular with areas of erythema, and rash.
# Red
Intact skin with redness that may have varying degrees of intensity from bright red to dark red; redness may be due to chemical effluent, fungal or sensitivity/allergy.
# Creases
A dip or fold in the abdomen. The depth may vary from shallow to very deep.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# MUCOCUTANEOUS JUNCTION: The point where the epidermis and the mucosa merge
# Intact
Mucocutaneous junction is well approximated.
# Separated
Area of detachment(s) from the stoma to the skin (dehiscence).
The separated area may be circumferential or partial.
# Rod/ bridge
This device may be a commercially available rod, a Penrose drain or red rubber catheter. It may, or may not, be sutured.
# Stents
A short-term small plastic tube which sits in each of the ureters and exits through the stoma; used to divert urine while the surgical area recovers.
# Allergic contact dermatitis
Peristomal erythema that mirrors the image of the allergen.
May be moist and pruritic.
Remove allergen.
Allergen may be a tape border or the barrier or both.
Medicated cortisone spray to relieve itch.
Crusting if moist.
If tape allergy use no tape product.
If barrier allergy, consider a different company.
May consider barrier between skin and pouch (e.g., skin protectant, transparent film, or hydrocolloid.
Consider patch testing.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# DESCRIPTION CLINICAL PRESENTATION TREATMENT OBJECTIVE
# TOPICAL TREATMENT OPTIONS
# Wound to peristomal skin
Wound to peristomal skin.
Identify cause of wound.
Heal the wound.
Prevent pouching system leakage.
Moisture balance to wound, follow wound treatment plan.
If using convexity, consider wider convexity or barrier ring instead to offload pressure.
# Pyoderma gangrenosum
Wound to peristomal skin.
Very painful purple borders.
Usually a history of autoimmune disease (e.g., inflammatory bowel disease, rheumatoid arthritis).
Identify cause of wound.
Manage pain.
Heal the wound.
# Prevent pouching system leakage
Physician/NP and CPCET referral required.
Prescription for steroids (steroid cream to be avoided as prevents pouch adherence).
Moisture balance to wound.
If using convexity, consider wider convexity or barrier ring instead to offload pressure.
Sharp debridement is contraindicated.
# Stoma with fungating tumour
Cancerous tumour protrudes beyond the epidermis causing pouching challenges.
May be dry or moist, have odour and is painful.
Prevent pouching system leakage.
Prevent bleeding.
Provide psychosocial support.
Flexible pouching system.
Cut wide to avoid tumour if needed to obtain a seal.
Consider closed pouching system.
Lubricate inside of pouch if friction causes bleeding (pouch rubbing against tumour).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# DESCRIPTION CLINICAL PRESENTATION TREATMENT OBJECTIVE TOPICAL TREATMENT OPTIONS
# Peristomal skin denudation due to leakage
Superficial erythema that is moist.
May be painful and pruritic.
Usually occurs where pouching system is leaking.
Treat and prevent leakage.
Change pouching system immediately if leaking.
Identify cause of leak.
Crusting procedure.
Correct leakage, fill in crevices/creases, or add a barrier ring/paste.
Change to a convex appliance if stoma located in a fold or crease, or if stoma is flushed or mobile.
# Peristomal growths
Growths protruding from the mucocutaneous junction.
Are painful and present a pouching challenge.
Refer to CPCET and physician/NP.
Prevent pouching system leakage.
Consult with physician/NP and CPCET.
Use paste or ring to create an even pouching surface. Treat inflammation and localized infection.
Prevent recurrence.
Crusting procedure as needed.
Clip hair to remove.
Use adhesive remover to remove pouching system.
# Yeast/candidiasis
Fungal infection of the skin usually related to leakage.
Area is denuded, red and has satellite lesions.
Can be pruritic.
Treat and prevent leakage.
Change pouching system immediately if leaking.
Treat fungal rash (i.e., crust with antifungal powder).
Identify cause of leak.
Crusting procedure using antifungal powder.
Correct leakage, fill in crevices/creases, or add a barrier ring/paste.
Change to a convex pouching system if stoma located in a fold or crease, or flush or mobile stoma.
Source: Reprinted from Interior Health. Peristomal skin breakdown: assessment and management. ; 2015. Reprinted with permission.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Overview of types of ostomies from a non-profit volunteer organization dedicated to all people with an ostomy and their families.
Website includes variety of information including, but not limited to, ostomy products, living life to the fullest, ostomy products, and healthy living. Journal article with overview of safe management of ileostomates with high-output stomas.
# A P P E N D I C E S
Supporting | These guidelines are not binding on nurses, other health providers, or the organizations that employ them. The use of these guidelines should be flexible and based on individual needs and local circumstances. They constitute neither a liability nor discharge from liability. While every effort has been made to ensure the accuracy of the contents at the time of publication, neither the authors nor the Registered Nurses' Association of Ontario (RNAO) gives any guarantee as to the accuracy of the information contained in them or accepts any liability with respect to loss, damage, injury, or expense arising from any such errors or omission in the contents of this work.With the exception of those portions of this document for which a specific prohibition or limitation against copying appears, the balance of this document may be produced, reproduced, and published in its entirety, without modification, in any form, including in electronic form, for educational or non-commercial purposes. Should any adaptation of the material be required for any reason, written permission must be obtained from RNAO. Appropriate credit or citation must appear on all copied materials as follows: Registered Nurses' Association of Ontario. Supporting adults who anticipate or live with an ostomy. 2nd ed. Toronto (ON): Registered Nurses' Association of Ontario; 2019.Declarations of competing interest that might be construed as constituting an actual, potential, or apparent conflict were made by all members of the RNAO expert panel, and members were asked to update their disclosures throughout the guideline development process. Information was requested about financial, intellectual, personal, and other interests and documented for future reference. No limiting conflicts were identified. Details regarding disclosures are available at https://rnao.ca/bpg/guidelines/ostomy.# Table of Contents
# Table of Contents
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Purpose and Scope Purpose RNAO's BPGs are systematically developed, evidence-based documents that include recommendations on specific clinical, healthy work environment, and health system topics that are intended for nurses, members of the interprofessional team, educators, leaders, policy-makers, researchers and persons and families with lived experience. BPGs promote consistency and excellence in clinical care, education, and administrative practices and policies with the aim of achieving optimal health outcomes for people, communities, and the health system as a whole.
This BPG replaces the RNAO BPG Ostomy Care and Management, which was released in 2009. The purpose of this BPG is to provide nurses and the interprofessional team with evidence-based recommendations for the most effective strategies to support adults (18 years and older) who anticipate or live with an ostomy that will (a) promote self-management G , (b) enhance access and delivery of care, and (c) lead to positive health outcomes. For this BPG, persons who anticipate an ostomy are those who are in the preoperative phase and awaiting an ostomy surgery. This BPG recognizes that adults who anticipate or live with an ostomy and their support network G are experts in their health and decision making; collaboration among the interprofessional team, the person anticipating or living with an ostomy, and their support network (if needed) therefore is essential for achieving improved health outcomes.
In October 2017, RNAO convened an expert panel to determine the scope of this revised BPG and to develop recommendation questions to inform the systematic reviews G . The RNAO expert panel included persons with lived experience and was interprofessional in composition, comprising of individuals with knowledge and experience in clinical practice, education, research, and policy across a range of health service organizations, practice areas, and sectors. These experts shared their insights on supporting and caring for adults who anticipate or live with an ostomy across the continuum of care (e.g., acute care, rehabilitation, community, and primary care). A systematic and comprehensive analysis was completed by the RNAO Best Practice Guideline Development and Research Team and the RNAO expert panel to determine the scope of this BPG and to prioritize recommendation questions for its development (see Appendix D).
# Scope
To determine the scope of this BPG, the RNAO development team conducted the following steps:
Reviewed the previous RNAO BPG, Ostomy Care and Management (2009). Conducted a guideline search and gap analysis.
Undertook a scoping review G of the literature to determine the depth of peer-reviewed studies in the area of pediatric populations (younger than 18 years) living with an ostomy.
Conducted six key informant interviews.
Held two virtual focus groups with experts in the field, including front-line health providers G , researchers, and persons with lived experience.
The analysis informed the scope of this BPG. This BPG will focus on adults (18 years and older) who live with or anticipate an ostomy. The scoping review identified a lack of peer-reviewed studies addressing pediatric populations living with an ostomy. It was thus concluded that a separate search for evidence and approach to guideline development was warranted to address this population.
Regulated health provider: In Ontario, the Regulated Health Professional Act, 1991 (RHPA) provides a framework for regulating 23 health professions, outlining the scope of practice and the profession-specific controlled or authorized acts that each regulated professional is authorized to perform when providing health care and services (5).
Unregulated health provider: Unregulated health providers fulfill a variety of roles in areas that are not subject to the RHPA. They are accountable to their employers but not to an external regulating professional body (e.g., College of Nurses of Ontario). Unregulated health providers fulfill a variety of roles and perform tasks that are determined by their employer and employment setting. Unregulated health providers only have the authority to perform a controlled act as set out in the RHPA if the procedure falls under one of the exemptions set out in the Act (6).
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Ostomy care program: An organization-level approach to standardize care for persons who anticipate or live with an ostomy. The ostomy care program includes structured treatment, management, and follow-up strategies developed by an interprofessional team, which may consist of NSWOCs, nurses, surgeons, physicians, social workers, dieticians, and pharmacists (among others).
Parastomal hernia: Occurs when one or more loops of the bowel protrude through the abdominal wall, creating a bulge around the peristomal skin G (7).
Topics Outside the Scope of this Best Practice Guideline
The following conditions and topics are not covered within the scope of this BPG:
Pharmaceutical interventions for the prevention and management of ostomy-related complications.
Surgical procedures in the creation of a stoma.
Surgical interventions for the prevention and management of ostomy-related complications.
Pediatric populations anticipating or living with an ostomy.
# Recommendation Questions
Within the determined scope defined above, the following priority recommendation questions and outcomes were developed by the RNAO expert panel and informed the development of this BPG:
Outcomes: Psychological health status and self-identity.
Note: These priority recommendation questions are condensed versions of the more comprehensive PICO G (population, intervention, comparison, outcomes) research questions developed by the RNAO expert panel to guide the systematic reviews and development of this BPG. For the PICO research questions and the detailed process of how the RNAO expert panel determined these priority questions and outcomes, see Appendix D.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Recommendations
Recommendations in this BPG address access to the appropriate specialist to support comprehensive care (i.e., NSWOCs G ), the need for a standardized ostomy care program within health service organizations, guidance on the prevention of parastomal hernias, and quality of life assessments in adults who anticipate or live with an ostomy. The evidence-based recommendations in this BPG are applicable to all practice settings where adults who anticipate or live with an ostomy are accessing services (such as, but not limited to, acute care, long-term care, community settings, and rehabilitation settings).
In this BPG, no recommendation questions were identified that addressed the core education and training strategies required for curricula, ongoing education, and professional development of nurses or the interprofessional team in order to support adults living with or anticipating an ostomy. Please refer to Appendix C for education statements G that educators, managers, administrators, and academic and professional institutions can use to support the uptake of this BPG.
Note: Recommendations in this BPG were developed for adults who anticipate or live with an ostomy, but in some cases, recommendations also may be applicable to adults with continent diversions G (bowel or urinary).
# RNAO Guidelines and Resources that Align with this Best Practice Guideline
Other RNAO guidelines and other resources may support implementation of this BPG. See Appendix B for RNAO guidelines and other resources on the following related topics:
Client centred learning.
Culturally sensitive care.
Implementation science, implementation frameworks, and resources.
Interprofessional collaboration.
Person-and family-centred care.
Self-management of chronic conditions.
Therapeutic relationships.
For more information on the guideline development process, systematic reviews, and search strategy for this BPG, see Appendix D.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Interpretation of Evidence and Recommendation Statements
RNAO Guidelines are developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) G and Confidence in the Evidence from Reviews of Qualitative Research (CERQual) G methods. For more information about the guideline development process, including the use of GRADE and GRADE-CERQual methods, refer to Appendix D.
# Certainty of Evidence
The certainty of evidence (i.e., the level of confidence we have that an estimate of effect is true) for quantitative research is determined using GRADE methods (8). After synthesizing the evidence for each prioritized outcome, the certainty of evidence is assessed. The overall certainty of evidence is then determined by considering the certainty of evidence across all prioritized outcomes per recommendation question. GRADE categorizes the overall certainty of evidence as high, moderate, low, or very low. See Table 1 for the definition of these categories.
# Table 1: Certainty of Evidence
# CERTAINTY OF EVIDENCE DEFINITION High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
# Very Low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Confidence in Evidence
The confidence in evidence for qualitative research G (i.e., the extent to which the review finding is a reasonable representation of the phenomenon of interest) is determined using GRADE-CERQual methods (hereafter referred to as CERQual) (9). For qualitative evidence, an overall judgment of the confidence is made per finding in relation to each recommendation statement, as relevant. CERQual categorizes the confidence in evidence as high, moderate, low, or very low. See Table 2 for the definitions of these categories.
# CONFIDENCE IN EVIDENCE DEFINITION High
It is highly likely that the review finding is a reasonable representation of the phenomenon of interest.
# Moderate
It is likely that the review finding is a reasonable representation of the phenomenon of interest.
# Low
It is possible that the review finding is a reasonable representation of the phenomenon of interest.
# Very Low
It is not clear whether the review finding is a reasonable representation of the phenomenon of interest.
Source: Reprinted from Lewin S, Booth A, Glenton C, et al. Applying GRADE-CERQual to qualitative evidence synthesis findings: introduction to the series. Implement Sci. 2018;13(Suppl 1):1-10. Table 3, Description of level of confidence in a review finding in the CERQual approach; p. 6. Reprinted with permission.
Note: The assigned certainty and/or confidence in evidence can be found directly below each recommendation statement. For more information on the process of determining the certainty and/or confidence in the evidence and the documented decisions made by RNAO Guideline Development Methodologists, see Appendix D.
# Strength of Recommendations
Recommendations are formulated as strong or conditional by considering the certainty and/or confidence in evidence and the following key criteria (see Discussion of Evidence for definitions):
Balance of benefits and harms.
Values and preferences.
Potential impact on health equity.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Strong Recommendation
"A strong recommendation reflects the expert panel's confidence that the desirable effects of an intervention outweigh its undesirable effects (strong recommendation for an intervention) or that the undesirable effects of an intervention outweigh its desirable effects (strong recommendation against an intervention)" (8). A strong recommendation implies that the majority of persons will be best served by the recommended action (8).
# Conditional Recommendation
"A conditional recommendation reflects the expert panel's confidence that the desirable effects probably outweigh the undesirable effects (conditional recommendation for an intervention) or undesirable effects probably outweigh desirable effects (conditional recommendation against an intervention), but some uncertainty exists" (8). A conditional recommendation implies that not all persons will be best served by the recommended action: "there is a need for more careful consideration of personal circumstances, preferences, and values" (8).
# Note:
The strength of the recommendation statement is detailed directly below each recommendation statement and in the Summary of Recommendations. For more information on the process the expert panel used for determining the strength of each recommendation, please see Appendix D.
# Discussion of Evidence
The Discussion of Evidence that follows each recommendation includes the following main sections:
1. Benefits and Harms: Identifies the potential desirable and undesirable outcomes reported in the literature when the recommended practice is used. Content in this section solely includes research from the systematic review.
# Values and Preferences:
Denotes the relative importance or worth of the health outcomes of following a particular clinical action from a person-centered perspective. Content for the Values and Preferences section may include research from the systematic reviews and (when applicable) the RNAO expert panel.
# Health Equity:
Identifies the potential impact that the recommended practice could have on health across different populations. Content for the Health Equity section may include research from the systematic reviews and (when applicable) the RNAO expert panel.
# Expert Panel Justification of Recommendation:
Provides a rationale for why the expert panel made the decision to rate a recommendation as strong or conditional.
# 5.
Practice Notes: Highlights pragmatic information for nurses and members of the interprofessional team. This section may include supporting evidence from the systematic review and/or from other sources (e.g., the RNAO expert panel).
6. Supporting Resources: Includes a list of relevant resources (such as websites, books, organizations, and more) that support recommendations. Content listed in this section was not part of the systematic review and therefore not all content was quality appraised. As such, the list is not exhaustive and the inclusion of a resource in one of these lists does not imply an endorsement from RNAO.
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Summary of Recommendations
This Guideline replaces the RNAO BPG Ostomy Care and Management (2009). A summary of how the recommendations in this Guideline compare to the recommendations in the previous Guideline is available at https://rnao.ca/bpg/guidelines/ostomy.
# RECOMMENDATIONS STRENGTH OF THE RECOMMENDATION
Recommendation Question #1: Should access to nurses specialized in wound, ostomy, and continence or no access to nurses specialized in wound, ostomy, and continence be recommended?
Outcomes: Peristomal dermatitis, peristomal irritation, ostomy leakage, quality of life, hospital length of stay and readmission rates to hospital .
# Recommendation 1 .1
The expert panel recommends that health service organizations provide access to nurses specialized in wound, ostomy, and continence as essential members of the interprofessional team for all persons who anticipate or live with an ostomy .
# Strong Recommendation 1 .2:
The expert panel recommends that access to nurses specialized in wound, ostomy, and continence includes the following support within the ostomy care continuum: Performing preoperative stoma site marking . Providing perioperative education and counselling . Providing ongoing follow-up consultation and management . Involving persons who anticipate or live with an ostomy and their support network in all steps of care, as appropriate .
# Strong
Recommendation Question #2: Should an ostomy care program or no ostomy care program be recommended?
Outcomes: Patient satisfaction, hospital length of stay, readmission rates to hospital and staff satisfaction.
# Recommendation 2 .1:
The expert panel recommends that health service organizations implement an internal expertguided, standardized ostomy care program that is developed using an interprofessional, teambased approach .
# Strong BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Recommendation 2 .2:
The expert panel recommends that health service organizations include the following interventions within a standardized ostomy care program:
Preoperative education and counselling on ostomy surgery, daily living, and self-care . Postoperative education regarding stoma self-management and potential complications . Discharge planning that is based on a readiness criteria and includes follow-up information . Scheduled home visits and telephone follow-up within the first four weeks . Access to nurses specialized in wound, ostomy, and continence perioperatively and on an ongoing basis, as necessary .
# Strong
Recommendation Question #3:
Should prevention strategies for parastomal hernia development or no prevention strategies for parastomal hernia development be recommended?
Outcomes: Parastomal hernia rates .
# Guideline Evaluation
As you implement the recommendations in this BPG, we ask you to consider how you will monitor and evaluate its implementation and impact.
The Donabedian model informs the development of indicators for evaluating quality health care, which includes three categories: structure, process, and outcome (10).
Structure describes the required attributes of the health system, health service organization or academic institution to ensure quality care. It includes physical resources, human resources, and information and financial resources.
Process examines the health-care activities being provided to, for, and with persons or populations as part of the provision of quality care.
Outcome analyzes the effect of quality care on the health status of persons and populations, health workforce, health service organizations, academic institutions or health systems (10).
For additional information, please refer to the RNAO Toolkit: Implementation of Best Practice Guidelines, Second Edition (2012).
Tables 3, 4, and 5 provide potential structure, process and outcome measures to assess Guideline success. It is important to evaluate evidence-based practice changes when implementing a Guideline. Select the measures most relevant to the practice setting. There are few data repositories/indicator libraries available for ostomy support in Ontario and Canada. The following measures will support quality improvement and evaluation.
Table 3 provides potential structure measures associated with all recommendation statements, to assess attributes related to human resources.
# Stakeholder Acknowledgment
As a component of the guideline development process, feedback was obtained from participants across a wide range of health service organizations, practice areas, and sectors. Participants include nurses and people with lived experience. Stakeholders G representing diverse perspectives were solicited for their feedback (see Appendix D). RNAO wishes to acknowledge the following individuals for their contribution in reviewing this BPG. Stakeholder reviewers have given consent to the publication of their names and relevant information in this BPG.
# Background Context
What is an Ostomy?
An ostomy is a surgically created opening in the abdominal wall that results in the external diversion of feces and urine (1). An ostomy may be permanent or temporary, and the surgery is performed for various etiologies, including (but not limited to) diverticulitis, colorectal cancer, bowel obstruction, inflammatory bowel disease G , or bladder cancer (11). Each procedure results in a stoma, which is the end of the small or large intestine that can be seen protruding through the abdominal wall (2). The most common types of ostomy are the following:
Colostomy: A surgically created opening from the colon to the abdominal wall to allow the elimination of feces (3).
Ileostomy: A surgically created opening from the last part of the small intestine (ileum) to the abdominal wall to allow elimination of small bowel effluent (3).
Urostomy: A surgically created opening to divert the flow of urine by transplanting the ureters into an isolated segment of the ileum, bringing one end through the abdominal wall to create a stoma. Urine flows from the kidney to the ureters, then through the ileal conduit, exiting through the stoma (3).
For some people, it is possible to have a continent bowel or urinary diversion in which an internal reservoir is surgically created using a section of the bowel to collect feces or urine. Continent diversions may or may not result in the creation of a stoma, and they eliminate the necessity for a pouching system G to be worn outside the body (2).
# Prevalence and Impact of Living with an Ostomy
An estimated 1.3 million people around the world have an ostomy, whether it be an ileostomy, colostomy, or urostomy (12). North Americans constitute a large portion of this population, with an estimated 750,000 living with an ostomy (13). In Canada alone, approximately 13,000 new ostomy surgeries are performed every year (13).
The creation of an ostomy is a life-changing event and has implications for various aspects of a person's healthrelated quality of life (11). Living with an ostomy may cause changes to physical and emotional well-being, and it may require lifestyle adjustments. One of the most common physical outcomes of living with an ostomy is the risk for stoma-related complications. Approximately 20 per cent to 71 per cent of persons with an ostomy experience stoma related complications, the most common being ostomy leakage and peristomal skin problems (14). Peristomal skin complications affect one third of persons with a colostomy and two thirds of persons with a urostomy or ileostomy (15).
Another common complication is the incidence of parastomal hernias. A parastomal hernia occurs when one or more loops of the bowel protrude through the abdominal muscle, creating a bulge around the peristomal skin (7).
Living with a parastomal hernia has been associated with impairments in quality of life, stressors related to body image, fatigue, and the physical burden of the hernia (1). The reported incidence of parastomal hernia varies widely within the literature, ranging from 0 per cent to 78 per cent; it is caused by risk factors such as high body mass index and waist circumference (7,16,17). When persons living with an ostomy have access to evidence-based care provided by knowledgeable and skilled health providers, however, many of these complications are preventable and treatable (18,19).
# BAC K G R O U N D
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Living with an ostomy can impact a person's psychological health and affect social functioning (20). For instance, living with an ostomy can negatively impact body image, sexual function, mood, and daily activities, thus impairing a person's overall psychological health (11,21). Lifestyle considerations and adjustments may also be required for aspects of daily life, such as diet, exercise, intimacy, and self-management of the ostomy (13). Despite so many challenges, if the right resources and supports are in place, it is certainly possible for persons to live an active and meaningful life after ostomy surgery.
There currently are no definite statistics determining the costs associated with living with an ostomy. However, maintaining an ostomy through the regular use of supplies can be expensive. In Canada, the type and availability of financial support for adults living with an ostomy varies across provinces, ranging from complete coverage to no coverage at all, resulting in many people having to pay out-of-pocket fees (22). Living with an ostomy, whether it is temporary or permanent, also increases the risk of costly complications (23). Research suggests that costs of care are substantially higher for persons with peristomal skin complications related to an ostomy (24). It is estimated that average treatment costs are $77 CDN greater (including pouching systems and accessories) over a seven-week period of treatment for people with peristomal skin complications versus those without peristomal skin complications (25).
# Streamlining Ostomy Support
In accordance with the Charter of Ostomates Rights (Appendix K), persons living with an ostomy have the right to comprehensive, personalized, and accessible care (26). As the number of persons living with an ostomy increases, the need to provide such care becomes increasingly critical for health service organizations and health systems in order to meet the needs of the persons they serve (23).
The interprofessional team supporting persons living with an ostomy throughout the health continuum includes (but is not limited to) NSWOCs, nurses, surgeons/physicians, social workers, dietitians, and pharmacists. In particular, NSWOCs are designated experts who are highly trained, both in the psychological aspects of care and the care of persons with fecal and urinary diversions (27). "NSWOC" is a protected title and limited to certain jurisdictions, however, its equivalent may be represented in other locations with titles such as stoma nurse, WOC nurse, or ostomy nurse. An NSWOC is deemed certified if they graduate from a WCET®-accredited ostomy education program and pass a national certification exam (4). Ostomy champion roles may assist and support the NSWOC expert in many organizations, but they are not independent subject experts.
Comprehensive ostomy care, which includes access to expert health providers, is related to improved health outcomes. Comprehensive care requires collaboration among the interprofessional team, the person anticipating or living with an ostomy and their support network, along with standardized work processes and care pathways. Furthermore, use of evidence-based practice enables informed decision making at the person, organization, and system levels to ensure improved health outcomes. Consistent use of evidence-based practices related to ostomy care is ultimately enabled by policies and programs that standardize work processes.
# Conclusion
Prevention strategies, timely interventions, knowledgeable providers, and accessible resources are required to facilitate optimal well-being for persons who anticipate or live with an ostomy. This BPG provides evidence-based best practice recommendations that will help health service organizations and the interprofessional team to support adults (18 years and older) anticipating or living with a colostomy, ileostomy, or urostomy to enhance access and care delivery, promote self-management, and lead to positive health outcomes. The expert panel recommends that health service organizations provide access to nurses specialized in wound, ostomy, and continence as essential members of the interprofessional team for all persons who anticipate or live with an ostomy.
# RECOMMENDATIONS
# Strength of recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
Evidence demonstrates that access to a NSWOC may promote positive health outcomes in persons living with or anticipating an ostomy. Studies examined the benefits of one or more of the following interventions: performing preoperative stoma site marking G , providing perioperative G education and counselling, providing ongoing followup consultation and management, and involving persons who anticipate or live with an ostomy and their support network. These interventions were provided by a NSWOC (or a NSWOC as a key member of the interprofessional team) compared to no access to a NSWOC in persons who anticipate or live with an ostomy.
The studies found that regardless of the intervention, access to a NSWOC may reduce the incidence of peristomal dermatitis or skin irritation, readmission rates to hospital, hospital length of stay and the rates of ostomy leakage; access also may improve quality of life in persons anticipating or living with an ostomy across various health settings (community and hospital) (11,(28)(29)(30)(31)(32)(33)(34)(35). The evidence was of low certainty due to limitations in how studies were conducted, use of different tools to measure outcomes across studies and the small number of study participants. In qualitative studies reporting on facets of quality of life, persons living with an ostomy indicated that care provided by NSWOCs could help address their psychosocial concerns and help them resume a normal life (36,37). The qualitative evidence was of low confidence due to limitations in how studies were conducted and the small number of study participants. There were no harms related to the interventions provided by NSWOCs in the literature.
For more detailed information of the impact of the intervention (access to NSWOCs) on each of the prioritized outcomes (peristomal dermatitis, peristomal irritation, ostomy leakage, quality of life, hospital length of stay and readmission rates to hospital), please refer to the evidence profiles available here: https://rnao.ca/bpg/guidelines/ostomy.
See Recommendation 1.2 for details on the specific interventions provided by NSWOCs and their associated benefits and harms.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Values and Preferences
The evidence indicates that persons with an ostomy attributed high value to the role of the NSWOC. Persons with an ostomy value the opportunity to speak about their challenges and concerns, and to receive timely follow-up advice from a NSWOC (37).
# Health Equity
The expert panel suggests that availability and timely access to expert assessment and management provided by a NSWOC in all care settings would improve health equity, particularly in rural settings. Literature demonstrates that living in a rural area was associated with a lack of access to expert ostomy assessment and management (38). Group education provided by NSWOCs may be more effective at increasing quality of life for persons living with an ostomy in rural areas, as these persons may be at greater risk for social isolation (32).
# Expert Panel Justification of Recommendation
There were benefits to having access to NSWOCs and no harms were found. However, the certainty in this evidence was low. The expert panel determined that persons would value improvements in outcomes and attributed high value to ensuring that persons who anticipate or live with an ostomy have equitable access to NSWOCs to decrease the risk of complications (peristomal dermatitis, peristomal irritation and ostomy leakage), improve organization-related outcomes (readmission rates to hospital and hospital length of stay) and improve quality of life across populations. Therefore, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
There are no practice notes associated with this recommendation. The expert panel recommends that access to nurses specialized in wound, ostomy, and continence includes the following support within the ostomy care continuum:
Performing preoperative stoma site marking.
Providing perioperative education and counselling.
Providing ongoing follow-up consultation and management.
Involving persons who anticipate or live with an ostomy and their support network in all steps of care, as appropriate.
# Strength of recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
Studies examined one or more of the following interventions: performing preoperative stoma site marking, providing perioperative education and counselling, providing ongoing follow-up consultation and management, and involving persons with an ostomy and their support network in all steps of care, as appropriate. These interventions were provided by a NSWOC (or the NSWOC as a key member of the interprofessional team) compared to no access to an NSWOC. The studies found benefits in outcomes for persons anticipating or living with an ostomy across various health settings (community and hospital) (11,(28)(29)(30)(31)(32)(33)(34)(35). The evidence was of low certainty due to limitations in how studies were conducted, use of different tools to measure outcomes across studies and the small number of study participants. For qualitative studies, the confidence in evidence was also low due to limitations in how studies were conducted and the small number of study participants. There were no harms related to these interventions provided by NSWOCs in the literature.
For more detailed information of the impact of the intervention on each of the prioritized outcomes (peristomal dermatitis, peristomal irritation, ostomy leakage, quality of life, hospital length of stay and readmission rates to hospital), refer to the evidence profiles available here: https://rnao.ca/bpg/guidelines/ostomy.
The key interventions provided by the NSWOC throughout the ostomy care continuum and the associated health outcomes are outlined below. Please see Table 6 under Practice Notes for more details on specific components of the interventions.
# Performing Preoperative Stoma Site Marking
The evidence was limited to two studies. The evidence suggests that persons who receive stoma site marking by a NSWOC may experience a reduction in hospital length of stay and peristomal dermatitis (34,35).
# Providing Perioperative Education and Counselling
There is consistent evidence that suggests when NSWOCs provide preoperative and/or postoperative education and counselling, it may reduce hospital length of stay (28,31,33) and rates of peristomal dermatitis/irritation (28,29,31,35). The majority of studies suggest that when NSWOCs provide preoperative and/or postoperative education and counselling, it may improve quality of life (28, 31, 32) and reduce readmission rates to hospital (28,31,33).
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Refer to Appendix J for a sample ostomy teaching record to guide perioperative education and counselling for persons anticipating or living with an ostomy. Refer to Appendix M for nutritional management tips for persons living with an ostomy, which is an important component of perioperative education and counselling.
# Providing Ongoing Follow-up Consultation and Management
There is consistent evidence that suggests when NSWOCs provide ongoing follow-up consultation and management, it may improve quality of life (29,30). The evidence regarding peristomal dermatitis/irritation was limited to one study; it suggests that when NSWOCs provide ongoing follow-up consultation and management, rates of peristomal dermatitis/irritation may be reduced (29).
In findings from qualitative research reporting on quality of life, persons living with an ostomy expressed that ongoing follow-up consultation and management by NSWOCs could help address their psychosocial concerns and help them resume a normal life (36,37).
# Involving Persons Who Anticipate or Live with an Ostomy and Their Support Network in all Steps of Care, as Appropriate
Education provided by NSWOCs for persons who anticipate or live with an ostomy and their support network may have benefits. The evidence regarding the outcome quality of life was limited to one study; it suggested that involving the support network may improve quality of life for persons who anticipate or live with an ostomy (32). Furthermore, the evidence regarding peristomal dermatistis/irritation and ostomy leakage was also limited to one study, which suggested that involving the support network may decrease rates of peristomal dermatitis/irritation and ostomy leakage (28).
# Values and Preferences
See Recommendation 1.1 for the applicable values and preferences. The research suggests that the values and preferences associated with this recommendation are consistent with those outlined in Recommendation 1.1.
# Health Equity
See Recommendation 1.1 for the applicable impact on health equity. The research and the expert panel suggest that the impacts on health equity associated with this recommendation are consistent with those outlined in Recommendation 1.1.
# Expert Panel Justification of Recommendation
There were benefits to the use of the following interventions when conducted by a NSWOC or the NSWOC as a key member of the interprofessional team: preoperative stoma site marking, providing perioperative education and counselling, providing ongoing follow-up consultation and management, and involving persons who anticipate or live with an ostomy and their support network in all steps of care, as appropriate. No harms were found. However, the certainty in this evidence was low.
The expert panel determined that persons would value improvements in outcomes and attributed high value to ensuring that persons who anticipate or live with an ostomy have equitable access to NSWOCs to decrease risks of complications (peristomal dermatitis, peristomal irritation, and ostomy leakage), to improve organization-related outcomes (readmission rates to hospital and hospital length of stay), and to improve quality of life across populations. The expert panel therefore determined the strength of the recommendation to be strong.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Practice Notes
# KEY INTERVENTION DETAILS FROM THE EVIDENCE
# Performing preoperative stoma site marking
No further details from the evidence regarding performing preoperative stoma site marking.
Procedural information can be found within the grey literature, under the Supporting Resources section for this Recommendation.
# Providing perioperative education and counselling
Preoperative education and counselling included the following:
A description of the surgical procedure and what an ostomy is (31,33).
An explanation of preoperative interventions (e.g. stoma site marking) (28,33).
Instruction and practical demonstration of stoma site care (28).
Reviewing ostomy supply needs (28).
Describing in-hospital interventions to expect after surgery (28,31).
Explaining how to manage common complications (28,32,33).
Describing the impact of a stoma on daily life (e.g. sexuality) (31).
Reviewing changes to diet and hydration needs (28,33).
# Postoperative education and counselling included the following:
Directions and hands-on experience on how to change a pouching system and care for the stoma (31,33).
Providing a description of supplies (31,33).
Reviewing changes to diet and hydration (33).
Providing resources for social support (31).
# Educational delivery considerations for preoperative group education:
Encouraging discussion, asking questions, and sharing lived experiences (28,32).
Reinforcing through a video demonstration that a person living with an ostomy can do anything (32).
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# KEY INTERVENTION DETAILS FROM THE EVIDENCE
# Providing ongoing follow-up consultation and management
Follow-up consultation and management included the following:
Conducting a peristomal assessment (29,37).
For resources to aid in conducting a peristomal assessment, please refer to:
Appendix G for ostomy assessment terms.
Appendix H for ostomy assessment parameters and definitions.
Appendix I for a sample assessment and management form for peristomal skin breakdown.
Conducting a pouching system assessment (29).
Evaluating and guiding a person's stoma self-care (36,37).
Helping persons to accept their new condition, and helping them to see that they can continue activities and have control over their lives (36,37).
Answering questions or concerns (36,37).
Providing appropriate referral as needed (in the context of telephone follow-up) (37).
# Involving persons with ostomy and their support network in all steps of care, as appropriate
No further details from the evidence regarding involving persons anticipating or living with an ostomy and their support network in their care. The expert panel recommends that health service organizations implement an internal expertguided, standardized ostomy care program that is developed using an interprofessional, teambased approach.
# Strength of the recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
A standardized ostomy care program is an organization-level approach established within individual health service organizations to standardize care for persons anticipating or living with an ostomy. The ostomy care program includes structured treatment, management, and follow-up strategies developed and implemented by an interprofessional team that is internal to each organization, which may consist of NSWOCs, nurses, surgeons/physicians, social workers, and dietitians (among others).
Findings from quantitative research suggest that implementing an internal expert-guided, standardized ostomy care program within health organizations-compared to not implementing an ostomy care program-may reduce hospital length of stay and 30-day readmission rates to hospital, and improve patient satisfaction for persons anticipating or living with an ostomy (18,19,31,33,(39)(40)(41)(42)(43). The evidence was of low certainty due to limitations in how studies were conducted, use of different tools to measure outcomes across studies and the small number of study participants. There were no harms related to these interventions provided within the ostomy care program in the literature.
For more detailed information of the impact of the intervention (ostomy care program) on each of the specified outcomes (patient satisfaction, hospital length of stay, readmission rates to hospital and staff satisfaction), refer to the evidence profiles available here: https://rnao.ca/bpg/guidelines/ostomy.
See Recommendation 2.2 for further details regarding specific interventions included within the ostomy care program and the associated benefits and harms.
Refer to Appendix L for a sample ostomy care program patient checklist that can be used by the person anticipating an ostomy surgery.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Values and Preferences
Evidence suggests that persons living with an ostomy attributed high value to clear postoperative education, such as understanding common post-operative occurrences and how to resolve complications while at home (41). Some persons also requested the opportunity for family involvement so that they are well informed and can ask questions, as well as more information on types of stomas and where to order supplies (44). Persons living with an ostomy prefer having direct access to an assigned NSWOC or health provider compared to an emergent health visit to address complications after discharge (41).
# Health Equity
The expert panel suggests that implementation of an internal, expert-guided, standardized ostomy care program would improve health equity by ensuring the consistency of care delivered across populations. An interprofessional, internal, expert-guided and standardized ostomy care program requires the appropriate health human resources. This may be a challenge in some settings.
# Expert Panel Justification of Recommendation
There were benefits in implementing an internal, expert-guided, standardized ostomy care program and no harms were found. However, this evidence was of low certainty. The expert panel determined that persons would value improvements in outcomes and attributed high value to ensuring that health service organizations implement a standardized ostomy care program to improve patient satisfaction, to improve organization-related outcomes (readmission rates to hospital and hospital length of stay) and to enhance staff satisfaction. Therefore, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
The expert panel attributed high value to having experts in ostomy care (e.g., NSWOCs) within health service organizations to guide the implementation of a standardized ostomy care program. Experts are identified as those with formal knowledge and experience in providing care for persons who anticipate or live with an ostomy. The expert panel emphasized the importance of collaboration among the interprofessional team to support standardization of care across the organization. The expert panel recommends that health service organizations include the following interventions within a standardized ostomy care program:
# RECOMMENDATIONS
Preoperative education and counselling on ostomy surgery, daily living, and self-care.
Postoperative education regarding stoma self-management and potential complications.
Discharge planning that is based on a readiness criteria and includes follow-up information.
Scheduled home visits and telephone follow-up within the first four weeks.
Access to nurses specialized in wound, ostomy, and continence perioperatively and on an ongoing basis, as necessary.
# Strength of the recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
Studies examined one or more of the components of a standardized ostomy care program within health service organizations. All interventions involved collaboration among one or more members of the interprofessional team. When compared to no standardized ostomy care program, the proposed interventions within a standardized ostomy care program displayed benefits in outcomes for persons who anticipate or live with an ostomy (18,19,27,33,(39)(40)(41)(42)(43)45). The evidence was of low certainty due to limitations in how studies were conducted and the use of different tools to measure outcomes across studies. The qualitative evidence was of low confidence due to limitations in how the study was conducted and the small number of study participants. There were no harms in the literature related to these interventions provided within the ostomy care program.
For more detailed information on the components of this intervention on each of the specified outcomes (patient satisfaction, hospital length of stay, readmission rates to hospital and staff satisfaction), refer to the evidence profiles available here: https://rnao.ca/bpg/guidelines/ostomy.
The key interventions included within a standardized ostomy care program and the associated health outcomes are outlined below. See Table 7 under Practice Notes for more details on specific interventions.
# Preoperative Education and Counselling on Stoma Surgery, Daily Living, and Self-care
There is consistent evidence that suggests when persons anticipating stoma surgery receive preoperative education and counselling, it may reduce hospital length of stay (19,31,33). The majority of studies also suggest that when persons anticipating stoma surgery receive preoperative education and counselling, it may reduce readmission rates to hospital (19,33,43). The evidence regarding the outcome patient satisfaction is limited to one study and suggests that when persons anticipating stoma surgery receive preoperative education and counselling, it may improve patient satisfaction (27).
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Postoperative Education regarding Stoma Self-management and Potential Complications and Discharge Planning That is Based on a Readiness Criteria and Includes Follow-up Information
There is consistent evidence that suggests when persons receive postoperative education, discharge planning that is based on a readiness criteria and includes follow-up information prior to discharge, it may reduce hospital length of stay (19,31,43) and improve patient satisfaction (27,40,41). The majority of studies suggest that when persons receive postoperative education, discharge planning that is based on a readiness criteria and includes follow-up information prior to discharge, readmission rates to hospital may be reduced (18,19,33,40,42,43).
# Scheduled Home Visits and Telephone Follow-up within the First Four Weeks
There is consistent evidence that suggests when persons receive scheduled home visits and telephone follow-up, it may reduce readmission rates to hospital (33,40,42,43) and it may improve patient satisfaction (27,40,45). In all studies, health providers carrying out the scheduled home visits and telephone follow-up included NSWOCs, colon and rectal surgeons, physicians, nurse practitioners, or visiting registered nurses.
There is consistent qualitative evidence that indicates that persons who receive home visits and/or telephone follow-up calls experience feelings of reassurance, safety, gratitude, and satisfaction with care (40,45). The evidence regarding the outcome staff satisfaction was limited to one qualitative study. In this study, NSWOCs who provided telephone follow-up support expressed finding meaningful worth through recognizing the significant impact they have on the lives of persons who anticipate or live with an ostomy (37).
# Access to Nurses Specialized in Wound, Ostomy, and Continence Perioperatively and on an Ongoing Basis, as Necessary
There is consistent evidence that suggests access to NSWOCs perioperatively and on an ongoing basis may improve patient satisfaction (27,40,41,45) and reduce hospital length of stay (31,33,40). The majority of studies suggest that access to NSWOCs perioperatively and on an ongoing basis may reduce readmission rates to hospital (18,33,40,42).
One qualitative study reported that persons who received telephone follow-up calls from NSWOCs felt excited, comfortable, safe, and reassured, and that they had greater satisfaction with care received (37).
# Values and Preferences
Research suggests that persons living with an ostomy attributed high value to having direct access to (or contact information of) a NSWOC (41). Persons with an ostomy indicated that they wanted clear and consistent postoperative education on stoma management, stoma supplies, potential stoma complications, and courses of actions to resolve issues (41). Persons with an ostomy also preferred receiving follow-up telephone calls from hospital staff, as such calls provided reassurance that no pertinent information related to their treatment and recovery had been missed (37).
In relation to staff satisfaction, NSWOCs who conducted the telephone follow-up calls attributed high value to receiving training related to communication skills and counselling techniques; such training helped them to overcome difficulties, such as language barriers, time limitations, and poor patient moods (37). They also felt that providing psychological support to patients to boost confidence and courage and help them resume normal lives was the most valuable component of the telephone follow-up intervention (37).
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Health Equity
See Recommendation 2.1 for the applicable impact on health equity. The expert panel suggests that the impact on health equity associated with this Recommendation is consistent with what is outlined in Recommendation 2.1.
# Expert Panel Justification of Recommendation
There were benefits of the intervention components included as part of a standardized ostomy care program within health service organizations. No harms were found. However, the certainty in this evidence was low. The expert panel determined that persons would value improvements in outcomes and attributed high value to health organizations implementing a standardized ostomy care program to improve patient satisfaction and organization-related outcomes (readmission rates to hospital and hospital length of stay) and to enhance staff satisfaction. Therefore, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
The expert panel attributed high value to providing persons with an ostomy with direct access to an NSWOC, as needed, during the first four weeks after surgery and on an ongoing basis in order to improve patient satisfaction and decrease readmission rates to hospital.
The expert panel emphasized that scheduled home visits should be conducted by nurses possessing the appropriate knowledge and skills.
The expert panel emphasized that persons who anticipate or live with an ostomy, and who have concerns regarding medications, be directed to their pharmacist.
The expert panel attributed high value to health providers conducting an ostomy assessment immediately postoperatively and throughout the ostomy care program. Refer to Appendices G, H and I for ostomy assessment terms, definitions, parameters and sample assessment form that can be used for persons who live with an ostomy.
The expert panel emphasized that the interventions within the ostomy care program are based on a plan of care promoting self-efficacy that has been established in collaboration with the person, their support network (if needed) and the interprofessional team.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Explaining what an ileostomy is (33).
Demonstrating pouching systems and techniques (33).
Introducing concepts of stoma output management in relation to diet and antidiarrheals (33).
Describing the surgical procedure and showing pictures of stomas (31).
Describing the potential impact of stoma on relationships, sexuality, showering, and other activities of daily life (31).
Explaining postoperative routines (31).
Holding practice sessions to change and manage stomas (31).
Provision of information regarding the purchase of stoma care equipment (31).
# Postoperative education regarding stoma selfmanagement and potential complications
# Discharge planning that is based on a readiness criteria and includes follow-up information
Postoperative education and discharge planning included the following:
Strategies to improve self-management of the ostomy in the hospital (18,33,42).
Using a readiness criteria or checklist to determine when a person can be discharged; for instance, using a person-centred checklist to teach stoma care and evaluate readiness for discharge (18,33,42).
Establishing discharge and follow-up plans that include providing home care support or referral (40)(41)(42)(43).
Providing an overview of signs and symptoms of dehydration and/or other complications (40,41).
Providing instructions on how to document intake and output and monitor for signs and symptoms of dehydration for persons with an ileostomy (33,42).
# Scheduled home visits and telephone followup within the first four weeks.
Scheduled home visits and telephone follow-up included the following:
Providing a telephone consult regarding intake/output and how to avoid dehydration (40).
Home visits by trained nurses after hospital discharge for four continuous weeks to assess for signs of dehydration, pouching issues, stoma output, and infection (42).
Providing appropriate referral for stoma nurse clinic, surgical consultation, or emergency room based on evaluation from the telephone consultation (45). The expert panel suggests that health providers implement the following interventions to prevent parastomal hernias for persons who anticipate or live with an ostomy:
# RECOMMENDATIONS
Conduct a risk factor assessment related to body mass index and waist circumference.
Provide expert advice on weight management, as needed.
Perform stoma site marking preoperatively.
Provide postoperative education related to:
abstinence from heavy lifting postoperatively;
consideration of lightweight support garments; and
abdominal exercises beginning within three months of surgery.
# Strength of the recommendation: Conditional
# Certainty of the evidence of effects: Very Low
Confidence in evidence: Not Applicable
# Discussion of Evidence: Benefits and Harms
Research suggests that six key interventions performed by health providers that support prevention of parastomal hernias may decrease incidence of parastomal hernias in persons who anticipate or live with an ostomy (16). However, two studies by Thompson and Trainer as cited in Bland and Young (1) reported a 17 per cent increase in the incidence of parastomal hernias after implementation of an early hernia prevention program that utilized the six key strategies. The studies concluded that the rise was related to participant non-adherence. The studies also reported a long term reduction in incidence of parastomal hernias among those who adhered to the early hernia prevention program (1). The body of evidence was of very low certainty due to limitations in how studies were conducted and the small number of study participants.
For more detailed information on the impact of the components of hernia prevention strategies on the outcome rates of parastomal hernia, please refer to the evidence profiles available here: https://rnao.ca/bpg/guidelines/ostomy.
The hernia prevention strategies and their impact on rates of parastomal hernia in persons who live with an ostomy are summarized on the next page. Specific components of the interventions noted in the literature and identified by the expert panel are outlined under Practice Notes.
# RECOMMENDATIONS
# Perform Stoma Site Marking Preoperatively
The evidence regarding performing stoma site marking preoperatively is limited to one study. According to Person et al. as cited in Bland and Young (1), preoperative stoma site marking by a NSWOC may reduce rates of parastomal hernia in persons living with an ostomy. The rate of parastomal hernia was 3.8 per cent in the group that received stoma site marking compared to 24.5 per cent in the group that did not receive a stoma site marking.
# Provide postoperative education related to: Abstinence from Heavy Lifting Postoperatively; Consideration of Lightweight Support Garments; and Abdominal Exercises Beginning within Three Months of Surgery
According to two studies by Thompson and Trainer as cited in Bland and Young (1) and North (16), persons who anticipate or live with an ostomy-and who receive advice on abstinence from heavy lifting, consideration of lightweight support garments and instructions to begin specific abdominal exercises within three months after surgery as part of a hernia prevention program-may experience a decrease in the rates of parastomal hernias. One research study reported that after implementing the program, the rates of parastomal hernia were 15 per cent in all study participants and 1 per cent among those who were fully compliant (compared to 23 per cent local incidence and 44 per cent overall incidence reported in existing studies) (16). The 2005 and 2007 studies by Thompson and Trainer as cited in Bland and Young (1) indicated that reduction in parastomal hernias was 14 per cent after implementing the hernia prevention program compared to 28 per cent before the program. There was limited and very low certainty of evidence about how long a person with an ostomy needs to abstain from heavy lifting postoperatively. Please refer to Practice Notes for the expert panel consensus time frame on abstaining from heavy lifting postoperatively.
# Values and Preferences
Evidence indicates that only 45 per cent of participants who ordered a support garment utilized it on a regular basis, and only 27 per cent of participants believed that wearing the garment was important to prevent hernia (1).
# Health Equity
The expert panel recognizes that there is limited evidence that supports the benefits of lightweight support garments in prevention of parastomal hernias. In addition, persons of lower socio-economic status may have challenges with access to lightweight support garments due to cost.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Expert Panel Justification of Recommendation
The expert panel determined that there is likely high variability in how much persons living with an ostomy value the outcomes associated with this recommendation. Given the unclear benefits associated with wearing lightweight support garments compared to other factors (such as cost and comfort), persons with an ostomy may choose not to receive the intervention. In addition, the overall evidence for hernia prevention strategies was of very low certainty. Therefore, the expert panel determined the strength of the recommendation to be conditional.
# Practice Notes
# Conducting a risk factor assessment related to body mass index (BMI) and waist circumference
An online calculator to measure BMI is provided in the Supporting Resources section.
A risk factor assessment should be conducted preoperatively, postoperatively and on an as needed basis.
# Providing expert advice on weight management, as needed
Referral to a registered dietician for education regarding nutrition and weight management.
# Advising abstinence from heavy lifting postoperatively
Providing immediate postoperative education on the following:
Heavy lifting.
Weight transfer.
Splinting with coughing, nausea, or vomiting.
Avoiding straining with constipation.
Avoid lifting no more than 10 lbs for the first month after surgery, and then slowly work back up to lifting normal weights.
# Consideration of lightweight support garments before discharge
Providing information on support garments.
# Providing instructions on abdominal exercises to begin within three months of surgery
Surgeons to recommend abdominal exercises with specific instructions on when to begin and how to perform them.
Providing appropriate referral to a physiotherapist to provide education on abdominal exercises and proper body mechanics to perform during the first three months after surgery.
# Additional considerations
Providing education on what a parastomal hernia is.
Having an anti-emetic protocol in place immediately after surgery.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Abdominal exercise
Gently place your hands on your lower tummy. Breathe in through your nose and, as you breathe out, gently pull your tummy button down towards your spine. Feel the muscles tighten, try to hold for a count of 3 and then relax. Breathe in and out normally.
# Pelvic tilting
Place your hands in the hollow of your back. Tighten your tummy muscles (as exercise 1), flatten your lower back onto your hands and tilt your bottom. Breathe normally. Hold for 3 seconds and release gently.
# Knee rolling
Tighten your tummy muscles (as exercise 1) and gently lower both knees to one side as far as is comfortable. Bring them back to the middle and relax. Repeat to the other side. This exercise has the added benefit of releasing trapped wind.
Aim to do each of these exercises five times, three times a day. Do more repetitions as you feel able. In order to guide person-centred care, the expert panel recommends that health providers assess quality of life in persons who anticipate or live with an ostomy. Specific areas of focus should include the following:
Psychological distress (anxiety and depression).
Self-identity (sexuality and body image).
# Strength of the recommendation: Strong
# Certainty of the evidence: Very Low
Confidence in evidence: Low
# Discussion of Evidence: Benefits and Harms
Systematic review results highlight the lack of literature on the impact of conducting a quality of life assessment for persons who anticipate or live with an ostomy. As a result, literature was examined to understand the relationship between anticipating or living with an ostomy, and quality of life outcomes of psychological distress and selfidentity. Studies demonstrate the impact of living with an ostomy on quality of life through the use of quality of life assessments. The evidence was of very low certainty due to limitations in how studies were conducted, the use of different tools to measure outcomes across studies and the small number of study participants. For qualitative studies, the evidence was of low confidence due to some limitations in how studies were conducted and the small number of study participants.
The creation of an ostomy is a life-changing event and may have implications on various aspects related to quality of life, most notably psychological health and self-identity. Descriptive studies report that 46 per cent to 63 per cent of people expressed feelings of depression following stoma surgery and had lower quality of life scores in the mental health domain compared to the general public (46,47). Conversely, a descriptive study reported no difference between the general public and persons with a stoma in quality of life scores after surveying 2,329 community-dwelling persons with an ostomy (48). However, specific to the mental health domain of the survey, Nichols (48) reported that persons with an ostomy were more likely to indicate feeling "down in the dumps" most or all of the time and downhearted and depressed most or all of time. Furthermore, Knowles et al. (49) reported that results from survey data indicated that nearly 50 per cent of respondents who had Crohn's disease G and were living with an ostomy had scores indicating possible or probable anxiety disorder, while 42 per cent had a depressive symptom score.
A majority of the literature reported that living with an ostomy may have a negative impact on aspects of self-identity, most notably on body image and sexuality. Descriptive studies reported that body image was inferior for persons living with a permanent stoma after rectal cancer surgery compared to those without a stoma, while most persons
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition reported their sexual life was affected negatively after creation of a stoma (50,51). Persons who were diagnosed with rectal cancer and were living with an ostomy were more likely to be fearful of resuming sexual activity or to have problems undressing in front of a partner, interference with personal relationships, decreased ability to be intimate, and less satisfaction with appearance (52). For persons who were sexually active, descriptive studies reported that 33 per cent of them resumed sexual activity after stoma surgery (46,47).
Similarly, qualitative studies found that persons living with an ostomy expressed several changes in sexual function, such as erectile dysfunction, vaginal dryness, and pain during intercourse. Persons also experienced psychological impacts such as fear and anxiety related to sexual competence and/or the potential for pouching system mishaps during intimacy (53,54).
Fewer studies reported that living with an ostomy has no substantial (or a lesser) effect on body image and sexuality (55,56). Furthermore, some persons in two qualitative studies expressed that their self-perceptions about body image did not change, while others described negative self-perceptions about body image (53,54).
# Values and Preferences
In a qualitative study, persons with an ostomy expressed that they valued nurses as a source of practical and psychological support (54). In another qualitative study, persons with an ostomy expressed that they expect sexual counselling from a nurse to help them normalize their sexual lives (53). Persons with an ostomy also expressed the importance of support from family and friends during the adaption stage after ostomy surgery (54).
# Health Equity
No studies were found that directly assessed the impact of conducting a quality of life assessment on health equity. In a study conducted by Knowles et al. (49), 77 per cent of participants reported no current or past professional support to address their mental health concerns, despite a substantial portion of participants who had psychological concerns. These findings highlight the need for improved access to psychological services for persons living with an ostomy (49). Psychological services may include further assessment and management of psychological distress (anxiety and depression) and self-identity (sexuality and body image).
# Expert Panel Justification of Recommendation
The impact of a quality of life assessment was not evident in the literature. Instead, evidence regarding the impact of living with an ostomy on psychological health and self-identity was explored, which was of very low certainty. However, as the majority of literature reported on the negative effects of living with an ostomy on psychological health status and self-identity, the expert panel felt it is necessary to assess quality of life in all persons who anticipate or live with an ostomy as a precaution so that the appropriate follow-up can be completed (if needed). Therefore, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
The How has getting the necessary ostomy supplies been for you?
For those who are in committed relationships:
Some people who have the same surgery as you report feelings of discomfort or anxiety with resuming sexual or intimate activities with their partner. Have you experienced this?
For those who are not in a relationship:
Some people who have the same surgery as you report that becoming involved in an intimate relationship is problematic. Have you been experiencing this since surgery?
The expert panel emphasized the importance of follow-up care after completing a quality of life assessment. Followup care can include the following:
Providing education and counselling on how to mititigate negative feelings.
Providing referrals for further support (e.g., psychotherapists, psychiatrists, and counselors).
Incorporating the person's needs (such as emotional or cultural needs) into the plan of care.
# Research Gaps and Future Implications
The RNAO Best Practice Guideline Development and Research Team and expert panel identified priority areas for future research (outlined in Table 10). Studies conducted in these areas would provide further evidence to support high-quality and equitable support for adults who anticipate or live with an ostomy. The list is not exhaustive; other areas of research may be required. Outcomes: Parastomal hernia rates.
The effectiveness of abdominal exercises in the prevention of parastomal hernias.
The identification of specific abdominal exercises to prevent occurrence of parastomal hernias.
Exploring the benefits of preoperative versus postoperative abdominal exercises to prevent occurrence of parastomal hernias.
The effectiveness of lightweight support garments in the prevention of parastomal hernias.
The identification of specific instructions and considerations related to heavy lifting at any point after stoma surgery.
# Implementation Strategies
Implementing guidelines at the point of care is multi-faceted and challenging. It takes more than awareness and distribution of guidelines for practice to change: guidelines must be adapted for each practice setting in a systematic and participatory way to ensure that recommendations fit the local context (57). The 2012 RNAO Toolkit: Implementation of Best Practice Guidelines, Second Edition provides an evidence-based process for doing this. It can be downloaded at www.RNAO.ca/bpg/resources/toolkit-implementation-best-practice-guidelines-second-edition.
The Toolkit is based on emerging evidence that successful uptake of best practices in health care is more likely when the following occur:
Leaders at all levels are committed to supporting guideline implementation.
Guidelines are selected for implementation through a systematic, participatory process.
Stakeholders for whom the guidelines are relevant are identified and engaged in the implementation.
Environmental readiness for implementing guidelines is assessed.
The guideline is tailored to the local context.
Barriers and facilitators to using the guideline are assessed and addressed.
Interventions to promote use of the guideline are selected.
Use of the guideline is systematically monitored and sustained.
Evaluation of the guideline's impact is embedded in the process.
There are adequate resources to complete all aspects of the implementation.
The Toolkit uses the "Knowledge-to-Action" framework to demonstrate the process steps required for knowledge inquiry and synthesis (58) (see Figure 3). It also guides the adaptation of the new knowledge to the local context and implementation. This framework suggests identifying and using knowledge tools (such as guidelines) to identify gaps and begin the process of tailoring the new knowledge to local settings.
RNAO is committed to widespread deployment and implementation of our BPGs. We use a coordinated approach to dissemination, incorporating a variety of strategies, including the following:
1. The Nursing Best Practice Champion Network®, which develops the capacity of individual nurses to foster awareness, engagement, and adoption of BPGs.
2. The BPG Order Set TM provide clear, concise, and actionable intervention statements derived from practice recommendations. BPG Order Sets can be readily embedded within electronic records, but they can also be used in paper-based or hybrid environments.
3. The Best Practice Spotlight Organization® (BPSO®) designation, which supports implementation at the organization and system levels. BPSOs focus on developing evidence-based cultures with the specific mandate to implement, evaluate, and sustain multiple RNAO BPGs.
# RECOMMENDATIONS
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
In addition, we offer annual capacity-building learning institutes on specific BPGs and their implementation.
Information about our implementation strategies can be found at:
RNAO
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Crohn's disease: Chronic idiopathic disease that causes inflammation of the lining of the gastrointestinal tract. This condition usually presents with abdominal pain and chronic diarrhea (3).
Diversion: Surgical creation of an alternative route through the abdominal wall to divert feces and urine (2).
# Downgrade:
In GRADE and GRADE-CERQual, when limitations in the individual studies potentially bias the results, the certainty of evidence will decrease (63). For example, a body of quantitative evidence for one priority outcome may begin with high certainty, but due to serious limitations in one or more of the five GRADE criteria, it will be rated down by one or two levels (64).
Education statement: Organizational approaches to the delivery of education in health service organizations and academic institutions to support evidence-based practice. Education statements are based on an analysis of educational recommendations across several BPGs on diverse clinical topics and populations. Education statements can be applicable to all clinical BPGs and can be contextually adapted within health service organizations and academic institutions to support implementation of clinical recommendations.
Effluent: Fecal or urinary discharge from the stoma after ostomy surgery (65).
# Evidence-based nursing practice:
The integration of research evidence with clinical expertise and patient values; unifies research evidence with clinical expertise and encourages the inclusion of patient preferences (66).
# Evidence-to-Decision (EtD) frameworks:
A table that facilitates expert panels to make decisions when moving from evidence to recommendations. The purpose of the EtD framework is to summarize the research evidence, outline important factors that can determine the recommendation, inform panel members about the benefits and harms of each intervention considered, and increase transparency about the decision-making process in the development of recommendations (67).
# GRADE:
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) is a methodological approach to assess the certainty of a body of evidence in a consistent and transparent way, and to develop recommendations in a systematic way. The body of evidence across identified important and/or critical outcomes is evaluated based on risk of bias, consistency of results, relevance of the studies, precision of the estimates, publication bias, large effect, dose response, and opposing confounding (67). cont.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition When using GRADE, five components contribute to the assessment of confidence in the evidence for each outcome. These components are as follows:
1. Risk of bias, which focuses on the flaws in the design of a study or problems in its execution. 2. Inconsistency, which looks at a body of evidence and assesses whether the results point in the same direction or are different. 3. Imprecision, which refers to the accuracy of results based on the number of participants and/or events included, and the width of the confidence intervals across a body of evidence. 4. Indirectness, whereby each primary study that supports an outcome is assessed and a decision is made regarding the applicability of the findings to the population, intervention, and outcome outlined in the research question. 5. Publication bias, where a decision is made about whether the body of published literature for an outcome potentially includes only positive or statistically significant results (67).
Health provider: Refers to both regulated (e.g., nurses, physicians, dieticians and social workers) and unregulated (e.g., personal support workers) workers that are part of the interprofessional team.
# Regulated health provider:
In Ontario, the Regulated Health Professional Act, 1991 (RHPA) provides a framework for regulating 23 health professions, outlining the scope of practice and the profession-specific controlled or authorized acts that each regulated professional is authorized to perform when providing health care and services (5).
Unregulated health provider: Unregulated health providers fulfill a variety of roles in areas that are not subject to the RHPA. They are accountable to their employers but not to an external regulating professional body (e.g., College of Nurses of Ontario). Unregulated health providers fulfill a variety of roles and perform tasks that are determined by their employer and employment setting. Unregulated health providers only have the authority to perform a controlled act as set out in the RHPA if the procedure falls under one of the exemptions set out in the Act (6).
# Hernia (parastomal):
A parastomal hernia occurs when one or more loops of the bowel protrude through the abdominal wall, creating a bulge around the peristomal skin (7).
Ileostomy: A surgically created opening from the last part of the small intestine (ileum) to the abdominal wall to allow the elimination of small bowel effluent. An ileostomy can be either temporary or permanent (3).
# Inflammatory bowel disease:
The term refers to a group of chronic, relapsing gastrointestinal tract conditions, with ulcerative colitis and Crohn's disease being two main forms (68).
Interprofessional team: "A team comprised of multiple health providers (regulated and unregulated) who work collaboratively to deliver comprehensive and quality health care and services to people within, between, and across health settings" (60). Key interprofessional team members supporting adults who anticipate or live with an ostomy include NSWOCs, nurses, surgeons, physicians, social workers, dietitians, and pharmacists.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Meta-analysis: A systematic review of randomized controlled trials that uses statistical methods to analyze and summarize the results of the included studies (69).
# See systematic review
Nurse: "Refers to registered nurses, licensed practical nurses (referred to as registered practical nurses in Ontario), registered psychiatric nurses, and nurses in advanced practice roles such as nurse practitioners and clinical nurse specialists" (70).
Nurse specialized in wound, ostomy, and continence (NSWOC): "A registered nurse with advanced and specialized knowledge and clinical skills in wound, ostomy, and continence care who has graduated from a World Council of Enterostomal Therapists (WCET ® ) recognized education program" (4). A NSWOC provides specialized holistic assessment and management as an interprofessional team member to meet the needs to individuals/families with ostomies, acute and chronic wounds, and urinary and fecal continence problems" (4).
The NSWOC equivalent may be represented with other titles around the world, such as (but not limited to): stoma nurse; wound, ostomy, continence nurse (WOC nurse); or ostomy nurse.
Ostomy: Ostomy refers to a surgically created opening in the abdominal wall that results in the external diversion of feces and urine. The most common types of ostomy are colostomy and ileostomy for feces and urostomy for urine (2). A permanent ostomy refers to an ostomy "that will never be closed" (59). In the case of a temporary ostomy, "usually the surgical plan is to reconnect the intestine and to close the ostomy" (59).
Ostomy care program: An ostomy care program is an organization-level approach to standardize care for persons anticipating or living with an ostomy. The ostomy care program includes structured treatment, management, and follow-up strategies developed by an interprofessional team that may consist of NSWOCs, nurses, surgeons, physicians, social workers, dieticians, and pharmacists (among others).
Ostomy leakage: Exudate that seeps out of the stoma.
Outcomes: A dependent variable, or the clinical and/or functional status of a patient or population, that is used to assess if an intervention is successful. In GRADE, outcomes are prioritized based on if they are critical for decision making, important but not critical for decision making, or not important. Use of these outcomes helps literature searches and systematic reviews to be more focused (67).
Perioperative: Something occurring "around the time of surgery. This usually lasts from the time the patient goes into the hospital or doctor's office for surgery until the time the patient goes home" (71).
# Peristomal dermatitis (allergic and irritant):
Peristomal dermatitis (allergic) is skin damage caused by pouching system adhesives, powders, or barriers. Allergic dermatitis occurs at the site where offending agents or adhesives contact the skin (65). Peristomal dermatitis (irritant) is skin damage resulting from contact with fecal or urinary drainage. Irritant contact dermatitis is the most common peristomal skin complication and occurs at the site of effluent leakage (65).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Peristomal irritation: Peristomal irritation is a common complication resulting from moisture-associated skin damage. It may cause the peristomal skin to be inflamed, sore, itchy, and red (72).
Peristomal skin/plane: An area of "3 to 4 inches (10 x 10 cm) of skin surface surrounding an abdominal stoma" (59).
PICO question: A framework to outline a focused question. It specifies four components:
1. The patient or population that is being studied.
2. The intervention to be investigated.
3. The alternative or comparison intervention. 4. The outcome that is of interest (67).
# Pouching systems (ostomy pouching systems):
A system "composed of a skin barrier and a collection device to collect drainage (effluent) and protect the skin. Pouching systems are one-piece or two-piece products. The pouch attaches to the skin barrier, which adheres to the abdomen, and is fitted over and around the stoma to collect stool or urine" (59).
Qualitative research: An approach to research that seeks to convey how human behaviour and experiences can be explained within the contexts of social structures and through the use of an interactive and subjective approach to investigate and describe phenomena (73).
# Quasi-experimental study:
A study that estimates causal effects by observing the exposure of interest, but in which the experiments are not directly controlled by the researcher and lack randomization (i.e., before-andafter designs) (74).
# Randomized controlled trial (RCT):
An experiment in which the investigator assigns one or more interventions to participants who are randomly allocated to either the experimental group (receives intervention) and the comparison (conventional treatment) or control group (no intervention or placebo) (69).
Recommendation: A course of suggested action(s) that directly answers a recommendation question. A recommendation is based on a systematic review of the literature and is made in consideration of its potential benefits and harms, values and preferences from a person-centered perspective, and impact on health equity. All recommendations are given a strength, either strong or conditional through expert panel consensus. It is important to note that recommendations should not be viewed as prescriptive, as recommendations cannot take into account all of the unique features of individual, organizational and clinical circumstances (8).
# Recommendation question:
A priority research area of practice, policy or education identified by expert panel members that requires evidence to answer. The recommendation question may also aim to answer a topic area around which there is ambiguity or controversy. The recommendation question informs the research question, which guides the systematic review.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Scoping review: "Scoping reviews have been described as a process of mapping the existing literature or evidence base. Scoping reviews can be used in a number of ways, for example identifying research gaps and summarizing findings of research. They can also be used to inform systematic reviews" (75).
Self-management: "The tasks that individuals must undertake to live well with one or more chronic conditions. These tasks include having the confidence to deal with medical management, role management, and emotional management of their conditions. The goal of self-management is increased confidence in the ability to change, rather than compliance with the caregiver's advice. The purpose of self-management support is to help persons become informed about their conditions and take an active role in treatment" (76).
Stakeholder: An individual, group, or organization that has a vested interest in the decisions and actions of organizations, and may attempt to influence decisions and actions (77). Stakeholders include all of the individuals and groups who will be directly or indirectly affected by the change or solution to the problem.
Stoma: An opening created on the abdominal wall by ostomy surgery to allow elimination of urine and feces. A stoma is usually dark pink in colour (2).
Stoma site marking: "Selection of the ideal location on the abdomen for a stoma prior to surgery by a trained health professional, usually a NSWOC or surgeon to help prevent future stoma complications and pouching problems" (59).
# Support network:
A term used to refer to those whom the person identifies as significant in his or her life. This can include individuals who are related (biologically, emotionally, or legally) and/or those with close bonds (friendships, commitments, shared household and child-rearing responsibilities, and romantic attachment) (70,78).
# Systematic review:
A comprehensive review of the literature that uses clearly formulated questions and systematic and explicit methods to identify, select, and critically appraise relevant research. A systematic review collects and analyzes data from the included studies and presents them, sometimes using statistical methods (69).
See meta-analysis Urostomy (ileal conduit): A surgical procedure to divert the flow of urine by transplanting the ureters into an isolated segment of the ileum, bringing one end through the abdominal wall to create a stoma. Urine flows from the kidney to the ureters, then through the ileal conduit, exiting through the stoma. A urostomy can be either temporary or permanent (3).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Appendix B: RNAO Guidelines and Resources that Align with this Guideline
The following are topics that align with this Guideline and with suggested RNAO guidelines and resources from other organizations.
# TOPIC RESOURCE(S)
Client centred learning Academic institutions should consider integrating guideline content into theoretical and practice-based courses for nurses and other regulated health providers, including social workers, physiotherapists, occupational therapists, dieticians and pharmacists in pre-licensure and post-licensure programs. Pre-licensure education establishes foundational knowledge that can be strengthened and augmented, as necessary, within health service organizations. Post-licensure education at the graduate level may include preparing nurses and other regulated health providers for advanced practice roles and functions within clinical practice, education, administration, research, and policy (79). As such, the integration of guideline content into curricula will differ in terms of educational content and complexity based on the overall educational objectives of the program. In both cases, integrating guideline content into curricula supports student learning consistent with evidence-based practices, with the ultimate goal of enhancing the health outcomes of persons and families.
To support the integration of evidence-based guidelines into curricula, the following approaches may be utilized: (a) developing multi-level guideline-related learning objectives and (b) designing guideline-related teaching and learning strategies (80). Both approaches are outlined below.
A) Developing multi-level guideline-related learning objectives: Guideline-related learning objectives at multiple levels of a program (pre-licensure and post-licensure) facilitate integration of guideline content into curricula. At the program level, such integration broadens student knowledge, attitude, judgment, and skills.
For instance, a program-level outcome at a graduate level may include student awareness of elements of implementation science to support uptake and sustained use of guidelines in clinical settings (80). At the course level, integration of guideline content supports student learning that is consistent with evidence-based practices within academic and practice settings. For example, course-level outcomes at the undergraduate level may include students being able to gain increased knowledge about guidelines, select guidelines relevant to practice (and provide rationale for their selection), and integrate guideline recommendations into plans of care for persons and families (80).
B) Designing guideline-related teaching and learning strategies: Teaching strategies should be tailored to address the program-level educational objectives and needs of learners, and to equip the learner to improve practice and promote positive outcomes (81). The various guideline-related teaching and learning strategies are outlined below.
Lectures: Educators can use lectures as a means to provide a broad understanding of guidelines, specifically the rigorous process of guideline development and their various recommendations. Lectures can provide students with an understanding of the scope and strength of evidence that inform the recommendations (80).
Interactive classroom activities: Interactive learning activities within the classroom setting can support students to obtain additional information, participate in problem-solving, and articulate knowledge gained. Examples include (a) assigning group work to help students learn how to navigate a guideline and become familiar with its recommendations, (b) using case studies to provide students with opportunities to identify and apply guideline recommendations in care plans, and (c) using videos and role playing to promote skills in articulating the rationale for selecting specific guidelines/recommendations in care plans (80).
Simulation: High-quality digital simulation within skills lab settings can ease the uncertainty of students related to clinical practice; it can also increase skill acquisition, self-confidence, and satisfaction. Faculty trained in pedagogy can use simulation to teach students content related to safe and effective person and family care within a standardized clinical environment (82). Educators can support students to incorporate guideline content into simulated practice sessions when teaching evidence-based practice (80). (80).
# A P P E N D I C E S
Supporting Adults
Access to BPG-related resources: Educators can promote and facilitate access to BPG-related links and resources. For example, providing access to the RNAO Nursing Best Practice Guidelines App (see https:// rnao.ca/bpg/pda/app) enables students to access content from guidelines within classroom and practice settings (80).
Assignments and tests: Students may be asked to incorporate guidelines into their learning plans or write a reflective journal related to a guideline important to their area of practice. Tests or exam questions that demonstrate critical thinking related to guidelines can also be used. Overall, guideline-related assignments and tests can assist students to reflect upon guidelines, understand their application, and critique them (80).
Preceptorship or mentorship in clinical placements: Preceptors within clinical settings play an integral role in teaching practical skills that complement the theoretical learning of students. Preceptors are responsible for providing clinical teaching and supervision, and they perform formal student evaluation (83). Preceptors can support students to integrate guideline content into their learning objectives and clinical activities to promote evidence-based knowledge and practice.
# EDUCATION STATEMENT 2:
Health service organizations use strategies to integrate evidence-based guidelines into education and training of nurses and other health providers.
# Discussion of Literature:
The thematic analysis of the education recommendations in a number of BPGs found the second theme of: "health service organizations use strategies to integrate evidence-based guidelines into education and training of nurses and other health providers, " as foundational to evidence-based practice capacity building. Education and training programs should be based on the principles of adult learning, including the following:
Adults have an awareness of learning needs/goals.
Adults are self-directed and autonomous.
Adults value and utilize prior life experiences.
Adults have readiness to learn.
Adults are motivated to learn.
Adults are presented knowledge and skills in the context of practical, real-life situations (85).
Furthermore, education and training should be appropriate to the health provider's scope of practice and their defined role. Education and training strategies may include the following:
In-service education sessions: In-service education sessions can be planned by clinical experts within practice settings to support the utilization of a specific guideline or recommendations stimulating evidence-based practice among staff. The education may include one-on-one or group sessions and should address the needs of learners. It is recommended that the education sessions are followed with refresher or booster sessions to provide feedback and enhance staff learning (86,87).
Workshops/seminars: Highly interactive workshops/seminars help nurses and health providers maintain practice based on best evidence when they incorporate a variety of teaching-learning strategies, including pre-circulated materials, small group discussions using case studies, and multimedia such as Power Point and videos that integrate relevant guidelines/recommendations. RNAO's Best Practice Champions Workshop and BPG Learning Institutes are examples of programs that provide education on how to implement BPGs within practice settings (88).
Quality improvement: Participating in quality improvement within workplace settings can support nurses and health workers to recognize sentinel events and examine ways to improve care. Meeting accreditation standards is an important quality improvement activity that bridges gaps between current and best practices and supports continued competence. Examples of strategies that nurses and other health providers can use to meet accreditation standards include the following:
Participating in a unit-based guideline implementation process to promote patient safety, reduce risks, and improve care outcomes. Choosing guideline-specific recommendations to facilitate practice change. Sharing knowledge and lessons learned from reviewing guidelines with the accreditation committee (89,90).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# EVALUATION
All educational strategies require evaluation to (a) monitor the adoption of knowledge and (b) measure the impact on clinical outcomes. RNAO has developed the Educator's Resource: Integration of Best Practice Guidelines (2005) to provide strategies for educators within academia and practice settings to introduce BPGs to student nurses, faculty, nurses and other health providers. The resource provides guidance on student evaluation strategies that include self-evaluation peer-evaluation and end-of-course evaluations by the educator.
Furthermore, RNAO has developed the Practice Education in Nursing (2016) BPG to provide evidence-based recommendations that support with the application of knowledge to various practice settings by student nurses. The guideline also assists nurses nurse educators, preceptors and other members of the interprofessional team to understand the effective use of teaching-learning strategies in clinical settings.
The RNAO Toolkit: Implementation of Best Practice Guidelines (2012)* identifies the following strategies for evaluation of provider practice change and health outcomes for persons within health service organizations:
Pre-and post-tests for staff educational sessions.
Staff focus groups/interviews.
Observation of patient-provider encounters.
Chart audits to determine the impact on person and family outcomes.
Person and family satisfaction surveys or interviews.
* The RNAO Toolkit: Implementation of Best Practice Guidelines (2012) is under review and the next edition is expected to be issued in 2020.
Other quality improvement opportunities include participating in incident reporting, patient safety initiatives, and other health initiatives within areas of practice.
Post-licensure mentorship: Post-licensure mentorship involves providing new graduates or less experienced staff with guidance for skill development and support for growth of professional roles.
Research suggests that working with mentors reduces stress and improves satisfaction for new staff during the transition process (91). Mentors can support integration of guideline content while teaching evidencebased practice.
2. A guideline search and gap analysis was undertaken. Two Guideline Development Methodologists (one of them being the Guideline Development Lead) searched an established list of websites for guidelines and other relevant content published between January 2007 and August 2017. The resulting list was compiled based on knowledge of evidence-based practice websites and recommendations from the literature. RNAO expert panel members were asked to suggest additional guidelines (see Figure 4 in Appendix E). The purpose of the guideline search and gap analysis was to gain an understanding of existing guidelines regarding ostomy care and support in order to identify opportunities for addressing the purpose and scope of this BPG. Detailed information about the search strategy for existing guidelines, including the list of websites searched and the inclusion criteria used, is available at https:// rnao.ca/bpg/guidelines/ostomy.
The guidelines were reviewed for content, applicability to nursing scope of practice, accessibility, and quality. The two Guideline Development Methodologists appraised three international guidelines using the AGREE II tool and came to consensus on an overall score for each guideline (92). Guidelines with a score of six or seven (on a 7-point Likert scale) were considered to be of high quality. The systematic reviews that answered research questions in high quality guidelines were considered to be beyond the scope of this guideline. The following guidelines were appraised as indicated:
Miller D, Pearsall E, Johnston D, et al. Executive summary: enhanced recovery after surgery: best practice guideline for care of patients with a fecal diversion. J Wound Ostomy Continence Nurs. 2017 Jan/Feb;44(1):74-7. (Score: 4 out of 7. This guideline was used as a supporting resource in this BPG) Ostomy Guidelines Task Force. Management of the patient with a fecal ostomy-best practice guidelines for clinicians. J Wound Ostomy Continence Nurs. 2010 Dec;37(6):596-8. (Score: 3 out of 7. This guideline was not used as a supporting resource in this BPG because the content was not as relevant)
World Council of Enterostomal Therapists (WCET). WCET international ostomy guideline. Perth (Australia): WCET; 2014. (Score: 4 out of 7. This guideline was used as a supporting resource in this BPG)
3. A scoping review of the literature was performed to determine the depth of peer-reviewed studies in the area of pediatric populations (younger than 18 years) living with an ostomy.
# 4.
Six key informant interviews took place with experts in the field including front-line health providers, researchers, and individuals with lived experiences, to understand the needs of nurses, members of the interprofessional health team, and persons with lived experience.
5. Two virtual focus groups were convened to understand the needs of nurses, members of the interprofessional health team, and persons with lived experience.
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# Assembly of the Expert Panel
RNAO aims for diversity in membership of an expert panel in alignment with its Organizational Statement on Diversity and Inclusivity which is part of the RNAO Mission and Values (93). RNAO also aims for persons impacted by guideline recommendations, especially persons with lived experiences and caregivers, to be included as expert panel members.
There are numerous ways in which RNAO finds and selects members of an expert panel, including searching the literature for researchers in the topic area; recommendations from key informant interviews; drawing from established professional networks such as RNAO interest groups, Champions Network © , and BPSO © ; other nursing and health provider associations; topic-relevant technical associations or organizations; and advocacy bodies.
For this Guideline, the RNAO Best Practice Guideline Development and Research Team assembled a panel of experts from nursing practice, administration, research, education and policy, as well as other members of the interprofessional team representing a range of sectors and practice areas, and persons with lived experiences (see the RNAO Expert Panel).
The expert panel engaged in the following activities:
Approved the scope of this BPG.
Determined the recommendation questions and outcomes to be addressed in this BPG.
Participated in a consensus development process to finalize recommendation statements.
Provided feedback on the draft of this BPG.
Participated in the development of evaluation indicators.
Identified appropriate stakeholders to review the draft guideline prior to publication.
The expert panel co-chairs led the following activities:
Monthly co-chair meetings with the Guideline Development Methodologists and Guideline Development Project Coordinator.
Facilitated expert panel meetings.
Provided in-depth guidance on clinical and/or research issues.
Moderated and acted as tiebreakers in voting processes.
# Declarations of Competing Interest
Declarations of competing interest that might be construed as constituting an actual, potential, or apparent conflict were made by all members of the RNAO's expert panel, and members were asked to update their disclosures throughout the guideline development process. Information was requested about financial, intellectual, personal, and other interests and documented for future reference. No limiting conflicts were identified. Declarations of competing interest are posted as a separate document on the RNAO webiste: https://rnao.ca/bpg/guidelines/ostomy.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Identifying Priority Recommendation Questions and Outcomes
In October 2017, the RNAO Best Practice Guideline Development and Research Team convened to determine the priority recommendation questions and outcomes for this Guideline. A comprehensive list of recommendation questions that the Guideline could potentially address was developed at the in-person meeting, informed by the following:
The guideline gap analysis.
The scoping review of the literature.
Key informant interviews and focus groups.
Expert panel discussion at the in-person meeting.
This comprehensive list of potential recommendation questions was presented to the expert panel for a vote. Each expert panel member was allowed four votes for preferred recommendation questions. The four recommendation questions with the most votes were deemed the final recommendation questions. Expert panel co-chairs did not participate in the vote as they functioned as tiebreakers for the fourth recommendation question.
Following this initial vote-and in alignment with GRADE standards for assessing and presenting the evidenceoutcomes were identified and prioritized per recommendation question. A comprehensive list of outcomes per recommendation question was developed at the in-person meeting, informed by the following:
The scoping review of the literature.
Key informant interviews and focus groups.
Expert panel discussion at the in-person meeting.
Based on the comprehensive list of outcomes, the expert panel was asked to rank order the relative importance of each outcome per recommendation question. Each panel member participated in a confidential online rank order vote. It was deemed feasible to have a total of 13 prioritized outcomes across the four recommendation questions. Expert panel co-chairs did not participate in the vote as they functioned as co-facilitators. Voting results were presented to the expert panel. Through a facilitated discussion, priority outcomes were determined per recommendation question. Each recommendation question informed a PICO research question which guided the systematic reviews. The four recommendation questions and their respective PICO research questions are presented below:
Recommendation Question 1: Should access to nurses specialized in wound, ostomy, and continence or no access to nurses specialized in wound, ostomy, and continence be recommended?
# PICO Research Question 1 Population:
Adults anticipating or living with an ostomy. Intervention: Access to nurses specialized in wound, ostomy, and continence. Comparison: No access to nurses specialized in wound, ostomy, and continence.
# Outcomes:
Peristomal skin breakdown*, ostomy leakage, quality of life, hospital length of stay and readmission rates to hospital.
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# Outcomes:
Quality of life and financial priorities.
Recommendation Question 4: Should the use of standardized assessment tool for quality of life to customize care plan (for education and referral) or no use of standardized assessment tool for quality of life to customize care plan (for education and referral) be recommended?
# PICO Research Question 4 Population:
Adults anticipating or living with an ostomy. Intervention: Use of a standardized assessment tool for quality of life to customize care plan (for education and referral). Comparison: Usual care.
# Outcomes:
Psychological health status and self-identity.
* The peristomal skin breakdown outcome was not found in the literature. As a result, peristomal dermatitis and peristomal irritation were chosen as surrogate outcomes after consultation with expert panel co-chairs. A surrogate outcome is one that is a similar measure to the desired outcome and reflects what would contribute to the desired outcome.
** The preoperative stoma site marking outcome was not found in the literature. A surrogate outcome was not chosen in replacement as there deemed to be a sufficient number of outcomes related to Research Question #2.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Literature regarding access to affordable ostomy supplies was not found. As access to affordable supplies was highlighted as a priority topic by the expert panel, RNAO is taking policy initiatives on universal funding for ostomy supplies to promote optimal health outcomes for all adults who anticipate or live with an ostomy.
In consultation with the co-chairs, an alternate priority research question identified by the expert panel was chosen.
The respective priority outcome was also determined by the co-chairs. The revised Recommendation Question #3 is outlined below:
Recommendation Question 3: Should prevention strategies for parastomal hernia development or no prevention strategies for parastomal hernia development be recommended?
# PICO Research Question 3 Population:
Adults living with an ostomy. Intervention: Prevention strategies for parastomal hernias. Comparison: Usual care.
# Outcomes:
Rates of parastomal hernias.
Literature specific to the use of standardized assessment tool for quality of life to customize care plan (for education and referral) was not found. In consultation with the co-chairs, a broader recommendation question was identified that could indirectly inform the need for quality of life assessment in adults who anticipate or live with an ostomy. The revised Recommendation Question #4 is outlined below: and 8). Detailed information on the search strategy for the systematic reviews, including the inclusion and exclusion criteria and search terms, is available at https://rnao.ca/bpg/guidelines/ostomy.
Recommendation
All studies were independently assessed for relevance and eligibility by the two Guideline Development Methodologists based on the inclusion and exclusion criteria. Any disagreements were resolved through consensus.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition All included articles were independently assessed for risk of bias by study design using validated and reliable tools.
Randomized controlled trials G were assessed using the Risk of Bias 2.0 tool (94), quasi-experimental studies G and other non-randomized studies were assessed using the ROBINS-I tool (95), systematic reviews were assessed using the AMSTAR 2 tool (96) and qualitative studies were assessed using the CASP qualitative checklist (97). Two reviewers reached consensus on all scores through discussion.
Data extraction was performed simultaneously. Reviewers completed independent data extraction for 75 per cent of the studies. The remaining studies were split between the reviewers and were cross-checked for accuracy. In total, 36 studies were included across all four systematic reviews.
In January 2019, an additional guideline search was conducted in an established list of websites for guidelines published between September 2017 and January 2019 to identity recommended resources. One guideline was found however it was for purchase, and therefore not accessible. Furthermore, searches in all databases were re-run on January 11, 2019 to capture recent research. Studies were screened for relevancy to inform values and preferences and health equity for all recommendations. Findings from one study were incorporated in the discussion of evidence for Recommendation 2.1 and 2.2.
# Determining Certainty and Confidence of Evidence
# Certainty of Evidence
The certainty of quantitative evidence (i.e., the extent to which one can be confident that an estimate of an effect is true) is determined using GRADE methods (8). First, the certainty of the evidence is rated for each prioritized outcome across studies (i.e., for a body of evidence) per research question (8). This process begins with the study design and then requires an examination of five domains-risk of bias, inconsistency, imprecision, indirectness, and publication bias-to potentially downgrade G the certainty of evidence for each outcome. Following the initial consideration for rating down, the following three factors that permit rating up the certainty of evidence are assessed: large magnitude of effect, dose-response gradient, and effect of plausible confounding. See Table 11 for a definition of each of these certainty criteria.
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# Risk of bias
Limitations in the study design and execution that may bias study results.
Valid and reliable quality appraisal tools are used to assess the risk of bias. First, risk of bias is examined for each individual study and then examined across all studies per defined outcome.
# Inconsistency
Unexplained differences (heterogeneity) of results across studies.
Inconsistency is assessed by exploring the magnitude of difference, and possible explanations, in the direction and size of effects reported across studies for a defined outcome.
# Indirectness
Variability between the research and review question and context within which the recommendations would be applied (applicability). There are four sources of indirectness which are assessed:
Differences in population.
Differences in interventions.
Differences in outcomes measured.
Differences in comparators.
# Imprecision
The degree of uncertainty around the estimate of effect. This is usually related to sample size and number of events. Studies are examined for sample size, number of events, and confidence intervals.
# Publication bias
Selective publication of studies based on study results. If publication bias is strongly suspected, downgrading is considered.
Source: The GRADE Working Group. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach 2013. Available from: http://gdt.guidelinedevelopment.org/app/handbook/handbook.html#h.svwngs6pm0f2.
Following the initial consideration for rating down the certainty of quantitative evidence, there are three factors assessed that permit rating up the certainty of evidence for observational studies:
1. Large magnitude of effect: If the body of evidence has not been rated down for any of the five criteria and a large estimate of the magnitude of intervention effect is present, there is consideration for rating up (8).
2. Dose-response gradient: If the body of evidence has not been rated down for any of the five criteria and a doseresponse gradient is present, there is consideration for rating up (8).
# Effect of plausible confounding:
If the body of evidence has not been rated down for any of the five criteria and all residual confounders would result in an underestimation of treatment effect, there is consideration for rating up (8).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
The overall certainty of evidence is the combined rating of the certainty of evidence across all prioritized outcomes per recommendation question. GRADE categorizes the overall certainty of evidence as high, moderate, low, or very low. See Table 12 for the definitions of these categories.
For this Guideline, the five GRADE certainty criteria for potentially rating down and the three GRADE certainty criteria for potentially rating up were independently assessed by the two Guideline Development Methodologists. Any discrepancies were resolved through consensus. An overall certainty of evidence per recommendation question was assigned based on these assessments. Recommendations that were derived from the recommendation questions were accordingly assigned this certainty of evidence.
# High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
# Very Low
We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
# Confidence in Evidence
Similar to GRADE, there are four CERQual criteria G to assess the confidence in qualitative findings related to a phenomenon of interest:
1. Methodological limitations.
2. Relevance.
3. Coherence.
# Adequacy.
See Table 13 for a definition of each of these criteria.
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# Methodological limitations
The extent to which there are concerns about the design or conduct of the primary studies that contributed evidence to an individual review finding.
# Coherence
An assessment of how clear and cogent the fit is between the data from the primary studies and a review finding that synthesises that data. By "cogent," we mean well supported or compelling.
# Adequacy of data
An overall determination of the degree of richness and quantity of data supporting a review finding.
# Relevance
The extent to which the body of evidence from the primary studies supporting a review finding is applicable to the context (perspective or population, phenomenon of interest, setting) specified in the review question.
Source: Reprinted from Lewin S, Booth A, Glenton C, et al. Applying GRADE-CERQUAL to qualitative evidence synthesis findings: introduction to the series. Implement Sci. 2018;13(Suppl 1):1-10. Table 2, Definitions of the components of the CERQual approach; p. 5. Reprinted with permission.
For qualitative findings related to one of the prioritized outcomes, these four criteria were independently assessed by the two Guideline Development Methodologists. Discrepancies were resolved through consensus. An overall judgment of the confidence in each review finding was made based on these assessments above (see Table 14 for the confidence of evidence judgments). Recommendations that included qualitative evidence were assigned an overall confidence in evidence based on the corresponding review finding.
# High
It is highly likely that the finding is a reasonable representation of the phenomenon of interest.
# Moderate
It is likely that the finding is a reasonable representation of the phenomenon of interest.
# Low
It is possible that the review finding is a reasonable representation of the phenomenon of interest.
# Very Low
It is not clear whether the review finding is a reasonable representation of the phenomenon of interest.
Source: Reprinted from Lewin S, Booth A, Glenton C, et al. Applying GRADE-CERQUAL to qualitative evidence synthesis findings: introduction to the series. Implement Sci. 2018;13(Suppl 1):1-10. Table 3, Description of level of confidence in a review finding in the CERQual approach; p. 6. Reprinted with permission.
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# Summarizing the Evidence
GRADE and GRADE CERQual evidence profiles are used to present decisions on determining the certainty and confidence of evidence, as well as general information about the body of research evidence, including key statistical or narrative results. Evidence profiles summarize the body of evidence for each systematic review per outcome and are developed by the two Guideline Development Methodologists.
Evidence profiles for the body of quantitative studies present the decisions made by the two reviewers on the five key GRADE certainty domains for rating down and the three GRADE certainty domains for rating up. The evidence profiles present general information about the body of evidence, including a description of the intervention, key results, and transparent judgments about the certainty underlying the evidence for each outcome (8). For this Guideline, meta-analyses G were not performed; results were therefore synthesized in narrative format in the evidence profiles.
CERQual evidence profiles were created for the body of qualitative evidence for each systematic review per outcome. Similar to the GRADE evidence profiles used for quantitative research, the CERQual evidence profiles present the body of evidence supporting each theme related to outcomes for every recommendation question. These evidence profiles presented the decisions made by the two Guideline Development Methodologists on the four key CERQual criteria and transparent judgements about the confidence underlying the evidence for each theme.
The GRADE and CERQual evidence profiles for each systematic review, organized per outcome, can be accessed online at https://rnao.ca/bpg/guidelines/ostomy.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Formulating Recommendations
# Evidence-to-Decision Frameworks
Evidence-to-Decision (EtD) frameworks G outline proposed recommendations and summarize all necessary factors and considerations based on available evidence and expert panel judgement for formulating the recommendation statements. EtD frameworks are used to help ensure that all important factors required to formulate recommendations are considered by an expert panel (8). Both quantitative and qualitative evidence are incorporated into the frameworks. The Guideline Development Methodologists draft the frameworks with available evidence from the systematic reviews.
For this Guideline, the EtD frameworks included the following areas of consideration for each drafted recommendation statement (see Table 15):
Background information on the magnitude of the problem.
Includes the PICO question and general context related to the research question.
The balance of benefits and harms of an intervention.
Certainty and/or confidence of the evidence.
Values and preferences.
Health equity.
# Decision Making: Determining the Direction and Strength of Recommendations
Expert panel members are provided with the EtD frameworks to review prior to a scheduled two-day in-person meeting to determine the direction (i.e., to provide a recommendation for or against an intervention) and the strength of the recommendations in the guideline. Expert panel members also are given access to the complete evidence profiles and full-text articles.
Using the EtD frameworks as a guiding document, the expert panel members participated in an online vote from May 15th to May 30th, 2018. The following questions were posed to all expert panel members for each draft recommendation:
Is there important uncertainty about or variability in how much people value the main outcomes?
Does the balance between desirable and undesirable effects favor the intervention or the comparison?
What would be the impact on health equity?
The Likert scales created by the GRADEpro software were used for voting on each factor (98). There also was the opportunity for expert panel members to provide written comments related to each of the judgement criteria.
The results of the online vote were calculated and presented to the expert panel at the two-day in-person meeting held June 21-22, 2018. The online vote results were used to help guide discussion. The expert panel co-chairs and the Guideline Development Lead facilitated the meeting to allow for adequate discussion for each proposed recommendation.
# A P P E N D I C E S
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The decision on direction and strength of each recommendation statement was determined by discussion and a consensus vote of 70 per cent. The voting process was moderated by the expert panel co-chairs and Guideline Development Lead. In determining the strength of a recommendation statement, the expert panel was asked to consider the following (see Table 15):
The balance of benefits and harms.
Certainty and confidence of the evidence.
Values and preferences.
Potential impact on health equity.
Following the in-person meeting, the final decisions made on all recommendations were summarized and sent to the full expert panel electronically.
# Benefits and harms
Potential desirable and undesirable outcomes reported in the literature when the recommended practice or intervention is used.
"The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a conditional recommendation is warranted" (99).
Includes research exclusively from the systematic review.
# Certainty and confidence of evidence
The extent of confidence that the estimates of an effect are adequate to support a recommendation. The extent of confidence that a review finding is a reasonable representation of the phenomenon of interest (100).
Recommendations are made with different levels of certainty or confidence; the higher the certainty or confidence, the higher the likelihood that a strong recommendation is warranted (99).
Includes research exclusively from the systematic review.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# FACTOR DEFINITION SOURCES
# Values and preferences
The relative importance or worth of the health outcomes of following a particular clinical action from a person-centred perspective.
"The more values and preferences vary or the greater the uncertainty in values and preferences the higher the likelihood that a conditional recommendation is warranted" (99).
Includes evidence from the systematic review (when available) and other sources, such as insights from the expert panel.
# Health equity
Represents the potential impact of the recommended practice or intervention on health outcomes or health quality across different populations.
The greater the potential for increasing health inequity, the higher the likelihood that a conditional recommendation is warranted.
Includes evidence from the systematic review (when available) and other sources, such as insights from the expert panel.
Source: Adapted by the RNAO expert panel from The GRADE Working Group. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach 2013. Available from: http://gdt.guidelinedevelopment.org/app/handbook/handbook.html#h.svwngs6pm0f2.
# Drafting the Guideline
The Guideline Development Methodologists wrote the draft of this Guideline. The expert panel reviewed the draft and provided written feedback. A teleconference was held October 2nd, 2018, to review panel feedback and incorporate changes, as necessary. The Guideline then proceeded to external stakeholder review.
# Stakeholder Review
RNAO is committed to obtaining feedback from (a) nurses and other health providers from a wide range of practice settings and roles, (b) knowledgeable administrators and funders of health services, and (c) stakeholder associations as part of the guideline development process.
Stakeholder reviewers for RNAO BPGs are identified in two ways. First, stakeholders are recruited through a public call issued on the RNAO website (RNAO.ca/bpg/get-involved/stakeholder). Second, individuals and organizations with expertise in the guideline topic area are identified by the RNAO Best Practice Guidelines Development and Research Team and the expert panel, and are directly invited to participate in the review.
Stakeholder reviewers are individuals with subject matter expertise in the guideline topic or those who may be affected by its implementation. Reviewers may be nurses, members of the interprofessional team, nurse executives, administrators, research experts, educators, nursing students, or persons with lived experience and family members.
# A P P E N D I C E S
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Reviewers are asked to read a full draft of the BPG and participate in the review of it prior to its publication. Stakeholder feedback is submitted online by completing a survey questionnaire. The stakeholders are asked the following questions:
Is the guideline title appropriate?
Is the guideline development process description clear?
In addition, the stakeholders are asked the following questions about each recommendation:
Is this recommendation clear?
Do you agree with this recommendation?
Is the discussion of evidence thorough and does the evidence support the recommendation?
The survey also provides an opportunity to include comments and feedback for each section of the BPG. Survey submissions are compiled and feedback is summarized by the RNAO Best Practice Guidelines Development and Research Team. The survey results are reviewed and discussed with the expert panel. If necessary, the guideline content and recommendations are modified prior to publication to reflect the feedback received.
For this Guideline, the stakeholder review process was completed from October 19th to November 2nd, 2018 and diverse perspectives provided feedback (see Stakeholder Acknowledgment).
# Procedure for Updating the Guideline
The RNAO commits to updating all BPGs, as follows:
1. Each BPG will be reviewed by a team of specialists in the topic area every five years following publication of the previous edition.
2. RNAO International Affairs and Best Practice Guidelines Centre staff regularly monitor for new systematic reviews, randomized controlled trials, and other relevant literature in the field.
3. Based on that monitoring, staff may recommend an earlier revision period for a particular BPG. Appropriate consultation with members of the original expert panel and other specialists and experts in the field will help inform the decision to review and revise the BPG earlier than planned. 5. New editions of BPGs will be disseminated based on established structures and processes.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Os tilted
Opening of bowel is tilted from center of stoma.
# Prolapsed
The telescoping of the bowel through the stoma, making the stoma longer.
# Raised
Stoma is sitting above level of the skin.
# Retracted
Disappearance of the normal stoma opening below skin level.
# Black (necrosis)
Ischemia of the stoma from inadequate blood supply.
# Dusky
Purple to a deep wine-coloured hue from altered blood supply.
# Edematous
Interstitial collection of fluid.
# Friable
Fragile tissue that bleeds easily.
# STOMA APPEARANCE
# Moist
Mucosal tissue is damp.
# Pale
Diminished colour.
# Pink
Pink in colour.
# Red
Red in colour.
# Red (Dark)
Stoma has a deep/dark red hue.
# Slough
Dry or wet, loose or firmly attached, yellow to brown dead tissue.
# Turgor
Ability to change shape and return to normal appearance after lightly touching stoma (elasticity).
# Trauma
Injury to surface of stoma like a cut, abrasion, or bruise.
# Cancerous lesion
Able to visualize cancerous lesion/tumor on or attached to stoma.
# Pseudoverrucous lesions
Wart-like lesions from chronic moisture irritation on or directly around stoma.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# PERIOSTOMY SKIN Macerated
Wet, white.
# Mucosal transplant
Seeding of viable intestinal mucosa along suture line and onto peristomal skin.
# Parastomal hernia
A deficit in the fascia that allows loops of the intestine to protrude in areas of weakness. Can present as abnormal bumps on the abdomen around the stoma.
# Pseudo-verrucous lesions
Wart-like lesions from chronic moisture irritation around stoma.
# Psoriasis
Chronic disease characterized by proliferation of epidermis that often appears as an erythematic, thick, silvery-white, and scaling plaque.
# Pyoderma gangrenosum
Ulcerative inflammatory skin condition of unknown etiology that starts as pustules and break open to form full thickness ulcers often with undermining, ragged edges, and overhanging margins.
# Trauma
Loss of epidermis around stoma.
# Ulceration
Ulcer located around stoma.
# Length & Width
Length: Longest measurement.
Width: Measured at widest area perpendicular to length.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition STOMA COLOUR: Stoma colour is usually pink or red but may vary depending on blood supply.
# Pink/red
Pink or red: ealthy with normal/adequate blood supply.
# Dusky
Bluish hue due to altered blood supply.
# Necrotic
Purple to a deep wine coloured hue due to ischemia of the stoma. The stomal tissue may turn to yellow slough and can progress to black dry tissue (eschar).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition STOMA TISSUE: Stoma tissue is usually moist and damp. The tissue can vary depending on blood supply, damage, trauma, etc.
# Moist
Mucosal tissue is damp.
# Edematous
Shiny, swollen, translucent, smooth appearance; due to interstitial collection of fluid.
# Slough
Soft, moist, devitalized tissue; may be white, yellow, tan or green. May be loose or firmly adherent.
# Friable (no image available)
Stoma tissue is fragile and bleeds easily with minimal contact.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition STOMA HEIGHT: An elevation above skin level of approximately 2cm is ideally for a good fit of the appliance. Due to surgical complication of body habitus, stomas can be either retracted or prolapsed.
# Protruding
Stoma protrudes above level of the skin by approximately 2cms.
# Flush
Stoma sits at the same level of the skin.
# Retracted
The stoma is pulled down below the level of the skin.
# Prolapsed
A prolapsed sttoma is a stoma that develops a length longer than what was created at the time of surgery. The prolapse is created by the outward telescoping of the bowel. The length of the prolapse can vary.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition PERISTOMAL SKIN: the skin surrounding the stoma.
# Intact
Unbroken skin.
# Excoriated
Superficial loss of tissue that presents irregular with areas of erythema, and rash.
# Red
Intact skin with redness that may have varying degrees of intensity from bright red to dark red; redness may be due to chemical effluent, fungal or sensitivity/allergy.
# Creases
A dip or fold in the abdomen. The depth may vary from shallow to very deep.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# MUCOCUTANEOUS JUNCTION: The point where the epidermis and the mucosa merge
# Intact
Mucocutaneous junction is well approximated.
# Separated
Area of detachment(s) from the stoma to the skin (dehiscence).
The separated area may be circumferential or partial.
# Rod/ bridge
This device may be a commercially available rod, a Penrose drain or red rubber catheter. It may, or may not, be sutured.
# Stents
A short-term small plastic tube which sits in each of the ureters and exits through the stoma; used to divert urine while the surgical area recovers.
# Allergic contact dermatitis
Peristomal erythema that mirrors the image of the allergen.
May be moist and pruritic.
Remove allergen.
Allergen may be a tape border or the barrier or both.
Medicated cortisone spray to relieve itch.
Crusting if moist.
If tape allergy use no tape product.
If barrier allergy, consider a different company.
May consider barrier between skin and pouch (e.g., skin protectant, transparent film, or hydrocolloid.
Consider patch testing.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# DESCRIPTION CLINICAL PRESENTATION TREATMENT OBJECTIVE
# TOPICAL TREATMENT OPTIONS
# Wound to peristomal skin
Wound to peristomal skin.
Identify cause of wound.
Heal the wound.
Prevent pouching system leakage.
Moisture balance to wound, follow wound treatment plan.
If using convexity, consider wider convexity or barrier ring instead to offload pressure.
# Pyoderma gangrenosum
Wound to peristomal skin.
Very painful purple borders.
Usually a history of autoimmune disease (e.g., inflammatory bowel disease, rheumatoid arthritis).
Identify cause of wound.
Manage pain.
Heal the wound.
# Prevent pouching system leakage
Physician/NP and CPCET referral required.
Prescription for steroids (steroid cream to be avoided as prevents pouch adherence).
Moisture balance to wound.
If using convexity, consider wider convexity or barrier ring instead to offload pressure.
Sharp debridement is contraindicated.
# Stoma with fungating tumour
Cancerous tumour protrudes beyond the epidermis causing pouching challenges.
May be dry or moist, have odour and is painful.
Prevent pouching system leakage.
Prevent bleeding.
Provide psychosocial support.
Flexible pouching system.
Cut wide to avoid tumour if needed to obtain a seal.
Consider closed pouching system.
Lubricate inside of pouch if friction causes bleeding (pouch rubbing against tumour).
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# DESCRIPTION CLINICAL PRESENTATION TREATMENT OBJECTIVE TOPICAL TREATMENT OPTIONS
# Peristomal skin denudation due to leakage
Superficial erythema that is moist.
May be painful and pruritic.
Usually occurs where pouching system is leaking.
Treat and prevent leakage.
Change pouching system immediately if leaking.
Identify cause of leak.
Crusting procedure.
Correct leakage, fill in crevices/creases, or add a barrier ring/paste.
Change to a convex appliance if stoma located in a fold or crease, or if stoma is flushed or mobile.
# Peristomal growths
Growths protruding from the mucocutaneous junction.
Are painful and present a pouching challenge.
Refer to CPCET and physician/NP.
Prevent pouching system leakage.
Consult with physician/NP and CPCET.
Use paste or ring to create an even pouching surface. Treat inflammation and localized infection.
Prevent recurrence.
Crusting procedure as needed.
Clip hair to remove.
Use adhesive remover to remove pouching system.
# Yeast/candidiasis
Fungal infection of the skin usually related to leakage.
Area is denuded, red and has satellite lesions.
Can be pruritic.
Treat and prevent leakage.
Change pouching system immediately if leaking.
Treat fungal rash (i.e., crust with antifungal powder).
Identify cause of leak.
Crusting procedure using antifungal powder.
Correct leakage, fill in crevices/creases, or add a barrier ring/paste.
Change to a convex pouching system if stoma located in a fold or crease, or flush or mobile stoma.
Source: Reprinted from Interior Health. Peristomal skin breakdown: assessment and management. [place unknown: publisher unknown]; 2015. Reprinted with permission.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Overview of types of ostomies from a non-profit volunteer organization dedicated to all people with an ostomy and their families.
Website includes variety of information including, but not limited to, ostomy products, living life to the fullest, ostomy products, and healthy living. Journal article with overview of safe management of ileostomates with high-output stomas.
# A P P E N D I C E S
Supporting
# Acknowledgments
External review provided by:
Dr. Nancy Santesso, RD, MLIS, PhD
# Funding
This work is funded by the Ontario Ministry of Health and Long-Term Care. All work produced by RNAO is editorially independent from its funding source.
# Appendix A: Glossary of Terms
Abdominoperineal resection: "A procedure using an abdominal and perineal approach for the resection of rectal resection (APR) cancer. The procedure involves removal of the rectum, anus and perirectal lymphatics" (59).
Best practice guideline: "Best practice guidelines are systematically developed, evidence-based documents that include recommendations for nurses and the interprofessional team, educators, leaders and policy-makers, persons and their families on specific clinical and healthy work environment topics. BPGs promote consistency and excellence in clinical care, health policies, and health education, ultimately leading to optimal health outcomes for people and communities and the health system" (60).
# CERQual:
The Confidence in the Evidence from Reviews of Qualitative Research (CERQual) is a methodological approach to assess the amount of confidence that can be placed in findings from a body of qualitative evidence about an outcome of interest. The assessment provides a transparent means to decide if the review finding reasonably represents the phenomenon under study, which can facilitate expert panels to make health recommendations (61).
CERQual criteria: When using CERQual, four components contribute to the assessment of confidence in the evidence for each individual finding: 1. Methodological limitations, which look at issues in the design of the primary study or problems in the way it is conducted. 2. Relevance, whereby each primary study that supports a finding is assessed together and a decision is made regarding the applicability of the findings to the population, phenomenon, and setting outlined in the research question. 3. Coherence, whereby an assessment is made of whether the primary studies provide sufficient data and a convincing explanation for the review findings. 4. Adequacy of data, whereby an overall assessment is made about the richness and quantity of data that supports the review finding and phenomenon of interest (61).
Colostomy: A surgically created opening from the colon to the abdominal wall to allow the elimination of feces. A colostomy can be either temporary or permanent (3).
Consensus: A process used to reach agreement among a group or panel during a Delphi or modified Delphi technique (62). A consensus of 70 per cent agreement from all panel members was required for the strength of recommendations within this Guideline.
# Continent diversion:
An internal reservoir is surgically created using a section of the bowel to collect feces and urine. Continent diversions may or may not result in the creation of a stoma, eliminating the necessity for a pouching system to be worn outside the body (2).
# Appendix C: Education Statements Education Statements for this Guideline
RNAO has been at the forefront of creating BPGs since 1999, with its first guideline being issued in 2002. From the outset, RNAO recognized the importance of individual and organizational approaches to the delivery of education on clinical BPG content to support evidence-based practice changes. As such, RNAO clinical BPGs included education recommendations directed to those responsible for the academic and in-service education of nursing students, nurses and the interprofessional team. These recommendations outlined core content and training strategies required for entry-level health programs, continued education, and professional development. A rigorous thematic analysis showed similarities across BPGs. Thus, it was deemed appropriate to create standard Education Statements that would be applicable to all clinical BPGs to support evidence-based practice changes. The resultant two education statements and the associated discussion of the literature are described below. These statements can be contextually adapted within health service organizations and academic institutions to support the implementation of clinical recommendations for various guideline topic areas.
# EDUCATION STATEMENT 1:
# ACADEMIC INSTITUTIONS INTEGRATE EVIDENCE-BASED GUIDELINES INTO CURRICULA FOR PRE-AND POST-LICENSURE NURSES AND OTHER REGULATED HEALTH PROVIDERS.
# Discussion of Literature:
The thematic analysis of the education recommendations described above, found the theme of: "academic institutions integrate evidence-based guidelines into curricula for pre-and post-licensure nurses and other regulated health providers, " as foundational to evidence-based practice capacity building.
# Appendix D: Guideline Development Methods
This Appendix presents an overview of the RNAO guideline development process and methods. RNAO is unwavering in its commitment that every BPG be based on the best available evidence. The GRADE and CERQual methods have been implemented to provide a rigorous framework and meet international standards for guideline development.
# Scoping the Guideline
The scope sets out what an RNAO guideline will and will not cover (see Purpose and Scope). To determine the scope of this Guideline, the RNAO Best Practice Guideline Development and Research Team conducted the following steps:
1. Reviewed the previous RNAO BPG Ostomy Care and Management (2009) to understand its purpose, scope, and recommendations.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Appendix E: Process for Guideline and Systematic Review Guideline Review The systematic reviews that answered research questions in existing high quality guidelines (scoring six and above on AGREE II) were considered to be beyond the scope of this guideline. In this case, no guidelines scored six or above on the AGREE II.
# Appendix F: Indicator Development Process
The RNAO indicator development process steps are summarized below (see Figure 9):
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition Steps 1 and 2
Step 3
Step 6
Step 4
Step 5
Appendix G: Ostomy Assessment Terms
# TYPE OF OSTOMY
# Brooke method
Surgical maturation of the bowel where the distal bowel is everted and sutured to the skin, thus exposing the mucosal surface eliminating the "natural maturation" process.
# Cecostomy
Rarely performed, the patient's cecum is brought through the abdomen.
Often a temporary measure to allow decompression of the colon. May be performed as a bowel management program allowing irrigation of the colon with tap water or saline.
# Colostomy
Portion of patient's colon is brought through the abdomen and everted to create a stoma. Can be permanent or temporary and allows the passage of stool into an external pouch or appliance.
# Ascending colostomy:
The ascending portion of the colon is used.
# Transverse colostomy:
The transverse portion of the colon is used.
# Descending colostomy:
The descending portion of the colon is used.
# Sigmoid colostomy:
The sigmoid portion of the colon is used.
# Continent cutaneous diversion fecal (e.g., Koch pouch)
Rarely performed, an internal continent cutaneous diversion is created using a portion of the ileum. The proximal portion is used to create an internal pouch with the distal end brought through the abdominal wall to create a one way valve and a stoma. After several weeks of healing, the patient will perform intermittent intubation and drain the pouch of the fecal contents.
# Continent cutaneous diversion urinary (e.g., Indiana pouch)
An internal continent cutaneous diversion is created from the ileum and cecum, and another segment of bowel, either colon or ileum, is used as a pouch. The ureters are brought through the back of the cecum. The cecum and bowel segment are each opened and then sewn together to create a reservoir for urine. The attached ileal segment is brought through the abdominal wall to create a stoma. Intermittent catheterization will be required.
# Ileal conduit (urostomy)
Portion of patient's ileum is brought through the abdomen and everted to create a stoma. Can be permanent or temporary and allows the passage of urine into an external pouching system.
# Ileostomy
Portion of patient's ileum is brought through the abdomen and everted to create a stoma. Can be permanent or temporary and allows the passage of stool into an external pouching system.
# Os flush
Opening of the bowel at skin level.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# STOMA DEVICES Bridge
Short-term device that sits on the surface of the skin to support a loop stoma. Resembles two half-moons back-to-back.
# Catheter
Rubber or plastic tube that sits in the stoma to act as a diversion.
# Rod
Short-term device that sits on the surface of the skin to support a loop stoma.
# Stent
Short-term small plastic tube that sits in the ureter and exits through the stoma. Used acutely to divert urine while surgical area recovers.
ABDOMINAL CONTOURS (creases, fold, hollows, and/or distension on the abdomen that effect the fit of a pouching system)
# Distended
Abnormal to patient; protruding of abdomen.
# Flabby
Normal to patient; protruding and folding of abdomen.
# Flat
Abdominal plane is flat.
# Hernia
Deficit in the fascia that allows loops of the intestine to protrude in areas of weakness. Can present as abnormal bumps on the abdomen.
# Loose/wrinkly
Abdomen has folds of loose skin.
# Rounded
Normal to patient; abdominal plane is rounded.
# Pendulous
Abdominal tissue hanging loosely.
# Soft
Abdomen is soft with palpation.
# Hard
Abdomen is firm or hard with palpation.
# Approximated
Margin where the skin and stoma meet is well adhered.
# Dissolvable sutures
A stitch that is made of a material that will dissolve with the body's fluids and disappear.
# Fistula
An abnormal track connecting an organ to the skin surface, wound bed, ostomy, or to another organ.
# Full epithelialized
Covered completely with new epithelial tissue.
# Removable sutures
A stitch that is made of a material that will need to be removed at some point in time.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# MUCOCUTANEOUS MARGIN (point where the epidermis and mucosa merge)
# Separated
Area of detachment(s) from the stoma to the skin.
# Suture granuloma
Red, friable tissue and skin in the stoma margin where there are areas of retained or reactive suture material.
# Tenuous
Thin or fragile connection between the skin and stoma.
# PERIOSTOMY SKIN
# Allergic contact dermatitis
Hypersensitivity to area where product was applied resulting in an inflammatory reaction. Area affected mirrors the shape of the product used.
# Bruised
Dark red, purplish, or blue tissue that fades to yellow, green, or grey depending on the skin colour.
# Cancerous lesion
Cancerous lesion/tumor on or protruding through the periostomy skin.
# Caput medusae (peristomal varices)
A purple hue caused by dilation of blood vessels noted around the stoma. Intermittent, spontaneous, or profuse bleeding may be noted by the patient and is often caused by portal hypertension.
# Denuded
Superficial smooth loss of epithelium.
# Erythema
Redness of the skin may be intense bright red to dark red.
# Excoriated
Superficial loss of tissue that presents irregular with areas of erythema and rash.
# Eczema
Superficial inflammation of the skin, often causing red papules that itch and weep, and can leave crusting and scaling.
# Folliculitis
Seen as red pustules and papules that are from bacterial inflammation of hair follicles.
# Fungal rash
Overgrowth of fungal organisms that present as pustules on the skin. Satellite lesions (small red pustules) are often seen advancing from the edge of affected area.
# Indurated
Abnormal firmness of the tissues with palpable margins.
# Inflammatory process
The periostomy skin has/is currently in an inflammatory process.
# Intact
Unbroken skin.
# Irritant contact dermatitis
Skin damage, often from contact with fecal or urine drainage.
# A P P E N D I C E S
Supporting Adults Who Anticipate or Live with an Ostomy -Second Edition
# Appendix H: Ostomy Assessment Parameters and Definitions
STOMA CONSTRUCTION: Refers to how a stoma is surgically created. The stoma may be created from either the small or large bowel.
# End
An end stoma is created by incising the intestine and bringing the proximal end of the intestine through an opening in the abdominal wall to just above skin level.
# Loop
A loop stoma is created by mobilizing the side of the intestine up through an opening in the abdominal wall and making a transverse incision on the intestine. This stoma will have two openings, proximal and distal. A temporary supporting rod may be placed under the stoma to prevent stoma retraction.
# Double barrel
A resection of the bowel is done; both the proximal end and the distal end are brought up through openings in the abdominal wall, creating two end stomas. The proximal will be functioning stoma and the distal is the non-functioning stoma -also known as a mucous fistula. The stomas can be positioned side by side or some distance apart.
# A P P E N D I C E S
Supporting Adults Who
# Appendix K: Charter of Ostomates Rights
This Charter of Ostomates Rights presents the special needs of this particular group and the care they require. They have to receive the information and care which will enable them to live a self-determined and independent life and to participate in all decision-making processes.
It is the declared objective of the International Ostomy Association that this CHARTER shall be realized in all Countries of the World.
The Ostomate shall:
Receive preoperative counseling to ensure that they are fully aware of the benefits of the operation and the essential facts about living with a stoma.
Have a well-constructed stoma placed at an appropriate site, and with full and proper consideration to the comfort of the patient.
Receive experienced and professional medical support and stoma nursing care in the preoperative and postoperative period both in hospital and in their community.
Receive support and information for the benefit of the family, personal caregivers and friends to increase their understanding of the conditions and adjustments which are necessary for achieving a satisfactory standard of life with a stoma.
Receive full and impartial information about all relevant supplies and products available in their Country.
Have unrestricted access to a variety of affordable ostomy products.
Be given information about their National Ostomy Association and the services and support which can be provided.
Be protected against all forms of discrimination.
Receive assurance that personal information regarding their ostomy surgery will be treated with discretion and confidentiality to maintain privacy; and that no information about their medical condition will be disclosed by anyone possessing this information, to an entity that engages in the manufacture, sales or distribution of ostomy or related products; nor shall it be disclosed to any person that will benefit, directly or indirectly, because of their relation to the commercial ostomy market without the expressed consent of the ostomate. Signs and symptoms of dehydration:
Dizziness.
Light-headedness.
Feelings of thirst.
Dry mouth and tongue.
Reduced urine output.
Dark yellow urine.
Feeling of agitation or restlessness.
Foods that may thicken stool:
Potatoes.
Marshmallows.
Peanut butter.
Soda crackers.
Rice.
Tapioca.
Bananas.
Pasta.
Bread.
Cheese.
Foods that may loosen stool:
Alcohol (beer, wine, and liquor).
Prune juice.
Legumes.
Black licorice.
Chocolate.
Spicy foods.
Caffeine containing beverages (tea, coffee, and colas). Support team includes a consumer service advisor, but no clinical or medical support.
Secure start is offered in English through email or telephone.
Services include assistance with finding the right product, identifying product supplier options, providing product-related information, and accessing local support. Services include informative monthly meetings, publications, a resource centre filled with information, and up-to-date news for people who anticipate or live with ostomies, their families, caregivers, and friends living in the Greater Toronto area.
# A P P E N D I C E S
Supporting Adults
In addition, Ostomy Toronto offers patients a visiting service.
United Ostomy Associations of America, Inc.
https://www.ostomy.org/ A non-profit organization dedicated to people living with an ostomy and their families.
The site includes many resources, including educational material (e.g., a continent urostomy guide, information regarding intimacy/sexuality and ostomy, and more).
# World Council of Enterostomal
Therapists (WCET ® ) www.wcetn.org An international association for those concerned with the care of people with stomas.
Provides the opportunity for members to meet for the purpose of discussing common interests related to enterostomal therapy.
Promotes activities that will assist members engaged in enterostomal therapy to increase their knowledge and enhance their contribution to the subject of stoma therapy.
Promotes increased awareness in others of the role and contribution of the WCET ® .
# Appendix O: Description of the Toolkit
BPGs can only be successfully implemented if planning, resources, and organizational and administrative supports are adequate, and if there is appropriate facilitation. To encourage successful implementation, an RNAO expert panel of nurses, researchers, and administrators has developed the Toolkit: Implementation of Best Practice Guidelines (2012). The Toolkit is based on available evidence, theoretical perspectives, and consensus. We recommend the Toolkit for guiding the implementation of any clinical practice guideline in a health organization.
The Toolkit provides step-by-step directions for the individuals and groups involved in planning, coordinating, and facilitating the guideline implementation. These steps reflect a process that is dynamic and iterative rather than linear. Therefore, at each phase, preparation for the next phases and reflection on the previous phase is essential. Specifically, the Toolkit addresses the following key steps, as illustrated in the Knowledge-to-Action framework (58).
# Best Practice Guideline
This project is funded by the Ontario Ministry of Health and Long-Term Care. | None | None |
e43ace6772cafe76dbebb0f7f7f83ea4c74cf4ab | cma | None | Signs and symptoms may be present regardless of the severity of the initial infection 1 : - They can occur in children, adolescents and adults.- Persistence of certain signs and symptoms present during the acute phase of the infection with or without the onset of new symptoms (e.g., postexertional malaise and mental fog); - Onset of signs and symptoms after a period of remission following the acute infection or following an asymptomatic infection. The prevalence of signs and symptoms of a post-COVID-19 condition varies between studies according to the severity of the initial infection, the participants' characteristics and the length of follow-up. According to studies, the proportion of individuals with at least 1 sign or symptom at least 4 weeks after infection was: - 13% to 41% in nonhospitalized persons; - 25% to 89% in hospitalized patients or patients admitted to intensive care. Recovery varies from person to person. There is limited experience and few available data, but it appears that: - Gradual improvement in health is observed in many persons up to 12 weeks after infection; - When symptoms persist beyond 12 weeks, subsequent improvement tends to be much slower. The long-term prognosis for these persons has not been clearly determined.#
- According to the World Health Organization classification: asymptomatic infection, mild disease (signs and symptoms with no signs of viral pneumonia or hypoxia), moderate disease (pneumonia), severe disease (severe pneumonia), critical disease (acute respiratory distress syndrome, sepsis, septic shock, acute thrombosis, or multisystemic inflammatory syndrome in children).
# UNCERTAINTIES
INESSS remains on the lookout for new data and will update this tool accordingly.
# Scientific evidence Epidemiology Etiology Diagnosis Risk factors
The currently available scientific data are limited and of low methodological quality.
A number of epidemiological aspects are still uncertain.
There is little long-term data on the evolution of signs and symptoms.
The etiology of the signs and symptoms is still unknown, and could involve various mechanisms of action.
There are no recognized diagnostic criteria and no validated specific management.
No risk factors for developing a post-COVID-19 condition have been confirmed. Advanced age, female sex, comorbidities, severe initial infection and hospitalization have been suggested among others.
# MANAGEMENT SUPPORT TOOL
# POST-COVID-19 CONDITIONS
This management support tool is intended primarily for front-line physicians, pharmacists and nurses. However, it is also intended as a source of information for other front-line professionals. It is provided for information purposes only and should not replace the judgment of the clinician who performs activities reserved under a statute or regulation. The contents are based on a systematic review of the clinical practice guidelines available when it was being developed and is supported by the knowledge and experience of Québec experts who contributed to its development. This tool is intended to complement other INESSS publications. For further details, go to inesss.qc.ca/COVID-19.
# JULY 2021
For the purposes of this tool, post-COVID-19 conditions refer to the health of an individual who meets the following 3 conditions:
Initial infection confirmed (nucleic acid amplification test or serology) or plausible (epidemiological link);
Presence of signs and symptoms beyond 4 weeks after the initial infection;
Persistence of signs and symptoms that cannot be explained by another condition and that were not present before the infection.
# SIGNS AND SYMPTOMS
There are no signs or symptoms specific to post-COVID-19 conditions.
Signs and symptoms:
- Are varied and can affect more than one system;
- Can be constant or transient, vary in severity and change over time.
# MANAGEMENT
# ASSESSMENT OF THE HEALTH CONDITION OBJECTIVES
- To determine if the condition might be due to:
-Complications or sequelae of the acute phase of COVID-19;
-An exacerbation or worsening of an existing comorbidity.
- To rule out conditions unrelated to COVID-19.
# GENERAL CONSIDERATIONS
- Exercise empathetic listening while the person expresses their concerns and worries.
# SIGNS AND SYMPTOMS
Document the signs and symptoms (onset, evolution and duration).
Document their impact on the person's quality of life, psychological status and overall functioning.
# HEALTH HISTORY
Document the COVID-19 episode in order to assess the presence of sequelae or complications associated with the acute phase.
- Dates, signs and symptoms, severity, examinations performed, treatments provided, and rehabilitation performed in hospital.
Inquire about the person's:
- History and comorbidities (relating to physical and mental health) to determine if there is a worsening or exacerbation.
- Medication history to determine if drugs might be having an effect on the signs and symptoms.
- Personal situation (e.g., financial losses, worries about their health or that of a family member) to assess the psychosocial risks.
There are no recognized diagnostic criteria for post-COVID-19 conditions.
# Individuals who have had an asymptomatic infection can develop post-COVID-19 conditions.
The symptoms can affect more than one system, fluctuate over time, be different from those of the acute phase or be rare.
Postexertional malaise: A worsening of signs and symptoms that occurs after effort, whether physical, mental or emotional. It usually occurs within 12 to 72 hours after the activity and can last for days or weeks.
# Mental fog:
The subjective perception of not being able to think as clearly as usual.
# EXAMINATIONS
Examinations should be chosen according to:
- Signs and symptoms;
- Health history. Examinations to be considered:
- Complete physical exam, including:
-Weight and any recent changes in weight; -Temperature; -Heart rate and blood pressure in the supine and then upright positions; -Respiration; -Resting and exercise pulse oximetry if any dyspnea or tachypnea.
- Mental status examination.
# Categories
Conditions and syndromes to be considered
# No scale has been validated for measuring the signs and symptoms of post-COVID-19 conditions.
The interpretation of the results of mental health problem screening tools may be distorted by the physical effects of post-COVID-19 conditions.
# Orthostatic hypotension:
Excessive decrease in blood pressure in the standing position.
- A decrease > 20 mm Hg in systolic blood pressure or > 10 mm Hg in diastolic blood pressure.
- Occurs within 3 minutes of going from the supine position to the standing position.
# Postural orthostatic tachycardia syndrome (POTS):
- Increase in pulse ≥ 30/minute in adults or ≥ 40/minute in individuals under 19 years of age.
- Occurs within 10 minutes of going from the supine position to the standing position.
- Presence of signs and symptoms in the standing position that improve when the person returns to the supine position (dizziness, palpitations, tremor or atypical chest discomfort). - No orthostatic hypotension.
A number of conditions and syndromes that are not mutually exclusive have been described in the context of post-COVID-19 conditions. There are currently no scientific data that permit determining if these conditions or syndromes are consequences of the SARS-CoV-2 virus, sequelae of prolonged hospitalization, or those of a health condition unrelated to COVID-19. The following list is subject to change as knowledge evolves and should be used as one tool among others to guide questions and examinations.
# Tests and investigations to be considered CHOOSE ON THE BASIS OF THE CLINICAL PICTURE
# CATEGORIES TESTS
# Basic tests
Hemogram, electrolytes and renal function
# TESTS AND INVESTIGATIONS
The tests and investigations should be chosen on the basis of:
- Signs and symptoms;
- Health history;
- Findings of the physical examination;
- Other suspected conditions.
Depending on the clinical picture, one might consider not ordering tests and investigations during post-infection weeks 4 to 12 since signs and symptoms may improve.
There are no specific tests or investigations for post-COVID-19 conditions, and no standard workup has yet been defined.
The results of the tests and investigations are mainly used to rule out associated complications. It appears that these results are often normal in the context of post-COVID-19 conditions.
The detection of antibodies against SARS-CoV-2 is not very informative, especially because a negative result does not rule out exposure to the virus.
# AVOID OVERINVESTIGATING THERAPEUTIC MANAGEMENT OBJECTIVES
- To eliminate the signs and symptoms or reduce their frequency and severity.
- To support optimal self-management and a safe return to activities.
- To refer the person to specialized resources, if necessary.
# GENERAL CONSIDERATIONS
- Establish a care plan in partnership with the person via a shared decision-making process.
- Keep abreast of the progress in knowledge regarding post-COVID-19 conditions.
- Assess the resumption of daily activities on a case-by-case basis (e.g., return to school or work).
- Draw on interdisciplinary collaboration.
- Self-management is a complementary intervention to others and requires a certain amount of supervision in order to be optimal.
# MEDICAL MANAGEMENT
Treat signs and symptoms according to standard practice.
Optimize management of any comorbidities and treat complications according to standard practice.
Consider self-monitoring based on signs and symptoms (e.g., blood pressure, pulse oximetry).
Reassess appropriateness of any pharmacological treatments that might be having an effect on the signs and symptoms, and adjust dosage as needed.
Consider referring the person to a medical specialist or a nearby post-COVID-19 service*, if available: - If the acute infection occurred ≥ 12 weeks ago and the person's health is not improving or is deteriorating;
- If the person has a condition that suggests an abnormality or a persistent neurological, cardiovascular or pulmonary problem.
# The usual emergency criteria prevail.
*Services are expanding and the criteria in place for access may vary according to the location and any ongoing research projects at the site.
# FUNCTIONAL RECOVERY
Offer counselling tailored to the person's needs and abilities in order to support resuming their activities (e.g., mobility and technical aids).
- Resuming activities too quickly could pose a risk of relapse.
Adjust management if postexertional malaise:
- Avoid evaluations that could trigger or exacerbate signs and symptoms (e.g., walking test);
- Do not encourage resuming activities for the purpose of increasing exercise endurance.
Do not prescribe fixed or standardized physical exercise programs.
Consider referring the person to rehabilitation services if they have:
- Difficulty managing their energy or their pain that is causing a significant functional disability; - Significant, persistent respiratory impairment; - Severe cognitive, cardiac, neurological or musculoskeletal involvement; - Post-intensive care syndrome.
# SOCIAL AND PSYCHOLOGICAL SUPPORT
Treat signs and symptoms related to mental status according to standard practice.
Provide support for social and psychological impact of post-COVID-19 conditions (e.g., inability to look after children, loss of employment, inability to return to school or work, and feelings of distress or isolation).
Consider referring the person to support and evaluation services according to standard practice and the organization of services (e.g., a CLSC's general social services, community organizations, and mental health entry points).
CLSC: local community services centre.
# There is no specific treatment for post-COVID-19 conditions.
Management should be pragmatic, symptomatic and individualized.
Certain delays in accessing specialized care and services can complicate the person's therapeutic management.
Ask the person to record their signs and symptoms (onset, deterioration and resolution) in order to identify triggers and exacerbators.
Stress a healthy lifestyle (e.g., rest, nutrition).
Ask the person to resume their activities according to their abilities and the effort thresholds that trigger their signs and symptoms.
Instruct persons with postexertional malaise on how to manage their energy by balancing their activity periods and rest periods. These individuals should:
- Identify the thresholds of physical, cognitive and emotional effort that trigger their signs and symptoms;
- Adjust the intensity of their activities and plan their activity and rest periods so as to not exceed the identified effort thresholds;
- Increase their activities cautiously and gradually, even if they are feeling well, to avoid relapses.
Inform them that optimal energy management may take some time to learn.
Explain to the person how to alleviate their signs and symptoms (e.g., pharmacological treatment).
Set incremental and realistic goals.
Provide instructions for self-monitoring, if necessary (e.g., blood pressure, pulse oximetry).
# FOLLOW-UP
Decide with the person on the follow-up to be done: method (by telephone or in-person), frequency (every 3 months at the longest), professionals involved.
Maintain standard follow-up for comorbidities.
During follow-up:
- Assess evolution of the person's signs and symptoms;
- Repeat tests and investigations as needed;
- Reassess the possible causes;
- Monitor the care plan, including self-management. | Signs and symptoms may be present regardless of the severity of the initial infection 1 : • They can occur in children, adolescents and adults.• Persistence of certain signs and symptoms present during the acute phase of the infection with or without the onset of new symptoms (e.g., postexertional malaise and mental fog); • Onset of signs and symptoms after a period of remission following the acute infection or following an asymptomatic infection. The prevalence of signs and symptoms of a post-COVID-19 condition varies between studies according to the severity of the initial infection, the participants' characteristics and the length of follow-up. According to studies, the proportion of individuals with at least 1 sign or symptom at least 4 weeks after infection was: • 13% to 41% in nonhospitalized persons; • 25% to 89% in hospitalized patients or patients admitted to intensive care. Recovery varies from person to person. There is limited experience and few available data, but it appears that: • Gradual improvement in health is observed in many persons up to 12 weeks after infection; • When symptoms persist beyond 12 weeks, subsequent improvement tends to be much slower. The long-term prognosis for these persons has not been clearly determined.#
1. According to the World Health Organization classification: asymptomatic infection, mild disease (signs and symptoms with no signs of viral pneumonia or hypoxia), moderate disease (pneumonia), severe disease (severe pneumonia), critical disease (acute respiratory distress syndrome, sepsis, septic shock, acute thrombosis, or multisystemic inflammatory syndrome in children).
# UNCERTAINTIES
INESSS remains on the lookout for new data and will update this tool accordingly.
# Scientific evidence Epidemiology Etiology Diagnosis Risk factors
The currently available scientific data are limited and of low methodological quality.
A number of epidemiological aspects are still uncertain.
There is little long-term data on the evolution of signs and symptoms.
The etiology of the signs and symptoms is still unknown, and could involve various mechanisms of action.
There are no recognized diagnostic criteria and no validated specific management.
No risk factors for developing a post-COVID-19 condition have been confirmed. Advanced age, female sex, comorbidities, severe initial infection and hospitalization have been suggested among others.
# MANAGEMENT SUPPORT TOOL
# POST-COVID-19 CONDITIONS
This management support tool is intended primarily for front-line physicians, pharmacists and nurses. However, it is also intended as a source of information for other front-line professionals. It is provided for information purposes only and should not replace the judgment of the clinician who performs activities reserved under a statute or regulation. The contents are based on a systematic review of the clinical practice guidelines available when it was being developed and is supported by the knowledge and experience of Québec experts who contributed to its development. This tool is intended to complement other INESSS publications. For further details, go to inesss.qc.ca/COVID-19.
# JULY 2021
For the purposes of this tool, post-COVID-19 conditions refer to the health of an individual who meets the following 3 conditions:
Initial infection confirmed (nucleic acid amplification test or serology) or plausible (epidemiological link);
Presence of signs and symptoms beyond 4 weeks after the initial infection;
Persistence of signs and symptoms that cannot be explained by another condition and that were not present before the infection.
# SIGNS AND SYMPTOMS
There are no signs or symptoms specific to post-COVID-19 conditions.
Signs and symptoms:
• Are varied and can affect more than one system;
• Can be constant or transient, vary in severity and change over time.
# MANAGEMENT
# ASSESSMENT OF THE HEALTH CONDITION OBJECTIVES
• To determine if the condition might be due to:
-Complications or sequelae of the acute phase of COVID-19;
-An exacerbation or worsening of an existing comorbidity.
• To rule out conditions unrelated to COVID-19.
# GENERAL CONSIDERATIONS
• Exercise empathetic listening while the person expresses their concerns and worries.
# SIGNS AND SYMPTOMS
Document the signs and symptoms (onset, evolution and duration).
Document their impact on the person's quality of life, psychological status and overall functioning.
# HEALTH HISTORY
Document the COVID-19 episode in order to assess the presence of sequelae or complications associated with the acute phase.
• Dates, signs and symptoms, severity, examinations performed, treatments provided, and rehabilitation performed in hospital.
Inquire about the person's:
• History and comorbidities (relating to physical and mental health) to determine if there is a worsening or exacerbation.
• Medication history to determine if drugs might be having an effect on the signs and symptoms.
• Personal situation (e.g., financial losses, worries about their health or that of a family member) to assess the psychosocial risks.
There are no recognized diagnostic criteria for post-COVID-19 conditions.
# Individuals who have had an asymptomatic infection can develop post-COVID-19 conditions.
The symptoms can affect more than one system, fluctuate over time, be different from those of the acute phase or be rare.
Postexertional malaise: A worsening of signs and symptoms that occurs after effort, whether physical, mental or emotional. It usually occurs within 12 to 72 hours after the activity and can last for days or weeks.
# Mental fog:
The subjective perception of not being able to think as clearly as usual.
# EXAMINATIONS
Examinations should be chosen according to:
• Signs and symptoms;
• Health history. Examinations to be considered:
• Complete physical exam, including:
-Weight and any recent changes in weight; -Temperature; -Heart rate and blood pressure in the supine and then upright positions; -Respiration; -Resting and exercise pulse oximetry if any dyspnea or tachypnea.
• Mental status examination.
# Categories
Conditions and syndromes to be considered
# No scale has been validated for measuring the signs and symptoms of post-COVID-19 conditions.
The interpretation of the results of mental health problem screening tools may be distorted by the physical effects of post-COVID-19 conditions.
# Orthostatic hypotension:
Excessive decrease in blood pressure in the standing position.
• A decrease > 20 mm Hg in systolic blood pressure or > 10 mm Hg in diastolic blood pressure.
• Occurs within 3 minutes of going from the supine position to the standing position.
# Postural orthostatic tachycardia syndrome (POTS):
• Increase in pulse ≥ 30/minute in adults or ≥ 40/minute in individuals under 19 years of age.
• Occurs within 10 minutes of going from the supine position to the standing position.
• Presence of signs and symptoms in the standing position that improve when the person returns to the supine position (dizziness, palpitations, tremor or atypical chest discomfort). • No orthostatic hypotension.
A number of conditions and syndromes that are not mutually exclusive have been described in the context of post-COVID-19 conditions. There are currently no scientific data that permit determining if these conditions or syndromes are consequences of the SARS-CoV-2 virus, sequelae of prolonged hospitalization, or those of a health condition unrelated to COVID-19. The following list is subject to change as knowledge evolves and should be used as one tool among others to guide questions and examinations.
# Tests and investigations to be considered CHOOSE ON THE BASIS OF THE CLINICAL PICTURE
# CATEGORIES TESTS
# Basic tests
Hemogram, electrolytes and renal function
# TESTS AND INVESTIGATIONS
The tests and investigations should be chosen on the basis of:
• Signs and symptoms;
• Health history;
• Findings of the physical examination;
• Other suspected conditions.
Depending on the clinical picture, one might consider not ordering tests and investigations during post-infection weeks 4 to 12 since signs and symptoms may improve.
There are no specific tests or investigations for post-COVID-19 conditions, and no standard workup has yet been defined.
The results of the tests and investigations are mainly used to rule out associated complications. It appears that these results are often normal in the context of post-COVID-19 conditions.
The detection of antibodies against SARS-CoV-2 is not very informative, especially because a negative result does not rule out exposure to the virus.
# AVOID OVERINVESTIGATING THERAPEUTIC MANAGEMENT OBJECTIVES
• To eliminate the signs and symptoms or reduce their frequency and severity.
• To support optimal self-management and a safe return to activities.
• To refer the person to specialized resources, if necessary.
# GENERAL CONSIDERATIONS
• Establish a care plan in partnership with the person via a shared decision-making process.
• Keep abreast of the progress in knowledge regarding post-COVID-19 conditions.
• Assess the resumption of daily activities on a case-by-case basis (e.g., return to school or work).
• Draw on interdisciplinary collaboration.
• Self-management is a complementary intervention to others and requires a certain amount of supervision in order to be optimal.
# MEDICAL MANAGEMENT
Treat signs and symptoms according to standard practice.
Optimize management of any comorbidities and treat complications according to standard practice.
Consider self-monitoring based on signs and symptoms (e.g., blood pressure, pulse oximetry).
Reassess appropriateness of any pharmacological treatments that might be having an effect on the signs and symptoms, and adjust dosage as needed.
Consider referring the person to a medical specialist or a nearby post-COVID-19 service*, if available: • If the acute infection occurred ≥ 12 weeks ago and the person's health is not improving or is deteriorating;
• If the person has a condition that suggests an abnormality or a persistent neurological, cardiovascular or pulmonary problem.
# The usual emergency criteria prevail.
*Services are expanding and the criteria in place for access may vary according to the location and any ongoing research projects at the site.
# FUNCTIONAL RECOVERY
Offer counselling tailored to the person's needs and abilities in order to support resuming their activities (e.g., mobility and technical aids).
• Resuming activities too quickly could pose a risk of relapse.
Adjust management if postexertional malaise:
• Avoid evaluations that could trigger or exacerbate signs and symptoms (e.g., walking test);
• Do not encourage resuming activities for the purpose of increasing exercise endurance.
Do not prescribe fixed or standardized physical exercise programs.
Consider referring the person to rehabilitation services if they have:
• Difficulty managing their energy or their pain that is causing a significant functional disability; • Significant, persistent respiratory impairment; • Severe cognitive, cardiac, neurological or musculoskeletal involvement; • Post-intensive care syndrome.
# SOCIAL AND PSYCHOLOGICAL SUPPORT
Treat signs and symptoms related to mental status according to standard practice.
Provide support for social and psychological impact of post-COVID-19 conditions (e.g., inability to look after children, loss of employment, inability to return to school or work, and feelings of distress or isolation).
Consider referring the person to support and evaluation services according to standard practice and the organization of services (e.g., a CLSC's general social services, community organizations, and mental health entry points).
CLSC: local community services centre.
# There is no specific treatment for post-COVID-19 conditions.
Management should be pragmatic, symptomatic and individualized.
Certain delays in accessing specialized care and services can complicate the person's therapeutic management.
Ask the person to record their signs and symptoms (onset, deterioration and resolution) in order to identify triggers and exacerbators.
Stress a healthy lifestyle (e.g., rest, nutrition).
Ask the person to resume their activities according to their abilities and the effort thresholds that trigger their signs and symptoms.
Instruct persons with postexertional malaise on how to manage their energy by balancing their activity periods and rest periods. These individuals should:
• Identify the thresholds of physical, cognitive and emotional effort that trigger their signs and symptoms;
• Adjust the intensity of their activities and plan their activity and rest periods so as to not exceed the identified effort thresholds;
• Increase their activities cautiously and gradually, even if they are feeling well, to avoid relapses.
Inform them that optimal energy management may take some time to learn.
Explain to the person how to alleviate their signs and symptoms (e.g., pharmacological treatment).
Set incremental and realistic goals.
Provide instructions for self-monitoring, if necessary (e.g., blood pressure, pulse oximetry).
# FOLLOW-UP
Decide with the person on the follow-up to be done: method (by telephone or in-person), frequency (every 3 months at the longest), professionals involved.
Maintain standard follow-up for comorbidities.
During follow-up:
• Assess evolution of the person's signs and symptoms;
• Repeat tests and investigations as needed;
• Reassess the possible causes;
• Monitor the care plan, including self-management. | None | None |
a655b594b1922fd8ba12c477d43127a50c7f3586 | cma | None | May 2023 Update: NEW eligibility criteria for nirmatrelvir/ritonavir, including a discussion of the evidence.Various agents are available in BC for the treatment of mild-moderated COVID-19. These therapies include a direct-acting oral antiviral nirmatrelvir/ritonavir (Paxlovid) and an IV antiviral, remdesivir (Veklury). A monoclonal antibody (mAB) sotrovimab (Xevudy) has also been shown efficacious in treating mild-moderate illness; however, it has reduced activity against many variants currently circulating in BC. Guidance on repurposed therapies such as inhaled steroids, fluvoxamine, colchicine is also included. This document provides general recommendations for the use of these therapeutics and supporting evidence, with additional practice tools available separately. See Toolkit #1 -Step-by-step Assessment for practical prescribing information. Immunocompromised individuals 1,2 and those with high-risk conditions 3 identified as Clinically Extremely Vulnerable Group 1 1 , Group 2 2 , and Group 3 3 (CEV 1, CEV 2, and CEV 3), regardless of age, vaccine status or previous infection. (See also Practice Tool 2 -CEV Definitions).#
- CEV 1: severe immunocompromise due to, e.g., solid organ transplant, bone marrow or stem cell transplant, treatment for hematological malignancy, receiving anti-CD20 or B-cell depleting therapies 2. CEV 2: moderate immunocompromise due to e.g., receiving immunosuppressive agents, moderate-severe primary immunodeficiency, cancer treatment for solid tumors, advanced or untreated HIV 3. CEV 3: e.g., cystic fibrosis, severe asthma or COPD, diabetes requiring insulin, intellectual and developmental disabilities, rare blood disorders, dialysis, neurological conditions requiring Bi-PAP or chronic ventilation, cancer not captured above ^ National Advisory Committee on Immunization: i.e., lack of a primary two-dose series PLUS a "Fall Booster" (or a booster in the last year), which may be delayed up to 6 months post COVID-19 infection *Serious chronic medical conditions may include stroke, heart failure, heart disease, diabetes, kidney or liver disease, chronic lung disease like COPD or interstitial lung disease, neurological conditions. Some discretion can be used See Practical Consideration below for further information about assessing eligibility.
# Therapy Recommendations
Nirmatrelvir/ritonavir 300/100mg PO BID x 5 days (150/100mg PO BID x 5 days in eGFR 30-60 ml/min) is recommended within 5 days of symptom onset for patients with a non-reassuring symptom presentation and trajectory^ who are at an increased risk for hospitalization or progression to severe COVID-19
OR, if nirmatrelvir/ritonavir cannot be given to patients with a 5% or greater risk- due to drug-drug interactions or contraindications (See Practice Tool 3 -Drug Interactions and Contraindications)
Remdesivir 200mg IV on day 1, followed by 100mg IV on days 2 and 3 (200mg IV on day 1, followed by 100mg IV 48-72 hours later in eGFR less than 30ml/min) is recommended within 7 days of symptom onset as an alternative to nirmatrelvir/ritonavir Patients with a risk of 5% or greater are currently being prioritized and offered treatment with remdesivir due to operational constraints and unclear benefit in lower risk individuals.
NOTES ^ Strong clinical judgment assessing symptoms and symptom trajectory is particularly important in immunocompromised patients *To estimate whether the risk is ≥ 5%, see Risk Assessment below The symptom window for nirmatrelvir/ritonavir can be extended to 7 days in patients with a 5% or greater risk if they would otherwise be referred for remdesivir solely based on its longer treatment window THESE THERAPIES SHOULD NOT BE COMBINED: Due a limited additional benefit, patients should receive ONE COVID-19-specfic therapy.
Nirmatrelvir/ritonavir may be considered in patients who reside in Long Term Care (LTC) facilities. There are a lack of data supporting the efficacy and safety of nirmatrelvir/ritonavir in patients residing in LTC facilities.
Treatment may be given depending on patient's clinical presentation, symptom trajectory, risk factors for progression to severe disease, goals of care, presence of drug-drug interactions and tolerance of potential adverse effects.
Sotrovimab 500mg IV X 1 dose has reduced efficacy against the BA. 5.1, BA. 5.2 and 5.2.1 variants, although it may retain some activity. Real-world evidence shows limited efficacy against the BA 1. and BA. 2 variants of concern (VoCs) in immunocompromised or non-immune individuals, which may predict its performance against most BA. 5 VoCs. Sotrovimab has unknown clinical efficacy against many currently circulating VoCs (e.g., BA. 4.6, BQ. 1, BQ 1.1, XBB and BF. 7) where a reduction in binding, but not complete resistance, is seen. If sotrovimab is used in cases where remdesivir or nirmatrelvir/ritonavir cannot be used, patient disclosure to risks and benefits in consideration of individual circumstances (clinical and immune status, patient values, logistics) is necessary. The convenience of single dose sotrovimab should not be the primary indication for use.
Inhaled budesonide 800 μg twice daily for 14 days may be considered on a case-by-case basis in patients who have lower respiratory tract symptoms (cough, shortness of breath) for symptom relief. There is no evidence of additional benefit of inhaled steroids to antivirals or antibody therapy.
Tixagevimab/cilgavimab 600mg IM x 1 dose has demonstrated a 50.5% relative risk reduction (RRR) in COVID-19 hospitalization and death in unvaccinated, non-hospitalized adults with mild-moderate COVID-19 (TACKLE), which is lower than the RRR seen with other COVID-19 treatments in similar trials. Tixagevimab/cilgavimab is likely ineffective against many currently circulating VoCs including BA. 4.6, BF. 7, BA. 2.75.2, BQ 1, BQ 1.1 and XBB where 300-1000-fold reductions in binding are seen. If tixagevimab/cilgavimab is used as a last line treatment in cases where nirmatrelvir/ritonavir, IV remdesivir or sotrovimab cannot be used, disclosure to patients of risks, including cardiovascular serious adverse events (SAEs), and benefits and consideration of individual circumstances (clinical and immune status, patient values, logistics) is necessary. The convenience of the IM route of administration of tixagevimab/cilgavimab should not be the primary indication for use.
Molnupiravir 800mg PO BID x 5 days is not routinely recommended (if/once available in Canada); if used on a case-by-case basis in patients who are unable to receive nirmatrelvir/ritonavir, sotrovimab or remdesivir, the uncertainty of benefit and the absolute risk of hospitalization, including factors such as age, number and type of co-morbidities and severity of symptoms need to be considered.
Colchicine is not recommended due to low certainty of benefit and potential risk of adverse events and additional immunosuppression in this population.
Fluvoxamine is not recommended due to low certainly of benefit and potential risk of adverse events associated with the dose evaluated (100mg PO BID), especially in vulnerable and elderly patients.
# PRACTICAL CONSIDERATIONS
# Risk Assessment
Single variable criteria (e.g., age only) identify patients who have a wide range of risk and are an imprecise way to determine who is at high risk of severe COVID-19 and would benefit from treatment. Unless patients are Clinically Extremely Vulnerable (CEV), real world data show that they require at least two risk factors to have a clinically meaningfully increased risk of hospitalization from COVID-19 and therefore derive a reasonable benefit from treatment.
Age: Age is the single most powerful predictor of hospitalization and death; an 80-year-old patient with COVID-19 has 28 times greater odds of requiring hospitalization than a patient who is 18. Patients over 70, even if vaccinated, experience significant hospitalization rates despite the decreased likelihood in the Omicron variant wave, whereas individuals younger than 50 years have a hospitalization rate of <1% even if unimmunized. The age cut-off of 70 years was chosen as there is a strong inflexion point with respect to the risk of hospitalization. The age cut off for Indigenous patients is lower, set at 60 years, which mirrors COVID-19 vaccine booster recommendations in BC.
Vaccine Status: The National Advisory Committee on Immunizations (NACI) COVID-19 Immunization Guidelines include recommendations regarding the optimal vaccination strategies for COVID-19, which are adopted in BC. These recommendations consider the complexities of vaccine waning and hybrid immunity. Recommendations are presented as "Strong Recommendations" (worded as "should be offered") where the evidence of benefit for a vaccine is convincing, and "Discretionary Recommendations" (worded as "may be offered") where there are limited data or an unclear clinical benefit.
Currently, NACI strongly recommends the following immunization strategy, which is used herein to define what is considered fully or optimally vaccinated:
- A primary two-dose mRNA vaccine series for all adults. A three-dose primary series for those who are immunocompromised (CEV 1 and 2). A "Fall Booster" for those ≥ 65 years and older or those < 65 who have serious chronic medical conditions The Fall Booster may be delayed for up to 6 months in case of a COVID-19 infection
Patients who have never received a COVID-19 vaccination are considered unvaccinated. Patients who are not vaccinated in accordance with NACI's strong recommendations would be considered under-vaccinated. When assessing vaccine status for treatment eligibility, a lack of a booster dose in the last year (and a lack of infection which could delay the dose) is a good gauge of under-vaccination since the presence of another risk factor (older age or chronic conditions) is required for treatment, which is also a risk factor where a booster would be recommended.
Chronic Conditions: Real world evidence shows that serious medical chronic conditions are the most strongly associated with risk of hospitalization from COVID-19. In BC, the most common conditions present when nirmatrelvir/ritonavir was prescribed were hypertension, dyslipidemia and benign prostatic hypertrophy, which are not associated with an increased risk of progression to severe disease. Non-CEV-defining conditions that are significant risk factors are similar to those defined by NACI, and include: The patient requires the presence of any ONE of these serious chronic medical conditions. Some discretion can be used by the prescriber when determining the significance of the severity of the comorbidity.
Other considerations: The risk models/thermal map below are still accurate in estimating the risk of progression to severe COVID-19. These models may be used to aid decision making, or when assessing for the appropriateness of remdesivir. Remdesivir can be offered to patients with contraindications to nirmatrelvir/ritonavir who have a ≥ 5% risk of hospitalization from COVID-19 (dark yellow and red on the thermal map).
# Local Data and Risk Models
# BC Study of Risk of Hospitalization
The CTC partnered with HSIAR, the BCCDC, and other epidemiology research groups to characterize the risk of hospitalization from Omicron in BC. Approximately 600,000 PCR test were included between January 3 to February 7, 2022, a period driven by the BA. 1 variant, where rapid antigen tests were not widely used, PCR testing centres were accessible, and therapy was not yet fully rolled out. Variables analysed that influenced risk that were included in the analysis were age, number of vaccine doses, and number and type of comorbidities (CEV 1, 2, 3 and non-CEV, as well as 1-2 vs. 3+ comorbidities). A chart review study was undertaken to exclude hospitalized patients who were incidentally diagnosed but did not require hospitallevel care for severe or critical COVID-19, which comprised 60% of all cases. These thermal maps can continue to be used to guide clinical decision making and assessing risk vs. benefit of therapy. There are various limitations of this study, including inability to capture patients who did not pursue testing or asymptomatic patients, and excluding those few who received therapies such as sotrovimab. Despite this, this study represents one of the best-available risk models in Canada and is used by other jurisdictions such as Ontario, and groups such as CADTH.
# Ongoing Validity of Risk Models
As BC risk models and thermal maps were developed during the first wave of Omicron (BA. 1), questions have emerged regarding the ongoing validity of this analysis in the BA. 2 and BA. 5 waves of Omicron. There is a notion that most BC residents have had COVID-19, yet hospitalizations have remained low, hence the risk is overestimated in the thermal maps. However, while the analysis cannot be redone due to an inability to identify test-positive patients who self-test via rapid antigen tests, various experts agree that this analysis remains a valid risk assessment useful for therapy eligibility for the following reasons:
- Wastewater surveillance data has indicated that there has been no other 5-week period, including during the April and June waves, where the number of people infected with COVID-19 had been substantially higher (and would thus greatly increase the denominator), than in the January-February study period. As hospitalizations after testing positive for SARS-COV-2 have remained stable over the last 9 months and through the April and June waves, the risk of hospitalization is likely also stable and still reflected by these thermal maps.
- Infection rates with the Omicron variant, which would increase the denominator in these models, have also been relatively infrequent in populations that are eligible for treatment in BC, namely the CEV populations and the elderly. For example, data from the Canadian Blood Services show that while nearly 80% of younger BC residents have contracted COVID-19, that rate is only about 40% in those over the age of 65. Similar trends have been observed in the UK.
- Real world data from jurisdictions that record rapid antigen test results, such as Israel, have not indicated a change in hospitalization risk in untreated patients throughout the various Omicron waves. For example, a large retrospective study from Israel that used a point system to identify patients eligible for treatment showed that untreated patients who have an ~2% risk of hospitalization have a combination of risk factors that would lead to the same risk estimate using BC thermal maps.
- While hybrid immunity (from vaccination and infection) has been shown to reduce the rate of reinfection with Omicron, it has not shown to reduce the risk of hospitalization beyond the high vaccine effectiveness against hospitalization conferred by vaccination alone. As such, even if a high proportion of BC's population has hybrid immunity, there is no strong data to support an adjustment of their hospitalization risk in these thermal maps by any factor.
# Testing
BC is continuing to rely on the federally acquired rapid antigen tests available at pharmacies. As this program comes to a gradual end, the testing strategy in BC will change, and this guideline will be updated to reflect this. Symptomatic patients are more likely to have a true positive RAT over those without symptoms Performing a test on day 3 or later since symptom onset as opposed to on days 1 or 2 Having higher viral loads, as seen in patients who have greater vaccine escape, are more symptomatic or are 48 hours or more into their illness Performing serial RATs at regular intervals (e.g., every 24-48 hours).
Various studies have evaluated serial RATs in symptomatic patients for their diagnostic accuracy. The largest study to-date, the Test Us at Home trial, showed that in patients who were pre-symptomatic but went on to develop symptoms of COVID-19, performing a self-administered RAT three times over a 48 hour interval produced an aggregate sensitivity of 93.4% (95% CI: 89.1-96.1%). Testing once on the day symptoms appeared had a sensitivity of 59.6%, which increased to 92.3% after a single repeated test (total of 2 tests within a 48-hour period). Testing asymptomatic patients, even in a serial fashion produced a sensitivity of 56.4%. This study has led to an FDA Guidance Update to recommend serial RAT testing for all symptomatic individuals as the optimal testing strategy to ensure maximum sensitivity. To ensure the quickest diagnosis possible through retesting considering the 5-day treatment window, the CTC and the Province recommend retesting 24 hours after a negative RAT, as opposed to a longer interval between tests.
# Testing and Treatment Evidence
There are currently no studies that compare the impact of different testing strategies (RAT vs. PCR) on treatment outcomes (e.g., hospitalization or death). While a positive PCR test is often a part of the inclusion criteria of randomized controlled trials of COVID-19 therapeutics, most real-world studies describe a mainly RAT-based approach through which COVID-19 was diagnosed and treated. As long as patients initiate treatment within the treatment window (5 days for nirmatrelvir/ritonavir and 7 days for remdesivir) landmark trials of nirmatrelvir/ritonavir and remdesivir show no difference in treatment outcomes based on the day the patient started therapy. For example, patients who started nirmatrelvir/ritonavir within 3 days of symptom onset had the same reduction in hospitalization as patients who initiate treatment within 5 days (0.7% vs. 6.5% and 0.8% vs. 6.3%). Very few patients initiate treatment on the first day of symptom onset where PCR testing may have a sensitivity advantage over a single RAT test.
# Practical Considerations for assessing validity of a Rapid Antigen Test:
-Ensure the test was done recently and that it is in fact positive -For patients who test positive via a RAT, verify how the test was done and how did the result present.
-While RATs have excellent clinical specificity as they are unlikely to pick up SARS-COV-2 virus in those who have recently recovered from COVID, are chronic shedders or have subclinical viral loads, false positives can occur. Potential causes for false positive results may include other respiratory viruses and reactions with certain foods or liquids. -The pre-test likelihood of COVID-19 infection may be influenced by known contact with COVID-19 cases, symptoms compatible with COVID-19, and the prevalence of disease in the community. The table below provides the positive predictive value for a single RAT test with 98% specificity and 80% sensitivity (similar to most RATs performed in symptomatic patients) for a range of pre-test probability of infection from 0.01 to 0.15. Epidemiologically linked cases (e.g., household contacts of those who test positive) who have not been confirmed via COVID-19 testing should not be offered treatment.
# Pre-test probability of infection
Indications for a PCR Test PCR testing will continue to be performed on patients within acute care settings, including hospitalized patients and those presenting to the emergency department, or to investigate an outbreak. PCR is required for genomic characterization of the virus (aka Variants of Concern typing) for surveillance purposes which also informs the activity of monoclonal antibody treatments. PCR is also used when there is a need to diagnose influenza (these tests are done together).
For patients who live in a rural, remote or Indigenous communities, the health care provider may suggest PCR-based testing, or other investigations based on their clinical evaluation. Offering PCR-based COVID-19 testing or more comprehensive clinical investigation might be appropriate due to barriers in accessing health services Indigenous people might experience, such as geographical remoteness or systemic racism. For full guidance on Testing in Remote, Rural and Indigenous Communities, click here.
PCR testing may also be ordered in the community for treatment purposes at the discretion of the primary care provider. Scenarios where PCR testing may be appropriate include:
- High-risk patients (≥ 5% risk of progression to severe disease) who test negative despite serial RATs Patients with a very high-level of suspicion (e.g., symptomatic with a household contact) who test negative despite serial RATs Patients in whom therapy was initiated despite a negative RAT(s) to ensure a diagnosis of COVID-19 Patients who have symptoms of severe disease who will have COVID-19 therapy (e.g., supplemental oxygen, dexamethasone) delivered outside of an acute care setting A non-reassuring presentation is clinical status that poses concern to the health care provider. For example, a CEV-1 cancer patient may only have a low-grade fever; however, this is non-reassuring to their oncology team.
Illness trajectory is a useful in establishing progression of COVID-19. Patients who are visibly deteriorating are more likely to become severely ill. Treatment is unlikely to benefit those who are mildly ill who are clearly improving on their own. Treatment should not be given to asymptomatic or minimally symptomatic patients.
# Symptom Window
Symptom windows vary with each therapeutic agent and follow study inclusion criteria. Remdesivir should be given within 7 days of symptom onset whereas for oral antivirals should be given within 5 days. It is appropriate to allow the addition of adequate time for drug delivery of medication for those living in remote and rural communities. Patients who are in the ≥5% risk category who have passed the 5-day but are within the 7-day treatment window and would be referred for remdesivir solely based on its longer treatment window can be prescribed nitmatrelvir/ritonavir within 7 days of symptom onset.
In clinical trials, viral loads decreased from the nasopharynx by 1000's-fold during treatment regardless of the receipt of an active treatment or placebo. Furthermore, most patients produced their own antibodies shortly after becoming infected and exogenous antibodies do not confer additional benefit. There is little clinical rationale for extending the treatment window past 7 days.
Patients who have had prolonged symptoms or more or protracted illness despite recently testing positive for COVID-19 may require a clinical assessment of the illness trajectory to rule out other causes responsible for their symptoms. Patients are encouraged to get tested as soon as possible after COVID symptoms appear to avoid conflating persistent symptoms with COVID-19 infection.
# Hospitalized Patients
Patients who are hospitalized for other reasons and are mildly-moderately ill with COVID-19 can be considered for treatment if they meet the eligibility criteria. Many patients admitted to hospital are incidentally diagnosed or are part of nosocomial outbreaks and are offered testing with very low thresholds that often does not warrant treatment. As with all mild-moderately ill patients offered treatment, patients in hospital need to be appreciably symptomatic, have a valid COVID-19 test, be assessed for contraindications and drug-drug interactions, and offered treatment on the basis of their risk of progression to severe disease. Even though patients are already hospitalized, the goal of such therapy is still progression of COVID-19 to require hospital-level care for COVID-19, namely supplemental oxygen, steroids and baricitinib.
The treatment guidance in this guide applies equally to all patients regardless of their location, including hospitalized patients.
# Contraindications
Nirmatrelvir/ritonavir should not be used in end-stage liver disease (Child-Pugh C). In patients with hepatitis B and C, or HIV infection regardless of treatment status may benefit from Specialist Consultation (e.g., Infectious Diseases, HIV Specialist), but treatment should not be withheld or delayed due to these conditions. Many drug-drug interactions contraindicate the co-administration of nirmatrelvir-ritonavir, but some can be held or managed. Contraindicated drugs include amiodarone, apixaban and rivaroxaban, certain antipsychotics like clozapine, midazolam and triazolam, as well as illicit drugs especially fentanyl and methamphetamine (see Practice Tool #3: Drug Interactions and Contraindications). Patients with hypersensitivity to ritonavir or other protease inhibitors should not be prescribed nirmatrelvir/ritonavir. Drug interactions must be verified and a management plan in place before prescribing. If drug-drug interactions pose safety concerns, treatment can be forgone, especially in those who have a very slightly increased risk of hospitalization.
Nirmatrelvir/ritonavir has not been clinically evaluated in patients with eGFRs < 30ml/min, although pharmacokinetic studies show that it is not nephrotoxic and can likely be adjusted accordingly in those with end-stage renal disease or on dialysis. The manufacturer is currently conducting a small trial in patients with eGFRs less than 30ml/min and safety and efficacy data are forthcoming. At this time, according to nephrology experts in BC, nirmatrelvir/ritonavir is thought to have a limited role in patients with end-stage renal disease due to the extensive number of drug-drug interactions such patients experience and not because of renal disease itself. However, the drug is not thought to be dangerous in such patients, and a lack of a recent serum creatinine should not contraindicate or delay its administration. Patients without known renal disease can be prescribed full dose nirmatrelvir/ritonavir, and in those with reduced renal function, the most recent SCr can be used to guide treatment decisions. Boarder-line eGFR (e.g., 28ml/min) should be assessed using clinical judgement and does not usually contraindicate prescribing dose-reduced nirmatrelvir/ritonavir 150mg/100mg PO BID.
Remdesivir is contraindicated in those with demonstrated hypersensitivity to the product or any of its ingredients. While the monograph states that there are no data to support its use in eGFR 1000 patients conducted by Gilead support its safety in this population. (For a full operational review of remdesivir, including renal dosing, consult your health authority to obtain the CTC and CTRAWG memo regarding remdesivir operationalization). Remdesivir should not be used in patients with ALT ≥5 times the ULN. The pharmacokinetics and safety of remdesivir in hepatic impairment have not been evaluated; expert consultation is recommended. While pregnancy and paediatric considerations are not part of the Canadian labelling, remdesivir has approval for children age ≥ 12 years weighing ≥ 40kgs in the US and has been given to pregnant women in independent studies. Specialty consultation is recommended for these populations.
Monoclonal antibodies like sotrovimab and tixagevimab/cilgavimab can cause hypersensitivity reactions and infusion/injection reactions, although they are rare.
Molnupiravir contraindications are not well articulated as the Canadian Monograph has not been published due to lack of Health Canada approval. This will be updated when known. Based on FDA data, molnupiravir will be contraindicated in pregnancy, breastfeeding, in those trying to conceive and in pediatrics.
# Pregnancy, Breastfeeding and Pre-Conception
Pregnancy is a risk factor for hospitalization and pregnant women have 3 times the odds of hospitalization in BC compared to age-matched non-pregnant women. Vaccination in this population is also lower than agematched cohorts. However, pregnant persons are young, and most do not have co-morbidities; as such the absolute risk of hospitalization in a pregnant person is still below the treatment threshold.
Currently available therapies have not been evaluated in pregnancy or breastfeeding. The Reproductive Infectious Disease and Maternal Fetal Medicine COVID-19 working group would potentially consider remdesivir for use in pregnant or breastfeeding women if they otherwise meet the above-mentioned treatment criteria (e.g., immunocompromise or unvaccinated). Nirmatrelvir/ritonavir may also be acceptable due to familiarity and comfort with prescribing protease inhibitors to this population. Sotrovimab is considered safe; however, this needs to be balanced against a potential loss of activity. Animal studies have not demonstrated a significant risk to the fetus from all three drugs. Prescribers may consult Reproductive Infectious Disease on call at BCCW if prescribing COVID-19 therapy, especially nirmatrelvir/ritonavir in pregnancy in high-risk women, or for advice during breastfeeding.
Molnupiravir has been found to negatively impact fertility, embryonic development and pregnancy outcomes in animal studies and is contraindicated in pregnancy or in those with childbearing potential unable or unwilling to use protection.
It is unknown whether COVID-19 therapies impact fertility. Patients are encouraged to use protection while taking these medications. Those who are on oral contraceptives should use a back-up method when taking nirmatrelvir/r due to drug interactions leading to lower plasma levels of estrogen, decreasing its efficacy in preventing pregnancy.
# Pediatrics
Nirmatrelvir/ritonavir is not approved for pediatric use, and remdesivir is not approved in children with mildmoderate COVID-19 in Canada (but is in the US). Sotrovimab has pediatric approval but has significant loss of neutralization capacity against BA.2 and may not be appropriate in very high-risk children. The following statement regarding pediatric therapy has been developed in collaboration with experts from BCCH:
Pediatric patients with immune compromise are generally considered to be at lower risk of developing severe COVID-19 illness and requiring hospitalizations compared to adults with immune compromise. Risk of severe COVID disease in immunocompromised children appears to be related to underlying comorbidities rather than immune suppression itself. Immunocompromised children may present with atypical signs and symptoms of COVID-19 that can fluctuate rapidly between being asymptomatic to having mild to moderate symptoms and vice versa. Information on COVID-19 vaccine immunogenicity in children with immune compromise is currently limited.
In consultation with pediatric infectious diseases and appropriate subspecialist, treatment with should be considered for COVID 19 positive immunosuppressed children 12 years of older and minimum 40kg with mild to moderate COVID-19 symptoms not requiring hospitalization who are:
- Solid organ transplant recipients Hematopoietic stem cell/bone marrow transplant recipients within the past 2 years and/or are currently receiving immunosuppression Immunosuppressed due to primary immunodeficiency or due to iatrogenic causes Have been otherwise classified as extremely clinically vulnerable due to immunosuppression (CEV 1 or 2)
# AND
- Have another major chronic condition/comorbidity putting then at risk of severe COVID-19, especially significant lung disease (e.g., lung transplant recipients, lung GVHD, obstructive lung disease). Being unvaccinated or partially vaccinated is a risk factor for severe COVID-19 disease, bearing in mind that some fully vaccinated children with immune compromise also may not generate vaccine immune response.
The choice of agent will depend on an individualized risk-benefit assessment of the available therapies.
Children with immune compromise and no major comorbidities are unlikely to develop severe COVID-19 disease. The benefit of providing treatment in these cases is likely very small.
Ultimately, decisions around the use of remdesivir or sotrovimab should be made on a case-by-case basis, weighing lack of RCT-level data in children, off-label use and the potential benefit of treatment. Clinicians are encouraged to discuss cases with the Pediatric Infectious Diseases physician on call at BC Children's hospital. If IV therapy is being pursued, infusions can be arranged at BC Children's hospital through the patient's BC Children's Main Responsible Physician/Service, as per hospital protocol. For those patients outside the vicinity of BC Children's hospital, arrangements will need to be made through the local health authority at an available infusion site.
# Drug-Drug Interactions
Nirmatrelvir and ritonavir have significant drug-drug interactions, many of which contraindicate its use. Nirmatrelvir and ritonavir are potent inhibitors of CYP 3A4 and increase the concentration of many drugs metabolized by this enzyme. Nirmatrelvir/ritonavir is also contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.
Some drug-drug interactions can be managed. For a comprehensive list of drug-drug interactions and management strategies see Practice Tool #3: Drug Interactions and Contraindications.
# The most comprehensive resource for DDI assessment with nirmatrelvir/ritonavir is available from the University of Liverpool at .
Remdesivir has no DDIs that contraindicate its treatment, except for chloroquine and hydroxychloroquine which may reduce its antiviral efficacy. Strong CYP 3A4 inducers (e.g., phenytoin, rifampin, carbamazepine) may decrease the serum level of remdesivir but the clinical relevance of this interaction is not known.
Sotrovimab and tixagevimab/cilgavimab pose no significant drug-drug interactions.
# Dosing
Nirmatrelvir/ritonavir is dosed at nirmatrelvir/ritonavir 300/100mg PO BID x 5 days for those with eGFR > 60 ml/min. It is supplied as a pre-packaged kit containing both products: 2 tablets of nirmatrelvir 150mg and 1 tablet of ritonavir 100mg per dose. The patient takes 3 tablets per dose, for a total of 30 tablets during the treatment course.
Patients with an eGFR of 30-60 ml/min should take nirmatrelvir/ritonavir 150/100mg PO BID x 5 days, or one nirmatrelvir 150mg tablet and one ritonavir 100mg tablet per dose. The second nirmatrelvir tablet should be removed from the kit from each dose by the dispensing pharmacist for the patient to avoid confusion and diversion.
# Renal Dosing of nirmatrelvir/ritonavir
Remdesivir for mild-moderate COVID-19 in patients with an eGFR ≥ 30ml/min is dosed with a loading dose of 200mg IV on day 1, followed by 100mg IV on days 2 and 3. This dose differs from its dose in the monograph for severe COVID-19 infection. Each vial contains remdesivir 100mg for a total of 4 vials per full treatment course. There is no dose adjustment required for obesity or mild-moderate renal or liver impairment. Patients with renal disease who have an eGFR <30 ml/min can safely receive standard dosing; however based on known PK and limited clinical data, renal and COVID experts in BC agree that a renally adjusted dosing can be used to optimize operationalizing administration of infusions. Such patients can receive 200mg IV on day 1, followed by 100mg IV 48 hours later. Patients on hemodialysis can receive their dose during dialysis, and can receive their second dose 48-72 hours later depending on their hemodialysis schedule.
Sotrovimab is dosed at 500mg IV x 1 dose infused over 60 minutes. The manufacturer is currently evaluating the in-vivo efficacy of a 1000mg dose against different variant of concern, as such dose is likely to overcome the reduced neutralization capacity. A regulatory decision regarding the approval of this dose is forthcoming.
There are no dose adjustments required for obesity or mild-moderate renal or liver impairment. The drug is not recommended for IM use.
Tixagevimab/cilgavimab for treatment is dosed at 600mg, 300mg of each tixagevimab and cilgavimab. The two antibodies are supplied separately and are injected intramuscularly into the gluteal muscles as four 1.5mL IM injections (two 1.5mL injections each mAb). There are no dose adjustments for renal or liver impairment.
# Patient Location
Patients with mild to moderate COVID-19 are usually outpatients recovering at home. However, many patients hospitalized for non-COVID reasons can also be offered treatment (see Hospitalized Patients above).
Patients in Long-Term Care are eligible for treatment if they meet criteria, with an understanding that IV therapeutics cannot be administered easily in LTC settings. Patients may also be offered treatment in Emergency Departments. This guidance is not specific to any particular patient location.
This guide does not specify priority for patients in remote or rural areas; CTRAWG (a committee responsible for equitable distribution of scarce drug resources) may prioritize different geographical areas if needed. Additional time added to the patient's symptom window is clinically acceptable for drug transport to remote and rural areas.
# Clinical Judgement
This guide should not replace clinical judgement. Patients who are technically eligible for treatment may not be good candidates due to clinical status, goals of care, or willingness to provide consent for treatment. These factors need to be considered with each patient assessment.
The current eligibility criteria are conservative, and the absolute risk of hospitalization depicted in thermal maps is overestimated due to a testing bias. There should be very few patients who have a risk of <3% who should be offered treatment and are not captured in this guide; however, such decisions are again deferred to the treating clinician.
# Rebounds, Re-infections and Retreatment
Rebounds A rebound, also knowns as a relapse, is defined as a COVID-19 infection which was treated (mainly with nirmatrelvir/ritonavir) where there was proven clearance of the SARS-COV-2 virus by a negative test and symptom improvement, but where symptoms then returned or worsened, followed by a subsequent positive SARS-COV-2 test. Rebounds are not frequently diagnosed because current guidance does not recommend a test of cure, especially since patients can shed virus for weeks after recovery and have an undulating symptom trajectory. It has been speculated that treatment with nirmatrelvir/ritonavir causes rebounds because it suppresses virus beyond detectable levels without complete clearance, and once the 5-day course is completed, the virus begins to replicate again, causing a rebound of illness. However, rebounds have since been shown to occur irrespective of whether treatment is given or not and are estimated to affect approximately 2% of patients. In a recent meta-analysis, the overall OR of rebound among COVID-19 patients taking nirmatrelvir/ritonavir vs. control group was 0.99 (95% CI, 0.28-3.57; p=0.99), showing no association between treatment and rebounds. Patients with COVID-19 should be counselled that rebounds may occur but are not linked to treatment, and post-treatment testing or test of cure should be discouraged.
# Re-infections
Re-infection is defined as a COVID-19 infection after complete recovery from a prior infection and usually occurs with a different variant of concern. Re-infections in BC have been documented by PCR as early as 8 weeks prior to the original infection and became common during the Omicron waves despite the protection previous infection confers. Studies show that re-infection rates in a highly vaccinated population are highest in the 18-29-year-olds (~15%) and about 10% in the general population.
# Retreatment
The CDC does not recommend routine re-treatments of rebounds. Rebounds have been shown to be generally milder than the index infection, and symptoms resolve quickly without re-treatment. Case series of rebounds, however, have been in already low risk individuals who would not have been eligible for treatment in BC. The CTC recommends that patients who meet treatment eligibility and rebound be reassessed on the basis of their symptoms and symptom trajectory. Those with symptoms that are milder than the initial infection or those that are improving rapidly should not be offered re-treatment. Retreatment with nirmatrelvir/ritonavir can be considered in those who have significant symptoms or rapidly progressing illness. Another 5-day course should be used; there is no evidence that supports longer courses of treatment, although a 10-day course is currently being investigated by the manufacturer.
Re-infections should be assessed and treated as new infections. Patients' eligibility criteria should be reassessed, and risk re-calculated considering previous infection in the risk scoring. Symptoms and symptom trajectory should continue to play a key role in determining whether another course of treatment is offered.
So far, a few dozen patients in BC have received more than one course of nirmatrelvir/ritonavir. There have been no observable differences in outcomes between the first vs. the second course of nirmatrelvir/ritonavir, although a significant survival bias exists.
# SUPPORTING EVIDENCE
# Summary of Trials
# Nirmatrelvir/ritonavir
Nirmatrelvir is a protease inhibitor with a 2-hour half-life; it is co-administered with ritonavir to allow BID dosing. The landmark trial of nirmatrelvir/ritonavir has been published in the NEJM in February 2022.
EPIC-HR was a randomized double-blind placebo-controlled trial:
- 2246 adult outpatients with mild-moderate COVID-19 who were enrolled o Patients had to be within 5 days or less of symptom onset o Patients included had to be unvaccinated and at increased risk of developing severe disease, defined as age 60 or older or having a chronic condition such as diabetes, heart condition or chronic kidney disease o The mean age of patients in the trial was 47; most had a single co-morbidity, the most common of which was smoking o Patients were randomized in a 1:1 fashion to receive nirmatrelvir/ritonavir or placebo o The primary endpoint was COVID-19-related hospitalization (not all-cause), or death from any cause. o The primary endpoint occurred in 66/1064 (6.3%) patients given placebo vs. 8/1039 (0.8%) patients randomized to active treatment for a relative risk reduction of 88%, an absolute risk reduction of 5.5% and an NNT of 18. o A high-risk subgroup of ~200 patients was analysed (those over 65 with more risk factors). This group, which is similar to the patients prioritized for treatment in this guide, experienced a nearly 15% absolute risk reduction in COVID-19 hospitalization (16.3% vs. 1%, p<0.001). o Side effects that were drug-related included diarrhea, nausea, dysgeusia, muscle aches and hypertension. The rate of drug related ADRs was 7.8% in the treatment arm vs. 3.8% in the placebo arm, for a NNH with one side effect of 25.
Based on these data, nirmatrelvir/ritonavir is given a AIIa recommendation by the NIH and a conditional recommendation by the IDSA to suggest treatment over no treatment.
Another RCT was also conducted by the manufacturer of nirmatrelvir/, but it remains unpublished, likely because it was negative.
# Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR), unpublished
- This was a randomized, double-blind, placebo-controlled trial conducted by Pfizer. o 1411 standard-risk individuals were randomized between August 2021 -February 2022 to receive nirmatrelvir/ritonavir or placebo within 5 days of symptom onset. o Patients had to be at "standard risk" of hospitalization and death from COVID-19, meaning having a single risk factor such as age 65 or older, a single chronic condition, or lack of vaccination in younger individuals. Most patients were infected with the Delta variant of concern. o There was no difference seen in the primary endpoint of time to sustained symptom alleviation, which was defined as the absence of key COVID-19 symptoms for 4 consecutive days. o There was also no difference in hospitalization due to COVID-19 or all-cause mortality (0.9% vs.1.8%, p=0.187).
The secondary endpoint of hospitalization and mortality was close to reaching statistical significance at the interim analysis, where the event rate in the placebo arm was 2.4%. However, due to the emergence of Omicron, the event rate in the placebo and treatment arms dropped to nearly zero, and recruitment stopped.
# Real World Evidence
Various observational studies characterize the association of nirmatrelvir/ritonavir and hospitalization related to COVID-19. A detailed overview of studies that support these recommendations is presented here. While nirmatrelvir/ritonavir tends to be associated with a reduction in hospitalizations, the populations in these studies vary greatly depending on who is eligible to receive nirmatrelvir/ritonavir in that jurisdiction and to whom the drug is ultimately dispensed. Patients represented in observational studies are generally high-risk individuals with a hospitalization rate well above 3%. Various sub-group analyses show that while, on average, patients seem to benefit from treatment, the benefit is very strongly driven by high-risk individuals, who experience higher absolute risk reductions, with low-risk individuals seeing no reduction in their already low rates of hospitalization/mortality from COVID-19.
The literature is consistent in showing that hospitalization/mortality among treated individuals with risk factors does not generally drop below 1%. BC data also show that ~1% of patients experience serious adverse effects and that the safety concerns are likely to outweigh a potential benefit in patients who have a risk of hospitalization from COVID-19 of less than 1%. Literature is also clear that that risk factors such as age, vaccination status and comorbid conditions continue to be associated with both a higher risk of hospitalization from COVID-19 and a greater likelihood of benefit. Lastly, subgroup analyses show that patients, except for those who are immunocompromised, need more than one risk factor to attain a risk of hospitalization of >1% and derive a benefit from nirmatrelvir/ritonavir. Groups of patients with a single risk factor, for example age over 65 without under-immunization or chronic conditions have been shown not to benefit from nirmatrelvir/ritonavir. A more detailed summary of studies used to support these recommendations is found in Table 1. Studies that report outcomes in duplicate from the same data sets have been omitted. In short: This was a retrospective, population-based cohort study from Israel conducted during the Omicron wave.
Patients were eligible to receive nirmatrelvir/ritonavir if they scored 2 points or more on a scoring system -age over 65 was given 2 points, most chronic conditions were given 1 point and un-vaccination was given 9 points. 3,902 nirmatrelvir/ritonavir recipients were compared to 105,352 nirmatrelvir/ritonavir nonrecipients for the primary endpoint of hospitalization and death in the 30 days of testing positive. The overall event rate in the study was very low (<1%). Those who has a higher risk of hospitalization/death (those 65 and older) saw a statistically significant benefit from nirmatrelvir/ritonavir (59 events / 100,000 patient days vs. 15 events / 100,000 patient days), whereas lower-risk individuals did not. Within those 65 and older, the benefit was driven by higher risk individuals such as those with immunosuppression (HR 2.23), cancer (HR 2.17), renal failure (HR 2.88), neurological disease (HR 2.01), COPD and diabetes (HR 1.5).
All other elderly with less severe comorbidities such as smoking, obesity and TIA did not derive a benefit from nirmatrelvir/ritonavir.
# Yip et. al. Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalization in Community Coronavirus Disease 2019 Patients (COVID-19), Clinical Infectious Diseases
This was a study of approximately 15,000 patients from China during the BA. 2 wave of Omicron. Those who received nirmatrelvir/ritonavir were compared to those who received standard of care for the primary endpoint of hospital admission in the 30 days after testing positive. Patients in the study had a median age of ~75 years old, 58% did not receive a primary vaccine series and most had multiple comorbidities, with 1/3 having a diagnosis of diabetes. Incidence of hospitalization was lower in nirmatrelvir/ritonavir users than in those receiving standard of care (3.5% vs. 1.6%). The high event rate was attributed to a large number of risk factors in the study population who was offered treatment. The largest cohort study (750,000 individuals) from the US where nirmatrelvir/ritonavir recipients were compared to those who did not receive nirmatrelvir/ritonavir. Overall, there was a statistically significant reduction in hospitalization due to COVID-19 (0.47% vs. 0.86%); however, there were many subgroups that did not benefit from treatment, including those with 3 or more mRNA vaccine doses and those with 1 or no underlying health care conditions. Elderly patients were more likely to benefit, but those with no underlying health conditions saw no benefit from treatment, and their hospitalization rate was below 0.5% in both groups. In this cohort study, patients were eligible for nirmatrelvir/ritonavir in QC if they did not receive a primary series of COVID-19 vaccination, or if they were immunocompromised. Those over 70 could receive nirmatrelvir/ritonavir if fully vaccinated in rare cases at the discretion of the prescriber. Overall, there was a benefit from nirmatrelvir/ritonavir (3.56% vs. 11.5%) in the primary endpoint of COVID-associated hospitalization; however, those fully vaccinated did not benefit (7.53% vs. 8.43% p=0.321) from treatment.
Most elderly in this study (76%) did not receive a primary vaccine series and those who received a vaccine dose in the last 6 months derived no benefit from nirmatrelvir/ritonavir (11.6% vs. 13%). The high rate of event was attributed to the fact that most patients in the study were unvaccinated.
- Therapeutics Initiative: Paxlovid in British Columbia -an interim real-world analysis. TI Letter
This study was conducted in collaboration with the Therapeutics Initiative where groups of nirmatrelvir/ritonavir recipients (CEV 1, CEV 2, CEV 3 and non-CEV patients) and compared to nonrecipients for the primary endpoint of all-cause hospitalization and mortality. Statistically significant differences were seen in the CEV 1 and CEV 3 populations, for a risk reduction of approximately 50%; CEV 2 patients experienced a reduction but it did not reach statistical significance. Importantly, those who were non-CEV experienced a higher, albeit non-statistically significant event rate after taking nirmatrelvir/ritonavir than non-recipients (1.9% vs. 1%). Non-CEV patients who were offered nirmatrelvir/ritonavir were in general those with multiple risk factors such as age, lack of optimal vaccination and 3 or more comorbidities.
Nirmatrelvir/ritonavir for symptom relief or to prevent Long COVID Other potential benefits of nirmatrelvir/ritonavir have thus far not been consistently shown in the literature.
As demonstrated by EPIC-SR, nirmatrelvir/ritonavir has no impact on the time to symptom alleviation.
Another study of a novel compound VV116 vs. nirmatrelvir/ritonavir in symptom resolution showed that on average, patients had 5.5. days of symptoms irrespective of the drug they took, and that was virtually identical to an observational cohort of patients from the same region in the same time period. The impact of nirmatrelvir/ritonavir on post-COVID condition, or long COVID, is also inconsistent. For example, a recent study from California showed that nirmatrelvir/ritonavir takers experienced a slightly higher, non-statistically significant rate of post-COVID condition based on self-reports, whereas a study published by the Lancet claimed to observe a benefit in treated patients when ICD-10 codes for non-specific conditions such as diabetes, arrhythmia and shortness of breath were taken to represent development of post-COVID condition.
# Remdesivir
Remdesivir is an intravenous antiviral initially evaluated in severely ill inpatients with COVID-19 requiring oxygen support in a landmark trial ACTT-1. It was approved by Health Canada for this indication, and some nationally procured supply remains unused due to subsequent data showing its lack of impact on meaningful outcomes in the severely ill population.
In December 2021, a trial called PINETREE was published:
- The trial evaluated remdesivir in 562 mildly-moderately ill outpatients o Patients were randomized to receive remdesivir 200mg IV on day 1, followed by 100mg on days 2 and 3 or placebo and evaluated in a double-blind fashion o Patients were included if they presented within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions) o The trial was stopped when only 45% of the planned population was recruited due to widespread use of vaccination and the availability of proven treatments making randomization to placebo ethically challenging o The primary outcome was COVID-19-related hospitalization or death from any cause o 2 of 279 patients (0.7%) in the remdesivir group and in 15/283 (5.3%) in the placebo group met the primary endpoint, p=0.008. o This equated to an 87% relative risk reduction, a 4.6% ARR and a NNT of 22, which is slightly higher than nirmatrelvir/ritonavir or sotrovimab (17 and 20, respectively). o A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a COVID-19-related medically attended visit by day 28 an no patients died by day 28. o Remdesivir was generally well tolerated; transaminases may need to be monitored in patients with baseline elevations of liver enzymes. Remdesivir has been given to patients with renal disease with and without dose adjustments; however, it was not evaluated in this trial and this population is excluded from Canadian labelling.
Remdesivir has the advantage of having few drug interactions while maintain comparable risk reductions to nirmatrelvir/ritonavir. However, the 3-day IV dosing regimen is difficult to administer, and the CTC recommends that it be used if nirmatrelvir/ritonavir cannot be prescribed only in the highest-risk population (patients with a ≥ 5% risk of hospitalization from Omicron). The NIH recommends remdesivir as an alternative to nirmatrelvir/ritonavir with a Grade BII rating. The IDSA suggests remdesivir with a conditional rating and low certainty evidence.
# Sotrovimab:
Sotrovimab has been evaluated in a single peer-reviewed, double blind, randomized-placebo controlled trial (COMET-ICE):
- 1057 patients with mild symptoms of COVID-19 and at least one risk factor for disease progression were included o Patients were randomized to receive a single dose of sotrovimab 500mg IV compared to placeb o Most patients were younger (24 hours or death within 29 days of the receipt of the infusion o Out of the 528 patients who received sotrovimab, 6 met the primary endpoint of hospitalization or death vs.
30 of the 529 who received placebo (1% vs. 6%; p<0.001; ARR=5%, NNT=20). There were only 2 deaths observed (placebo arm); the primary endpoint was driven entirely by hospitalizations. o Hospitalizations were consistent with progressive COVID-19 requiting oxygen support and hospital-level care; only 1 hospitalization was not COVID-related o Secondary outcome results demonstrated that sotrovimab significantly reduced progression to severe/critical respiratory COVID-19 compared with placebo (1 vs. 5% p=0.002) o Sotrovimab did not reduce length of stay or ICU-bed-days o The proportion of patients reporting adverse events was similar between treatment groups; sotrovimab was well tolerated, and no safety concerns were identified; 6 patients in each placebo and sotrovimab groups experienced mild to moderate infusion reactions.
The COMET-ICE trial was well conducted, with a high degree of generalizability posing no major concerns during critical appraisal. Sotrovimab is given a positive conditional recommendation by the Infectious Diseases Society of America and a Grade AIIa recommendations supporting its use by the NIH.
# Tixagevimab/cilgavimab
Tixagevimab/cilgavimab is a long-acting monoclonal antibody cocktail initially approved in Canada for the prevention of COVID-19 in those who are unlikely to mount an adequate immune response to COVID-19 vaccination or in whom such vaccination is contraindicated.
Tixagevimab/cilgavimab was also evaluated for treatment in a double-blind placebo-controlled trial called TACKLE:
- 910 unvaccinated patients with mild-moderate COVID-19 presenting within 7 days of symptom onset were assigned in a 1:1 fashion to received tixagevimab/cilgavimab 600mg IM x 1 dose or placebo o The primary endpoint was COVID-19 hospitalization or death from any cause through day 29 o The median age of participants was 46.1 years; 90% were at high risk of progression of COVID-19 defined as age over 65 or presence of a comorbidity. The most commonly occurring comorbidities were obesity, smoking and hypertension o Out of the 415 patients who received placebo, 37 (9%) met the primary outcome vs. 18/407 (4%) in the tixagevimab/cilgavimab arm for an adjusted relative risk reduction of 50.5% ; p=0.0096 o The absolute risk reduction was 4.5% (95% CI 1.1-8.0; p<00001), for a number needed to treat of 22 o Tixagevimab/cilgavimab was generally well tolerated and no differences between it and placebo were observed (29% vs. 36%) o There was one myocardial infraction and one sudden cardiac death, both in the tixagevimab/cilgavimab arm Overall, the TACKLE trial, which was carried out mainly during the delta wave and was similar to trials of nirmatrelvir/ritonavir, remdesivir and sotrovimab, demonstrated a lower relative risk reduction than those agents, despite the baseline hospitalization rate being slightly higher.
# Molnupiravir
Molnupiravir is a nucleotide analogue which when incorporated into viral RNA causes base-pair mismatch leading to mutations and viral catastrophe. The mechanism of action of the drug has been scrutinized by regulators for the theoretical fear of promoting emergence of variants of concern due to promoting mutations as well as reproductive safety.
Molnupiravir was evaluated by a randomized, double-blind placebo-controlled trial called MOVe-Out: o 1408 outpatients with mild-moderate COVID-19 presenting within 5 days of symptom onset were assigned in a 1:1 fashion to receive molnupiravir 800mg PO BID x 5 days or placebo o The primary endpoint was all cause hospitalization or mortality within 29 days o The trial stopped when a pre-planned interim analysis revealed that it met the primary endpoint with a 50% relative risk reduction and a p value (set at p20%) that were apparent in countries like Brazil, whereas higher income countries like the US had no appreciable reductions in hospitalization resulting from the effects of the drug.
Molnupiravir carries the advantage of having few or no drug-drug interactions and is not impacted by renal or liver disease. Such details, however, are not currently available as the drug is undergoing evaluation by Health Canada and the monograph has not been issued in Canada.
# Repurposed Therapies
The CTC has evaluated various other therapies that are not routinely recommended, including colchicine and the abovementioned SSRI fluvoxamine.
In short, Colchicine was evaluated at 0.6 mg PO BID x 3 days, then 0.6 mg daily x 27 days in a single large Canadian RCT (COLCORONA) and demonstrated a reduction in progression of COVID-19 and hospitalization in a sub-group of patients with PCR confirmed COVID-19. The trial was stopped early; due to decreased power leading to the low certainty of its results, as well as a higher risk of adverse events (diarrhea and blood clots) guidelines (WHO, NIH) do not recommend colchicine. The CTC states that if colchicine is used outside of clinical trials, full disclosure of risks and benefits with consideration of patient values are necessary.
Overall, the uptake of the drug in BC has been very low to none.
Fluvoxamine was evaluated at 100 mg PO BID x 14 days in a Brazilian RCT and shown to reduce emergency room visits > 6 hours, a surrogate endpoint for hospitalizations. It has not demonstrated a benefit in reducing actual hospitalizations from COVID-19, length of stay or mortality. For every 12 trial participants, one additional patient stopped fluvoxamine prematurely. Due to low generalizability from a very high event rate, as well as lack of robust safety data, guidelines (e.g., IDSA) do not recommend the use of fluvoxamine outside of clinical trials. A Canadian fluvoxamine study stopped enrolment due to futility. The CTC states that if fluvoxamine is used outside of clinical trials, full disclosure of risks and benefits with consideration of patient values are necessary. There were also additional concerns posed about the lack of full safety evaluation with this dose. The recommended starting dose in patients over 55 years old is 25mg daily, whereas the trial's dosing is 8 times that dose. As fluvoxamine can cause a variety of side effects such as hypotension, dizziness, falls, QT prolongation and GI effects, the safety of this regimen deserves further study before the drug can be routinely used for treating COVID-19.
Five trials have evaluated inhaled steroids for the symptomatic relief of COVID-19 manifestations such as shortness of breath and cough, showing that treatment with inhaled steroids reduces symptoms and may reduce the need for hospitalization (although the latter has not been consistently demonstrated and has thus far been a secondary endpoint of most trials). Due to familiarity and safety, inhaled budesonide 800 μg twice daily or ciclesonide 320 μg twice for 14 days may be considered on a case-by-case basis in adults with lower respiratory tract symptoms of COVID-19 aged 65 and over or aged 50 and over with underlying health conditions and within 14 days of symptom onset, acknowledging the limitations of these trials. There is no evidence to combine inhaled steroids with nirmatrelvir/ritonavir or remdesivir; some inhaled steroids interact with nirmatrelvir/ritonavir. | May 2023 Update: NEW eligibility criteria for nirmatrelvir/ritonavir, including a discussion of the evidence.Various agents are available in BC for the treatment of mild-moderated COVID-19. These therapies include a direct-acting oral antiviral nirmatrelvir/ritonavir (Paxlovid) and an IV antiviral, remdesivir (Veklury). A monoclonal antibody (mAB) sotrovimab (Xevudy) has also been shown efficacious in treating mild-moderate illness; however, it has reduced activity against many variants currently circulating in BC. Guidance on repurposed therapies such as inhaled steroids, fluvoxamine, colchicine is also included. This document provides general recommendations for the use of these therapeutics and supporting evidence, with additional practice tools available separately. See Toolkit #1 -Step-by-step Assessment for practical prescribing information. Immunocompromised individuals 1,2 and those with high-risk conditions 3 identified as Clinically Extremely Vulnerable Group 1 1 , Group 2 2 , and Group 3 3 (CEV 1, CEV 2, and CEV 3), regardless of age, vaccine status or previous infection. (See also Practice Tool 2 -CEV Definitions).#
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1. CEV 1: severe immunocompromise due to, e.g., solid organ transplant, bone marrow or stem cell transplant, treatment for hematological malignancy, receiving anti-CD20 or B-cell depleting therapies 2. CEV 2: moderate immunocompromise due to e.g., receiving immunosuppressive agents, moderate-severe primary immunodeficiency, cancer treatment for solid tumors, advanced or untreated HIV 3. CEV 3: e.g., cystic fibrosis, severe asthma or COPD, diabetes requiring insulin, intellectual and developmental disabilities, rare blood disorders, dialysis, neurological conditions requiring Bi-PAP or chronic ventilation, cancer not captured above ^ National Advisory Committee on Immunization: i.e., lack of a primary two-dose series PLUS a "Fall Booster" (or a booster in the last year), which may be delayed up to 6 months post COVID-19 infection *Serious chronic medical conditions may include stroke, heart failure, heart disease, diabetes, kidney or liver disease, chronic lung disease like COPD or interstitial lung disease, neurological conditions. Some discretion can be used See Practical Consideration below for further information about assessing eligibility.
# Therapy Recommendations
Nirmatrelvir/ritonavir 300/100mg PO BID x 5 days (150/100mg PO BID x 5 days in eGFR 30-60 ml/min) is recommended within 5 days of symptom onset for patients with a non-reassuring symptom presentation and trajectory^ who are at an increased risk for hospitalization or progression to severe COVID-19
OR, if nirmatrelvir/ritonavir cannot be given to patients with a 5% or greater risk* due to drug-drug interactions or contraindications (See Practice Tool 3 -Drug Interactions and Contraindications)
Remdesivir 200mg IV on day 1, followed by 100mg IV on days 2 and 3 (200mg IV on day 1, followed by 100mg IV 48-72 hours later in eGFR less than 30ml/min) is recommended within 7 days of symptom onset** as an alternative to nirmatrelvir/ritonavir Patients with a risk of 5% or greater are currently being prioritized and offered treatment with remdesivir due to operational constraints and unclear benefit in lower risk individuals.
NOTES ^ Strong clinical judgment assessing symptoms and symptom trajectory is particularly important in immunocompromised patients *To estimate whether the risk is ≥ 5%, see Risk Assessment below **The symptom window for nirmatrelvir/ritonavir can be extended to 7 days in patients with a 5% or greater risk if they would otherwise be referred for remdesivir solely based on its longer treatment window THESE THERAPIES SHOULD NOT BE COMBINED: Due a limited additional benefit, patients should receive ONE COVID-19-specfic therapy.
Nirmatrelvir/ritonavir may be considered in patients who reside in Long Term Care (LTC) facilities. There are a lack of data supporting the efficacy and safety of nirmatrelvir/ritonavir in patients residing in LTC facilities.
Treatment may be given depending on patient's clinical presentation, symptom trajectory, risk factors for progression to severe disease, goals of care, presence of drug-drug interactions and tolerance of potential adverse effects.
Sotrovimab 500mg IV X 1 dose has reduced efficacy against the BA. 5.1, BA. 5.2 and 5.2.1 variants, although it may retain some activity. Real-world evidence shows limited efficacy against the BA 1. and BA. 2 variants of concern (VoCs) in immunocompromised or non-immune individuals, which may predict its performance against most BA. 5 VoCs. Sotrovimab has unknown clinical efficacy against many currently circulating VoCs (e.g., BA. 4.6, BQ. 1, BQ 1.1, XBB and BF. 7) where a reduction in binding, but not complete resistance, is seen. If sotrovimab is used in cases where remdesivir or nirmatrelvir/ritonavir cannot be used, patient disclosure to risks and benefits in consideration of individual circumstances (clinical and immune status, patient values, logistics) is necessary. The convenience of single dose sotrovimab should not be the primary indication for use.
Inhaled budesonide 800 μg twice daily for 14 days may be considered on a case-by-case basis in patients who have lower respiratory tract symptoms (cough, shortness of breath) for symptom relief. There is no evidence of additional benefit of inhaled steroids to antivirals or antibody therapy.
Tixagevimab/cilgavimab 600mg IM x 1 dose has demonstrated a 50.5% relative risk reduction (RRR) in COVID-19 hospitalization and death in unvaccinated, non-hospitalized adults with mild-moderate COVID-19 (TACKLE), which is lower than the RRR seen with other COVID-19 treatments in similar trials. Tixagevimab/cilgavimab is likely ineffective against many currently circulating VoCs including BA. 4.6, BF. 7, BA. 2.75.2, BQ 1, BQ 1.1 and XBB where 300-1000-fold reductions in binding are seen. If tixagevimab/cilgavimab is used as a last line treatment in cases where nirmatrelvir/ritonavir, IV remdesivir or sotrovimab cannot be used, disclosure to patients of risks, including cardiovascular serious adverse events (SAEs), and benefits and consideration of individual circumstances (clinical and immune status, patient values, logistics) is necessary. The convenience of the IM route of administration of tixagevimab/cilgavimab should not be the primary indication for use.
Molnupiravir 800mg PO BID x 5 days is not routinely recommended (if/once available in Canada); if used on a case-by-case basis in patients who are unable to receive nirmatrelvir/ritonavir, sotrovimab or remdesivir, the uncertainty of benefit and the absolute risk of hospitalization, including factors such as age, number and type of co-morbidities and severity of symptoms need to be considered.
Colchicine is not recommended due to low certainty of benefit and potential risk of adverse events and additional immunosuppression in this population.
Fluvoxamine is not recommended due to low certainly of benefit and potential risk of adverse events associated with the dose evaluated (100mg PO BID), especially in vulnerable and elderly patients.
# PRACTICAL CONSIDERATIONS
# Risk Assessment
Single variable criteria (e.g., age only) identify patients who have a wide range of risk and are an imprecise way to determine who is at high risk of severe COVID-19 and would benefit from treatment. Unless patients are Clinically Extremely Vulnerable (CEV), real world data show that they require at least two risk factors to have a clinically meaningfully increased risk of hospitalization from COVID-19 and therefore derive a reasonable benefit from treatment.
Age: Age is the single most powerful predictor of hospitalization and death; an 80-year-old patient with COVID-19 has 28 times greater odds of requiring hospitalization than a patient who is 18. Patients over 70, even if vaccinated, experience significant hospitalization rates despite the decreased likelihood in the Omicron variant wave, whereas individuals younger than 50 years have a hospitalization rate of <1% even if unimmunized. The age cut-off of 70 years was chosen as there is a strong inflexion point with respect to the risk of hospitalization. The age cut off for Indigenous patients is lower, set at 60 years, which mirrors COVID-19 vaccine booster recommendations in BC.
Vaccine Status: The National Advisory Committee on Immunizations (NACI) COVID-19 Immunization Guidelines include recommendations regarding the optimal vaccination strategies for COVID-19, which are adopted in BC. These recommendations consider the complexities of vaccine waning and hybrid immunity. Recommendations are presented as "Strong Recommendations" (worded as "should be offered") where the evidence of benefit for a vaccine is convincing, and "Discretionary Recommendations" (worded as "may be offered") where there are limited data or an unclear clinical benefit.
Currently, NACI strongly recommends the following immunization strategy, which is used herein to define what is considered fully or optimally vaccinated:
A primary two-dose mRNA vaccine series for all adults. A three-dose primary series for those who are immunocompromised (CEV 1 and 2). A "Fall Booster" for those ≥ 65 years and older or those < 65 who have serious chronic medical conditions The Fall Booster may be delayed for up to 6 months in case of a COVID-19 infection
Patients who have never received a COVID-19 vaccination are considered unvaccinated. Patients who are not vaccinated in accordance with NACI's strong recommendations would be considered under-vaccinated. When assessing vaccine status for treatment eligibility, a lack of a booster dose in the last year (and a lack of infection which could delay the dose) is a good gauge of under-vaccination since the presence of another risk factor (older age or chronic conditions) is required for treatment, which is also a risk factor where a booster would be recommended.
Chronic Conditions: Real world evidence shows that serious medical chronic conditions are the most strongly associated with risk of hospitalization from COVID-19. In BC, the most common conditions present when nirmatrelvir/ritonavir was prescribed were hypertension, dyslipidemia and benign prostatic hypertrophy, which are not associated with an increased risk of progression to severe disease. Non-CEV-defining conditions that are significant risk factors are similar to those defined by NACI, and include: The patient requires the presence of any ONE of these serious chronic medical conditions. Some discretion can be used by the prescriber when determining the significance of the severity of the comorbidity.
Other considerations: The risk models/thermal map below are still accurate in estimating the risk of progression to severe COVID-19. These models may be used to aid decision making, or when assessing for the appropriateness of remdesivir. Remdesivir can be offered to patients with contraindications to nirmatrelvir/ritonavir who have a ≥ 5% risk of hospitalization from COVID-19 (dark yellow and red on the thermal map).
# Local Data and Risk Models
# BC Study of Risk of Hospitalization
The CTC partnered with HSIAR, the BCCDC, and other epidemiology research groups to characterize the risk of hospitalization from Omicron in BC. Approximately 600,000 PCR test were included between January 3 to February 7, 2022, a period driven by the BA. 1 variant, where rapid antigen tests were not widely used, PCR testing centres were accessible, and therapy was not yet fully rolled out. Variables analysed that influenced risk that were included in the analysis were age, number of vaccine doses, and number and type of comorbidities (CEV 1, 2, 3 and non-CEV, as well as 1-2 vs. 3+ comorbidities). A chart review study was undertaken to exclude hospitalized patients who were incidentally diagnosed but did not require hospitallevel care for severe or critical COVID-19, which comprised 60% of all cases. These thermal maps can continue to be used to guide clinical decision making and assessing risk vs. benefit of therapy. There are various limitations of this study, including inability to capture patients who did not pursue testing or asymptomatic patients, and excluding those few who received therapies such as sotrovimab. Despite this, this study represents one of the best-available risk models in Canada and is used by other jurisdictions such as Ontario, and groups such as CADTH.
# Ongoing Validity of Risk Models
As BC risk models and thermal maps were developed during the first wave of Omicron (BA. 1), questions have emerged regarding the ongoing validity of this analysis in the BA. 2 and BA. 5 waves of Omicron. There is a notion that most BC residents have had COVID-19, yet hospitalizations have remained low, hence the risk is overestimated in the thermal maps. However, while the analysis cannot be redone due to an inability to identify test-positive patients who self-test via rapid antigen tests, various experts agree that this analysis remains a valid risk assessment useful for therapy eligibility for the following reasons:
Wastewater surveillance data has indicated that there has been no other 5-week period, including during the April and June waves, where the number of people infected with COVID-19 had been substantially higher (and would thus greatly increase the denominator), than in the January-February study period. As hospitalizations after testing positive for SARS-COV-2 have remained stable over the last 9 months and through the April and June waves, the risk of hospitalization is likely also stable and still reflected by these thermal maps.
Infection rates with the Omicron variant, which would increase the denominator in these models, have also been relatively infrequent in populations that are eligible for treatment in BC, namely the CEV populations and the elderly. For example, data from the Canadian Blood Services show that while nearly 80% of younger BC residents have contracted COVID-19, that rate is only about 40% in those over the age of 65. Similar trends have been observed in the UK.
Real world data from jurisdictions that record rapid antigen test results, such as Israel, have not indicated a change in hospitalization risk in untreated patients throughout the various Omicron waves. For example, a large retrospective study from Israel that used a point system to identify patients eligible for treatment showed that untreated patients who have an ~2% risk of hospitalization have a combination of risk factors that would lead to the same risk estimate using BC thermal maps.
While hybrid immunity (from vaccination and infection) has been shown to reduce the rate of reinfection with Omicron, it has not shown to reduce the risk of hospitalization beyond the high vaccine effectiveness against hospitalization conferred by vaccination alone. As such, even if a high proportion of BC's population has hybrid immunity, there is no strong data to support an adjustment of their hospitalization risk in these thermal maps by any factor.
# Testing
BC is continuing to rely on the federally acquired rapid antigen tests available at pharmacies. As this program comes to a gradual end, the testing strategy in BC will change, and this guideline will be updated to reflect this. Symptomatic patients are more likely to have a true positive RAT over those without symptoms Performing a test on day 3 or later since symptom onset as opposed to on days 1 or 2 Having higher viral loads, as seen in patients who have greater vaccine escape, are more symptomatic or are 48 hours or more into their illness Performing serial RATs at regular intervals (e.g., every 24-48 hours).
Various studies have evaluated serial RATs in symptomatic patients for their diagnostic accuracy. The largest study to-date, the Test Us at Home trial, showed that in patients who were pre-symptomatic but went on to develop symptoms of COVID-19, performing a self-administered RAT three times over a 48 hour interval produced an aggregate sensitivity of 93.4% (95% CI: 89.1-96.1%). Testing once on the day symptoms appeared had a sensitivity of 59.6%, which increased to 92.3% after a single repeated test (total of 2 tests within a 48-hour period). Testing asymptomatic patients, even in a serial fashion produced a sensitivity of 56.4%. This study has led to an FDA Guidance Update to recommend serial RAT testing for all symptomatic individuals as the optimal testing strategy to ensure maximum sensitivity. To ensure the quickest diagnosis possible through retesting considering the 5-day treatment window, the CTC and the Province recommend retesting 24 hours after a negative RAT, as opposed to a longer interval between tests.
# Testing and Treatment Evidence
There are currently no studies that compare the impact of different testing strategies (RAT vs. PCR) on treatment outcomes (e.g., hospitalization or death). While a positive PCR test is often a part of the inclusion criteria of randomized controlled trials of COVID-19 therapeutics, most real-world studies describe a mainly RAT-based approach through which COVID-19 was diagnosed and treated. As long as patients initiate treatment within the treatment window (5 days for nirmatrelvir/ritonavir and 7 days for remdesivir) landmark trials of nirmatrelvir/ritonavir and remdesivir show no difference in treatment outcomes based on the day the patient started therapy. For example, patients who started nirmatrelvir/ritonavir within 3 days of symptom onset had the same reduction in hospitalization as patients who initiate treatment within 5 days (0.7% vs. 6.5% and 0.8% vs. 6.3%). Very few patients initiate treatment on the first day of symptom onset where PCR testing may have a sensitivity advantage over a single RAT test.
# Practical Considerations for assessing validity of a Rapid Antigen Test:
-Ensure the test was done recently and that it is in fact positive -For patients who test positive via a RAT, verify how the test was done and how did the result present.
-While RATs have excellent clinical specificity as they are unlikely to pick up SARS-COV-2 virus in those who have recently recovered from COVID, are chronic shedders or have subclinical viral loads, false positives can occur. Potential causes for false positive results may include other respiratory viruses and reactions with certain foods or liquids. -The pre-test likelihood of COVID-19 infection may be influenced by known contact with COVID-19 cases, symptoms compatible with COVID-19, and the prevalence of disease in the community. The table below provides the positive predictive value for a single RAT test with 98% specificity and 80% sensitivity (similar to most RATs performed in symptomatic patients) for a range of pre-test probability of infection from 0.01 to 0.15. Epidemiologically linked cases (e.g., household contacts of those who test positive) who have not been confirmed via COVID-19 testing should not be offered treatment.
# Pre-test probability of infection
Indications for a PCR Test PCR testing will continue to be performed on patients within acute care settings, including hospitalized patients and those presenting to the emergency department, or to investigate an outbreak. PCR is required for genomic characterization of the virus (aka Variants of Concern typing) for surveillance purposes which also informs the activity of monoclonal antibody treatments. PCR is also used when there is a need to diagnose influenza (these tests are done together).
For patients who live in a rural, remote or Indigenous communities, the health care provider may suggest PCR-based testing, or other investigations based on their clinical evaluation. Offering PCR-based COVID-19 testing or more comprehensive clinical investigation might be appropriate due to barriers in accessing health services Indigenous people might experience, such as geographical remoteness or systemic racism. For full guidance on Testing in Remote, Rural and Indigenous Communities, click here.
PCR testing may also be ordered in the community for treatment purposes at the discretion of the primary care provider. Scenarios where PCR testing may be appropriate include:
High-risk patients (≥ 5% risk of progression to severe disease) who test negative despite serial RATs Patients with a very high-level of suspicion (e.g., symptomatic with a household contact) who test negative despite serial RATs Patients in whom therapy was initiated despite a negative RAT(s) to ensure a diagnosis of COVID-19 Patients who have symptoms of severe disease who will have COVID-19 therapy (e.g., supplemental oxygen, dexamethasone) delivered outside of an acute care setting A non-reassuring presentation is clinical status that poses concern to the health care provider. For example, a CEV-1 cancer patient may only have a low-grade fever; however, this is non-reassuring to their oncology team.
Illness trajectory is a useful in establishing progression of COVID-19. Patients who are visibly deteriorating are more likely to become severely ill. Treatment is unlikely to benefit those who are mildly ill who are clearly improving on their own. Treatment should not be given to asymptomatic or minimally symptomatic patients.
# Symptom Window
Symptom windows vary with each therapeutic agent and follow study inclusion criteria. Remdesivir should be given within 7 days of symptom onset whereas for oral antivirals should be given within 5 days. It is appropriate to allow the addition of adequate time for drug delivery of medication for those living in remote and rural communities. Patients who are in the ≥5% risk category who have passed the 5-day but are within the 7-day treatment window and would be referred for remdesivir solely based on its longer treatment window can be prescribed nitmatrelvir/ritonavir within 7 days of symptom onset.
In clinical trials, viral loads decreased from the nasopharynx by 1000's-fold during treatment regardless of the receipt of an active treatment or placebo. Furthermore, most patients produced their own antibodies shortly after becoming infected and exogenous antibodies do not confer additional benefit. There is little clinical rationale for extending the treatment window past 7 days.
Patients who have had prolonged symptoms or more or protracted illness despite recently testing positive for COVID-19 may require a clinical assessment of the illness trajectory to rule out other causes responsible for their symptoms. Patients are encouraged to get tested as soon as possible after COVID symptoms appear to avoid conflating persistent symptoms with COVID-19 infection.
# Hospitalized Patients
Patients who are hospitalized for other reasons and are mildly-moderately ill with COVID-19 can be considered for treatment if they meet the eligibility criteria. Many patients admitted to hospital are incidentally diagnosed or are part of nosocomial outbreaks and are offered testing with very low thresholds that often does not warrant treatment. As with all mild-moderately ill patients offered treatment, patients in hospital need to be appreciably symptomatic, have a valid COVID-19 test, be assessed for contraindications and drug-drug interactions, and offered treatment on the basis of their risk of progression to severe disease. Even though patients are already hospitalized, the goal of such therapy is still progression of COVID-19 to require hospital-level care for COVID-19, namely supplemental oxygen, steroids and baricitinib.
The treatment guidance in this guide applies equally to all patients regardless of their location, including hospitalized patients.
# Contraindications
Nirmatrelvir/ritonavir should not be used in end-stage liver disease (Child-Pugh C). In patients with hepatitis B and C, or HIV infection regardless of treatment status may benefit from Specialist Consultation (e.g., Infectious Diseases, HIV Specialist), but treatment should not be withheld or delayed due to these conditions. Many drug-drug interactions contraindicate the co-administration of nirmatrelvir-ritonavir, but some can be held or managed. Contraindicated drugs include amiodarone, apixaban and rivaroxaban, certain antipsychotics like clozapine, midazolam and triazolam, as well as illicit drugs especially fentanyl and methamphetamine (see Practice Tool #3: Drug Interactions and Contraindications). Patients with hypersensitivity to ritonavir or other protease inhibitors should not be prescribed nirmatrelvir/ritonavir. Drug interactions must be verified and a management plan in place before prescribing. If drug-drug interactions pose safety concerns, treatment can be forgone, especially in those who have a very slightly increased risk of hospitalization.
Nirmatrelvir/ritonavir has not been clinically evaluated in patients with eGFRs < 30ml/min, although pharmacokinetic studies show that it is not nephrotoxic and can likely be adjusted accordingly in those with end-stage renal disease or on dialysis. The manufacturer is currently conducting a small trial in patients with eGFRs less than 30ml/min and safety and efficacy data are forthcoming. At this time, according to nephrology experts in BC, nirmatrelvir/ritonavir is thought to have a limited role in patients with end-stage renal disease due to the extensive number of drug-drug interactions such patients experience and not because of renal disease itself. However, the drug is not thought to be dangerous in such patients, and a lack of a recent serum creatinine should not contraindicate or delay its administration. Patients without known renal disease can be prescribed full dose nirmatrelvir/ritonavir, and in those with reduced renal function, the most recent SCr can be used to guide treatment decisions. Boarder-line eGFR (e.g., 28ml/min) should be assessed using clinical judgement and does not usually contraindicate prescribing dose-reduced nirmatrelvir/ritonavir 150mg/100mg PO BID.
Remdesivir is contraindicated in those with demonstrated hypersensitivity to the product or any of its ingredients. While the monograph states that there are no data to support its use in eGFR < 30ml/min (due to the cyclodextrin component), numerous studies, including a yet-to-be published RCT of >1000 patients conducted by Gilead support its safety in this population. (For a full operational review of remdesivir, including renal dosing, consult your health authority to obtain the CTC and CTRAWG memo regarding remdesivir operationalization). Remdesivir should not be used in patients with ALT ≥5 times the ULN. The pharmacokinetics and safety of remdesivir in hepatic impairment have not been evaluated; expert consultation is recommended. While pregnancy and paediatric considerations are not part of the Canadian labelling, remdesivir has approval for children age ≥ 12 years weighing ≥ 40kgs in the US and has been given to pregnant women in independent studies. Specialty consultation is recommended for these populations.
Monoclonal antibodies like sotrovimab and tixagevimab/cilgavimab can cause hypersensitivity reactions and infusion/injection reactions, although they are rare.
Molnupiravir contraindications are not well articulated as the Canadian Monograph has not been published due to lack of Health Canada approval. This will be updated when known. Based on FDA data, molnupiravir will be contraindicated in pregnancy, breastfeeding, in those trying to conceive and in pediatrics.
# Pregnancy, Breastfeeding and Pre-Conception
Pregnancy is a risk factor for hospitalization and pregnant women have 3 times the odds of hospitalization in BC compared to age-matched non-pregnant women. Vaccination in this population is also lower than agematched cohorts. However, pregnant persons are young, and most do not have co-morbidities; as such the absolute risk of hospitalization in a pregnant person is still below the treatment threshold.
Currently available therapies have not been evaluated in pregnancy or breastfeeding. The Reproductive Infectious Disease and Maternal Fetal Medicine COVID-19 working group would potentially consider remdesivir for use in pregnant or breastfeeding women if they otherwise meet the above-mentioned treatment criteria (e.g., immunocompromise or unvaccinated). Nirmatrelvir/ritonavir may also be acceptable due to familiarity and comfort with prescribing protease inhibitors to this population. Sotrovimab is considered safe; however, this needs to be balanced against a potential loss of activity. Animal studies have not demonstrated a significant risk to the fetus from all three drugs. Prescribers may consult Reproductive Infectious Disease on call at BCCW if prescribing COVID-19 therapy, especially nirmatrelvir/ritonavir in pregnancy in high-risk women, or for advice during breastfeeding.
Molnupiravir has been found to negatively impact fertility, embryonic development and pregnancy outcomes in animal studies and is contraindicated in pregnancy or in those with childbearing potential unable or unwilling to use protection.
It is unknown whether COVID-19 therapies impact fertility. Patients are encouraged to use protection while taking these medications. Those who are on oral contraceptives should use a back-up method when taking nirmatrelvir/r due to drug interactions leading to lower plasma levels of estrogen, decreasing its efficacy in preventing pregnancy.
# Pediatrics
Nirmatrelvir/ritonavir is not approved for pediatric use, and remdesivir is not approved in children with mildmoderate COVID-19 in Canada (but is in the US). Sotrovimab has pediatric approval but has significant loss of neutralization capacity against BA.2 and may not be appropriate in very high-risk children. The following statement regarding pediatric therapy has been developed in collaboration with experts from BCCH:
Pediatric patients with immune compromise are generally considered to be at lower risk of developing severe COVID-19 illness and requiring hospitalizations compared to adults with immune compromise. Risk of severe COVID disease in immunocompromised children appears to be related to underlying comorbidities rather than immune suppression itself. Immunocompromised children may present with atypical signs and symptoms of COVID-19 that can fluctuate rapidly between being asymptomatic to having mild to moderate symptoms and vice versa. Information on COVID-19 vaccine immunogenicity in children with immune compromise is currently limited.
In consultation with pediatric infectious diseases and appropriate subspecialist, treatment with should be considered for COVID 19 positive immunosuppressed children 12 years of older and minimum 40kg with mild to moderate COVID-19 symptoms not requiring hospitalization who are:
Solid organ transplant recipients Hematopoietic stem cell/bone marrow transplant recipients within the past 2 years and/or are currently receiving immunosuppression Immunosuppressed due to primary immunodeficiency or due to iatrogenic causes Have been otherwise classified as extremely clinically vulnerable due to immunosuppression (CEV 1 or 2)
# AND
o Have another major chronic condition/comorbidity putting then at risk of severe COVID-19, especially significant lung disease (e.g., lung transplant recipients, lung GVHD, obstructive lung disease). Being unvaccinated or partially vaccinated is a risk factor for severe COVID-19 disease, bearing in mind that some fully vaccinated children with immune compromise also may not generate vaccine immune response.
The choice of agent will depend on an individualized risk-benefit assessment of the available therapies.
Children with immune compromise and no major comorbidities are unlikely to develop severe COVID-19 disease. The benefit of providing treatment in these cases is likely very small.
Ultimately, decisions around the use of remdesivir or sotrovimab should be made on a case-by-case basis, weighing lack of RCT-level data in children, off-label use and the potential benefit of treatment. Clinicians are encouraged to discuss cases with the Pediatric Infectious Diseases physician on call at BC Children's hospital. If IV therapy is being pursued, infusions can be arranged at BC Children's hospital through the patient's BC Children's Main Responsible Physician/Service, as per hospital protocol. For those patients outside the vicinity of BC Children's hospital, arrangements will need to be made through the local health authority at an available infusion site.
# Drug-Drug Interactions
Nirmatrelvir and ritonavir have significant drug-drug interactions, many of which contraindicate its use. Nirmatrelvir and ritonavir are potent inhibitors of CYP 3A4 and increase the concentration of many drugs metabolized by this enzyme. Nirmatrelvir/ritonavir is also contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.
Some drug-drug interactions can be managed. For a comprehensive list of drug-drug interactions and management strategies see Practice Tool #3: Drug Interactions and Contraindications.
# The most comprehensive resource for DDI assessment with nirmatrelvir/ritonavir is available from the University of Liverpool at https://www.covid19-druginteractions.org/checker.
Remdesivir has no DDIs that contraindicate its treatment, except for chloroquine and hydroxychloroquine which may reduce its antiviral efficacy. Strong CYP 3A4 inducers (e.g., phenytoin, rifampin, carbamazepine) may decrease the serum level of remdesivir but the clinical relevance of this interaction is not known.
Sotrovimab and tixagevimab/cilgavimab pose no significant drug-drug interactions.
# Dosing
Nirmatrelvir/ritonavir is dosed at nirmatrelvir/ritonavir 300/100mg PO BID x 5 days for those with eGFR > 60 ml/min. It is supplied as a pre-packaged kit containing both products: 2 tablets of nirmatrelvir 150mg and 1 tablet of ritonavir 100mg per dose. The patient takes 3 tablets per dose, for a total of 30 tablets during the treatment course.
Patients with an eGFR of 30-60 ml/min should take nirmatrelvir/ritonavir 150/100mg PO BID x 5 days, or one nirmatrelvir 150mg tablet and one ritonavir 100mg tablet per dose. The second nirmatrelvir tablet should be removed from the kit from each dose by the dispensing pharmacist for the patient to avoid confusion and diversion.
# Renal Dosing of nirmatrelvir/ritonavir
Remdesivir for mild-moderate COVID-19 in patients with an eGFR ≥ 30ml/min is dosed with a loading dose of 200mg IV on day 1, followed by 100mg IV on days 2 and 3. This dose differs from its dose in the monograph for severe COVID-19 infection. Each vial contains remdesivir 100mg for a total of 4 vials per full treatment course. There is no dose adjustment required for obesity or mild-moderate renal or liver impairment. Patients with renal disease who have an eGFR <30 ml/min can safely receive standard dosing; however based on known PK and limited clinical data, renal and COVID experts in BC agree that a renally adjusted dosing can be used to optimize operationalizing administration of infusions. Such patients can receive 200mg IV on day 1, followed by 100mg IV 48 hours later. Patients on hemodialysis can receive their dose during dialysis, and can receive their second dose 48-72 hours later depending on their hemodialysis schedule.
Sotrovimab is dosed at 500mg IV x 1 dose infused over 60 minutes. The manufacturer is currently evaluating the in-vivo efficacy of a 1000mg dose against different variant of concern, as such dose is likely to overcome the reduced neutralization capacity. A regulatory decision regarding the approval of this dose is forthcoming.
There are no dose adjustments required for obesity or mild-moderate renal or liver impairment. The drug is not recommended for IM use.
Tixagevimab/cilgavimab for treatment is dosed at 600mg, 300mg of each tixagevimab and cilgavimab. The two antibodies are supplied separately and are injected intramuscularly into the gluteal muscles as four 1.5mL IM injections (two 1.5mL injections each mAb). There are no dose adjustments for renal or liver impairment.
# Patient Location
Patients with mild to moderate COVID-19 are usually outpatients recovering at home. However, many patients hospitalized for non-COVID reasons can also be offered treatment (see Hospitalized Patients above).
Patients in Long-Term Care are eligible for treatment if they meet criteria, with an understanding that IV therapeutics cannot be administered easily in LTC settings. Patients may also be offered treatment in Emergency Departments. This guidance is not specific to any particular patient location.
This guide does not specify priority for patients in remote or rural areas; CTRAWG (a committee responsible for equitable distribution of scarce drug resources) may prioritize different geographical areas if needed. Additional time added to the patient's symptom window is clinically acceptable for drug transport to remote and rural areas.
# Clinical Judgement
This guide should not replace clinical judgement. Patients who are technically eligible for treatment may not be good candidates due to clinical status, goals of care, or willingness to provide consent for treatment. These factors need to be considered with each patient assessment.
The current eligibility criteria are conservative, and the absolute risk of hospitalization depicted in thermal maps is overestimated due to a testing bias. There should be very few patients who have a risk of <3% who should be offered treatment and are not captured in this guide; however, such decisions are again deferred to the treating clinician.
# Rebounds, Re-infections and Retreatment
Rebounds A rebound, also knowns as a relapse, is defined as a COVID-19 infection which was treated (mainly with nirmatrelvir/ritonavir) where there was proven clearance of the SARS-COV-2 virus by a negative test and symptom improvement, but where symptoms then returned or worsened, followed by a subsequent positive SARS-COV-2 test. Rebounds are not frequently diagnosed because current guidance does not recommend a test of cure, especially since patients can shed virus for weeks after recovery and have an undulating symptom trajectory. It has been speculated that treatment with nirmatrelvir/ritonavir causes rebounds because it suppresses virus beyond detectable levels without complete clearance, and once the 5-day course is completed, the virus begins to replicate again, causing a rebound of illness. However, rebounds have since been shown to occur irrespective of whether treatment is given or not and are estimated to affect approximately 2% of patients. In a recent meta-analysis, the overall OR of rebound among COVID-19 patients taking nirmatrelvir/ritonavir vs. control group was 0.99 (95% CI, 0.28-3.57; p=0.99), showing no association between treatment and rebounds. Patients with COVID-19 should be counselled that rebounds may occur but are not linked to treatment, and post-treatment testing or test of cure should be discouraged.
# Re-infections
Re-infection is defined as a COVID-19 infection after complete recovery from a prior infection and usually occurs with a different variant of concern. Re-infections in BC have been documented by PCR as early as 8 weeks prior to the original infection and became common during the Omicron waves despite the protection previous infection confers. Studies show that re-infection rates in a highly vaccinated population are highest in the 18-29-year-olds (~15%) and about 10% in the general population.
# Retreatment
The CDC does not recommend routine re-treatments of rebounds. Rebounds have been shown to be generally milder than the index infection, and symptoms resolve quickly without re-treatment. Case series of rebounds, however, have been in already low risk individuals who would not have been eligible for treatment in BC. The CTC recommends that patients who meet treatment eligibility and rebound be reassessed on the basis of their symptoms and symptom trajectory. Those with symptoms that are milder than the initial infection or those that are improving rapidly should not be offered re-treatment. Retreatment with nirmatrelvir/ritonavir can be considered in those who have significant symptoms or rapidly progressing illness. Another 5-day course should be used; there is no evidence that supports longer courses of treatment, although a 10-day course is currently being investigated by the manufacturer.
Re-infections should be assessed and treated as new infections. Patients' eligibility criteria should be reassessed, and risk re-calculated considering previous infection in the risk scoring. Symptoms and symptom trajectory should continue to play a key role in determining whether another course of treatment is offered.
So far, a few dozen patients in BC have received more than one course of nirmatrelvir/ritonavir. There have been no observable differences in outcomes between the first vs. the second course of nirmatrelvir/ritonavir, although a significant survival bias exists.
# SUPPORTING EVIDENCE
# Summary of Trials
# Nirmatrelvir/ritonavir
Nirmatrelvir is a protease inhibitor with a 2-hour half-life; it is co-administered with ritonavir to allow BID dosing. The landmark trial of nirmatrelvir/ritonavir has been published in the NEJM in February 2022.
EPIC-HR was a randomized double-blind placebo-controlled trial:
o 2246 adult outpatients with mild-moderate COVID-19 who were enrolled o Patients had to be within 5 days or less of symptom onset o Patients included had to be unvaccinated and at increased risk of developing severe disease, defined as age 60 or older or having a chronic condition such as diabetes, heart condition or chronic kidney disease o The mean age of patients in the trial was 47; most had a single co-morbidity, the most common of which was smoking o Patients were randomized in a 1:1 fashion to receive nirmatrelvir/ritonavir or placebo o The primary endpoint was COVID-19-related hospitalization (not all-cause), or death from any cause. o The primary endpoint occurred in 66/1064 (6.3%) patients given placebo vs. 8/1039 (0.8%) patients randomized to active treatment for a relative risk reduction of 88%, an absolute risk reduction of 5.5% and an NNT of 18. o A high-risk subgroup of ~200 patients was analysed (those over 65 with more risk factors). This group, which is similar to the patients prioritized for treatment in this guide, experienced a nearly 15% absolute risk reduction in COVID-19 hospitalization (16.3% vs. 1%, p<0.001). o Side effects that were drug-related included diarrhea, nausea, dysgeusia, muscle aches and hypertension. The rate of drug related ADRs was 7.8% in the treatment arm vs. 3.8% in the placebo arm, for a NNH with one side effect of 25.
Based on these data, nirmatrelvir/ritonavir is given a AIIa recommendation by the NIH and a conditional recommendation by the IDSA to suggest treatment over no treatment.
Another RCT was also conducted by the manufacturer of nirmatrelvir/, but it remains unpublished, likely because it was negative.
# Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR), unpublished
o This was a randomized, double-blind, placebo-controlled trial conducted by Pfizer. o 1411 standard-risk individuals were randomized between August 2021 -February 2022 to receive nirmatrelvir/ritonavir or placebo within 5 days of symptom onset. o Patients had to be at "standard risk" of hospitalization and death from COVID-19, meaning having a single risk factor such as age 65 or older, a single chronic condition, or lack of vaccination in younger individuals. Most patients were infected with the Delta variant of concern. o There was no difference seen in the primary endpoint of time to sustained symptom alleviation, which was defined as the absence of key COVID-19 symptoms for 4 consecutive days. o There was also no difference in hospitalization due to COVID-19 or all-cause mortality (0.9% vs.1.8%, p=0.187).
The secondary endpoint of hospitalization and mortality was close to reaching statistical significance at the interim analysis, where the event rate in the placebo arm was 2.4%. However, due to the emergence of Omicron, the event rate in the placebo and treatment arms dropped to nearly zero, and recruitment stopped.
# Real World Evidence
Various observational studies characterize the association of nirmatrelvir/ritonavir and hospitalization related to COVID-19. A detailed overview of studies that support these recommendations is presented here. While nirmatrelvir/ritonavir tends to be associated with a reduction in hospitalizations, the populations in these studies vary greatly depending on who is eligible to receive nirmatrelvir/ritonavir in that jurisdiction and to whom the drug is ultimately dispensed. Patients represented in observational studies are generally high-risk individuals with a hospitalization rate well above 3%. Various sub-group analyses show that while, on average, patients seem to benefit from treatment, the benefit is very strongly driven by high-risk individuals, who experience higher absolute risk reductions, with low-risk individuals seeing no reduction in their already low rates of hospitalization/mortality from COVID-19.
The literature is consistent in showing that hospitalization/mortality among treated individuals with risk factors does not generally drop below 1%. BC data also show that ~1% of patients experience serious adverse effects and that the safety concerns are likely to outweigh a potential benefit in patients who have a risk of hospitalization from COVID-19 of less than 1%. Literature is also clear that that risk factors such as age, vaccination status and comorbid conditions continue to be associated with both a higher risk of hospitalization from COVID-19 and a greater likelihood of benefit. Lastly, subgroup analyses show that patients, except for those who are immunocompromised, need more than one risk factor to attain a risk of hospitalization of >1% and derive a benefit from nirmatrelvir/ritonavir. Groups of patients with a single risk factor, for example age over 65 without under-immunization or chronic conditions have been shown not to benefit from nirmatrelvir/ritonavir. A more detailed summary of studies used to support these recommendations is found in Table 1. Studies that report outcomes in duplicate from the same data sets have been omitted. In short: This was a retrospective, population-based cohort study from Israel conducted during the Omicron wave.
Patients were eligible to receive nirmatrelvir/ritonavir if they scored 2 points or more on a scoring system -age over 65 was given 2 points, most chronic conditions were given 1 point and un-vaccination was given 9 points. 3,902 nirmatrelvir/ritonavir recipients were compared to 105,352 nirmatrelvir/ritonavir nonrecipients for the primary endpoint of hospitalization and death in the 30 days of testing positive. The overall event rate in the study was very low (<1%). Those who has a higher risk of hospitalization/death (those 65 and older) saw a statistically significant benefit from nirmatrelvir/ritonavir (59 events / 100,000 patient days vs. 15 events / 100,000 patient days), whereas lower-risk individuals did not. Within those 65 and older, the benefit was driven by higher risk individuals such as those with immunosuppression (HR 2.23), cancer (HR 2.17), renal failure (HR 2.88), neurological disease (HR 2.01), COPD and diabetes (HR 1.5).
All other elderly with less severe comorbidities such as smoking, obesity and TIA did not derive a benefit from nirmatrelvir/ritonavir.
# Yip et. al. Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalization in Community Coronavirus Disease 2019 Patients (COVID-19), Clinical Infectious Diseases
This was a study of approximately 15,000 patients from China during the BA. 2 wave of Omicron. Those who received nirmatrelvir/ritonavir were compared to those who received standard of care for the primary endpoint of hospital admission in the 30 days after testing positive. Patients in the study had a median age of ~75 years old, 58% did not receive a primary vaccine series and most had multiple comorbidities, with 1/3 having a diagnosis of diabetes. Incidence of hospitalization was lower in nirmatrelvir/ritonavir users than in those receiving standard of care (3.5% vs. 1.6%). The high event rate was attributed to a large number of risk factors in the study population who was offered treatment. The largest cohort study (750,000 individuals) from the US where nirmatrelvir/ritonavir recipients were compared to those who did not receive nirmatrelvir/ritonavir. Overall, there was a statistically significant reduction in hospitalization due to COVID-19 (0.47% vs. 0.86%); however, there were many subgroups that did not benefit from treatment, including those with 3 or more mRNA vaccine doses and those with 1 or no underlying health care conditions. Elderly patients were more likely to benefit, but those with no underlying health conditions saw no benefit from treatment, and their hospitalization rate was below 0.5% in both groups. In this cohort study, patients were eligible for nirmatrelvir/ritonavir in QC if they did not receive a primary series of COVID-19 vaccination, or if they were immunocompromised. Those over 70 could receive nirmatrelvir/ritonavir if fully vaccinated in rare cases at the discretion of the prescriber. Overall, there was a benefit from nirmatrelvir/ritonavir (3.56% vs. 11.5%) in the primary endpoint of COVID-associated hospitalization; however, those fully vaccinated did not benefit (7.53% vs. 8.43% p=0.321) from treatment.
Most elderly in this study (76%) did not receive a primary vaccine series and those who received a vaccine dose in the last 6 months derived no benefit from nirmatrelvir/ritonavir (11.6% vs. 13%). The high rate of event was attributed to the fact that most patients in the study were unvaccinated.
Therapeutics Initiative: Paxlovid in British Columbia -an interim real-world analysis. TI Letter
This study was conducted in collaboration with the Therapeutics Initiative where groups of nirmatrelvir/ritonavir recipients (CEV 1, CEV 2, CEV 3 and non-CEV patients) and compared to nonrecipients for the primary endpoint of all-cause hospitalization and mortality. Statistically significant differences were seen in the CEV 1 and CEV 3 populations, for a risk reduction of approximately 50%; CEV 2 patients experienced a reduction but it did not reach statistical significance. Importantly, those who were non-CEV experienced a higher, albeit non-statistically significant event rate after taking nirmatrelvir/ritonavir than non-recipients (1.9% vs. 1%). Non-CEV patients who were offered nirmatrelvir/ritonavir were in general those with multiple risk factors such as age, lack of optimal vaccination and 3 or more comorbidities.
Nirmatrelvir/ritonavir for symptom relief or to prevent Long COVID Other potential benefits of nirmatrelvir/ritonavir have thus far not been consistently shown in the literature.
As demonstrated by EPIC-SR, nirmatrelvir/ritonavir has no impact on the time to symptom alleviation.
Another study of a novel compound VV116 vs. nirmatrelvir/ritonavir in symptom resolution showed that on average, patients had 5.5. days of symptoms irrespective of the drug they took, and that was virtually identical to an observational cohort of patients from the same region in the same time period. The impact of nirmatrelvir/ritonavir on post-COVID condition, or long COVID, is also inconsistent. For example, a recent study from California showed that nirmatrelvir/ritonavir takers experienced a slightly higher, non-statistically significant rate of post-COVID condition based on self-reports, whereas a study published by the Lancet claimed to observe a benefit in treated patients when ICD-10 codes for non-specific conditions such as diabetes, arrhythmia and shortness of breath were taken to represent development of post-COVID condition.
# Remdesivir
Remdesivir is an intravenous antiviral initially evaluated in severely ill inpatients with COVID-19 requiring oxygen support in a landmark trial ACTT-1. It was approved by Health Canada for this indication, and some nationally procured supply remains unused due to subsequent data showing its lack of impact on meaningful outcomes in the severely ill population.
In December 2021, a trial called PINETREE was published:
o The trial evaluated remdesivir in 562 mildly-moderately ill outpatients o Patients were randomized to receive remdesivir 200mg IV on day 1, followed by 100mg on days 2 and 3 or placebo and evaluated in a double-blind fashion o Patients were included if they presented within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions) o The trial was stopped when only 45% of the planned population was recruited due to widespread use of vaccination and the availability of proven treatments making randomization to placebo ethically challenging o The primary outcome was COVID-19-related hospitalization or death from any cause o 2 of 279 patients (0.7%) in the remdesivir group and in 15/283 (5.3%) in the placebo group met the primary endpoint, p=0.008. o This equated to an 87% relative risk reduction, a 4.6% ARR and a NNT of 22, which is slightly higher than nirmatrelvir/ritonavir or sotrovimab (17 and 20, respectively). o A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a COVID-19-related medically attended visit by day 28 an no patients died by day 28. o Remdesivir was generally well tolerated; transaminases may need to be monitored in patients with baseline elevations of liver enzymes. Remdesivir has been given to patients with renal disease with and without dose adjustments; however, it was not evaluated in this trial and this population is excluded from Canadian labelling.
Remdesivir has the advantage of having few drug interactions while maintain comparable risk reductions to nirmatrelvir/ritonavir. However, the 3-day IV dosing regimen is difficult to administer, and the CTC recommends that it be used if nirmatrelvir/ritonavir cannot be prescribed only in the highest-risk population (patients with a ≥ 5% risk of hospitalization from Omicron). The NIH recommends remdesivir as an alternative to nirmatrelvir/ritonavir with a Grade BII rating. The IDSA suggests remdesivir with a conditional rating and low certainty evidence.
# Sotrovimab:
Sotrovimab has been evaluated in a single peer-reviewed, double blind, randomized-placebo controlled trial (COMET-ICE):
o 1057 patients with mild symptoms of COVID-19 and at least one risk factor for disease progression were included o Patients were randomized to receive a single dose of sotrovimab 500mg IV compared to placeb o Most patients were younger (<50) and had one single chronic condition, with obesity being the most prevalent comorbidity o The primary endpoint was a composite outcome of all-cause hospitalization for >24 hours or death within 29 days of the receipt of the infusion o Out of the 528 patients who received sotrovimab, 6 met the primary endpoint of hospitalization or death vs.
30 of the 529 who received placebo (1% vs. 6%; p<0.001; ARR=5%, NNT=20). There were only 2 deaths observed (placebo arm); the primary endpoint was driven entirely by hospitalizations. o Hospitalizations were consistent with progressive COVID-19 requiting oxygen support and hospital-level care; only 1 hospitalization was not COVID-related o Secondary outcome results demonstrated that sotrovimab significantly reduced progression to severe/critical respiratory COVID-19 compared with placebo (1 vs. 5% p=0.002) o Sotrovimab did not reduce length of stay or ICU-bed-days o The proportion of patients reporting adverse events was similar between treatment groups; sotrovimab was well tolerated, and no safety concerns were identified; 6 patients in each placebo and sotrovimab groups experienced mild to moderate infusion reactions.
The COMET-ICE trial was well conducted, with a high degree of generalizability posing no major concerns during critical appraisal. Sotrovimab is given a positive conditional recommendation by the Infectious Diseases Society of America and a Grade AIIa recommendations supporting its use by the NIH.
# Tixagevimab/cilgavimab
Tixagevimab/cilgavimab is a long-acting monoclonal antibody cocktail initially approved in Canada for the prevention of COVID-19 in those who are unlikely to mount an adequate immune response to COVID-19 vaccination or in whom such vaccination is contraindicated.
Tixagevimab/cilgavimab was also evaluated for treatment in a double-blind placebo-controlled trial called TACKLE:
o 910 unvaccinated patients with mild-moderate COVID-19 presenting within 7 days of symptom onset were assigned in a 1:1 fashion to received tixagevimab/cilgavimab 600mg IM x 1 dose or placebo o The primary endpoint was COVID-19 hospitalization or death from any cause through day 29 o The median age of participants was 46.1 years; 90% were at high risk of progression of COVID-19 defined as age over 65 or presence of a comorbidity. The most commonly occurring comorbidities were obesity, smoking and hypertension o Out of the 415 patients who received placebo, 37 (9%) met the primary outcome vs. 18/407 (4%) in the tixagevimab/cilgavimab arm for an adjusted relative risk reduction of 50.5% [95% CI 14.6-71.3]; p=0.0096 o The absolute risk reduction was 4.5% (95% CI 1.1-8.0; p<0•0001), for a number needed to treat of 22 o Tixagevimab/cilgavimab was generally well tolerated and no differences between it and placebo were observed (29% vs. 36%) o There was one myocardial infraction and one sudden cardiac death, both in the tixagevimab/cilgavimab arm Overall, the TACKLE trial, which was carried out mainly during the delta wave and was similar to trials of nirmatrelvir/ritonavir, remdesivir and sotrovimab, demonstrated a lower relative risk reduction than those agents, despite the baseline hospitalization rate being slightly higher.
# Molnupiravir
Molnupiravir is a nucleotide analogue which when incorporated into viral RNA causes base-pair mismatch leading to mutations and viral catastrophe. The mechanism of action of the drug has been scrutinized by regulators for the theoretical fear of promoting emergence of variants of concern due to promoting mutations as well as reproductive safety.
Molnupiravir was evaluated by a randomized, double-blind placebo-controlled trial called MOVe-Out: o 1408 outpatients with mild-moderate COVID-19 presenting within 5 days of symptom onset were assigned in a 1:1 fashion to receive molnupiravir 800mg PO BID x 5 days or placebo o The primary endpoint was all cause hospitalization or mortality within 29 days o The trial stopped when a pre-planned interim analysis revealed that it met the primary endpoint with a 50% relative risk reduction and a p value (set at p<0.0092 to allow for alpha spending) which was statistically significant o In that analysis, 28/385 (7.3%) of patients on active treatment experienced the primary outcome, vs. 53/377 (14.1%) who received placebo, for an ARR of 6.8%. Trial recruitment stopped, but there were still another ~600 patient who were undergoing 29-day follow-up. o In the final analysis published in December 2021, it was discovered that the ARR for the entire trial population declined to just 3%, with 6.8% (48/709) patients in the treatment arm experiencing the primary outcome vs. 9.7% (68/699) in the placebo arm o This difference, if the same pre-specified p-value from the interim analysis is applied, is not statistically significant (p=0.0218. A time-to-event analysis depicted by a Kaplan-Meier curve as also not statistically significant o Data from the FDA reveal that during the second half of the study, the event rate was numerically higher in the molnupiravir arm than the placebo arm (20 vs. 15 events, respectively). o The primary outcome appeared to be driven by very high event rates (>20%) that were apparent in countries like Brazil, whereas higher income countries like the US had no appreciable reductions in hospitalization resulting from the effects of the drug.
Molnupiravir carries the advantage of having few or no drug-drug interactions and is not impacted by renal or liver disease. Such details, however, are not currently available as the drug is undergoing evaluation by Health Canada and the monograph has not been issued in Canada.
# Repurposed Therapies
The CTC has evaluated various other therapies that are not routinely recommended, including colchicine and the abovementioned SSRI fluvoxamine.
In short, Colchicine was evaluated at 0.6 mg PO BID x 3 days, then 0.6 mg daily x 27 days in a single large Canadian RCT (COLCORONA) and demonstrated a reduction in progression of COVID-19 and hospitalization in a sub-group of patients with PCR confirmed COVID-19. The trial was stopped early; due to decreased power leading to the low certainty of its results, as well as a higher risk of adverse events (diarrhea and blood clots) guidelines (WHO, NIH) do not recommend colchicine. The CTC states that if colchicine is used outside of clinical trials, full disclosure of risks and benefits with consideration of patient values are necessary.
Overall, the uptake of the drug in BC has been very low to none.
Fluvoxamine was evaluated at 100 mg PO BID x 14 days in a Brazilian RCT and shown to reduce emergency room visits > 6 hours, a surrogate endpoint for hospitalizations. It has not demonstrated a benefit in reducing actual hospitalizations from COVID-19, length of stay or mortality. For every 12 trial participants, one additional patient stopped fluvoxamine prematurely. Due to low generalizability from a very high event rate, as well as lack of robust safety data, guidelines (e.g., IDSA) do not recommend the use of fluvoxamine outside of clinical trials. A Canadian fluvoxamine study stopped enrolment due to futility. The CTC states that if fluvoxamine is used outside of clinical trials, full disclosure of risks and benefits with consideration of patient values are necessary. There were also additional concerns posed about the lack of full safety evaluation with this dose. The recommended starting dose in patients over 55 years old is 25mg daily, whereas the trial's dosing is 8 times that dose. As fluvoxamine can cause a variety of side effects such as hypotension, dizziness, falls, QT prolongation and GI effects, the safety of this regimen deserves further study before the drug can be routinely used for treating COVID-19.
Five trials have evaluated inhaled steroids for the symptomatic relief of COVID-19 manifestations such as shortness of breath and cough, showing that treatment with inhaled steroids reduces symptoms and may reduce the need for hospitalization (although the latter has not been consistently demonstrated and has thus far been a secondary endpoint of most trials). Due to familiarity and safety, inhaled budesonide 800 μg twice daily or ciclesonide 320 μg twice for 14 days may be considered on a case-by-case basis in adults with lower respiratory tract symptoms of COVID-19 aged 65 and over or aged 50 and over with underlying health conditions and within 14 days of symptom onset, acknowledging the limitations of these trials. There is no evidence to combine inhaled steroids with nirmatrelvir/ritonavir or remdesivir; some inhaled steroids interact with nirmatrelvir/ritonavir. | None | None |
aee55edfd36bd36fc9cbf60106d68e468fd8dd38 | cma | None | # MANITOBA OPIOID AGONIST THERAPY RECOMMENDED PRACTICE MANUAL
# Introduction: Recommendations for Opioid Use Disorder
# EVIDENCE SUMMARY
The treatment of choice for people with opioid use disorder (OUD) is opioid agonist therapy (OAT), ideally, though not necessarily, in combination with psychosocial interventions such as counseling, contingency management, and/or peer support. The main options for OAT include buprenorphine/naloxone (Suboxone) and methadone, with Sustained Release Oral Morphine (SROM) as a third line option. Novel long-acting formulations of buprenorphine are also available.
# First-line Treatment
Due to its comparable effectiveness and an enhanced safety and side-effect profile, buprenorphine/naloxone is the preferred first-line treatment for OUD. For the majority of people with OUD, it should be used preferentially. Further reasons to strongly consider buprenorphine/naloxone as the optimal pharmacologic treatment include significant alcohol, benzodiazepine, or other sedative/hypnotic use, or significant respiratory disease.
Consideration for methadone as an alternative agent may be appropriate in the presence of: Significant cirrhosis (where activity of the naloxone component is enhanced due to reduced first pass effect, causing problematic withdrawal symptoms), Previous failed treatment with buprenorphine/naloxone, or Very high opioid tolerance unlikely to stabilize on a partial opioid agonist.
Personal preference should also be considered, though it is important to ensure that people understand the risks and benefits of the various OAT medications and make an informed choice.
In rare situations, a third-line option such as SROM or injectable OAT (iOAT) may be appropriate, in consultation with an addiction medicine specialist. Please see Alternative Treatment Approaches for OUD Including SROM (Kadian®) for detailed recommendations.
# Opioid Antagonists
Alternative pharmacologic options that have been studied include opioid antagonists. While there is emerging evidence to support sustained release injectable naltrexone as an alternative to OAT in some populations, it is not currently available in Canada.
Oral naltrexone is available but is not supported by the evidence. However, in people who decline OAT in favour of abstinence-based treatment, oral naltrexone may be considered as an adjunct to reduce risk of overdose in the event of resumption of opioid use.
# Detox NOT Recommended
Withdrawal management, or detox, without transition to OAT and long-term treatment is specifically NOT recommended as it has been associated with increased morbidity, such as HIV transmission, and mortality secondary to overdose.
If people decline OAT despite the risks, a slow outpatient taper of opioids is a safer approach than admission to a hospital or residential detox setting. Other considerations to improve safety include the use of oral naltrexone for overdose protection, take-home naloxone for overdose treatment, and enrolment in intensive psychosocial interventions including long-term residential treatment or recovery housing. Please refer to Alternative Treatment Approaches for OUD for further considerations around home-based withdrawal management.
# Harm-Reduction is Paramount
Finally, there is ample evidence to support harm-reduction interventions for all people who use opioids, including those engaged in OAT or other treatment.
# In Summary
For the treatment of opioid use disorder, the evidence suggests:
- OAT with buprenorphine is the preferred first-line treatment.
- OAT with methadone is an alternative first-line treatment.
- OAT with SROM or injectable options are specialist-led approaches for severe or complex disease.
- Oral naltrexone is not recommended as primary treatment. It may be used to reduce the risk of overdose if OAT is refused.
- Withdrawal management (i.e., detox), without immediate transition to OAT and longterm treatment, is NOT recommended.
- Harm reduction interventions, including supply distribution, supervised consumption, and take-home-naloxone training should be widely available, promoted, and considered standard of care for all people at risk of opioid related harms. | # MANITOBA OPIOID AGONIST THERAPY RECOMMENDED PRACTICE MANUAL
# Introduction: Recommendations for Opioid Use Disorder
# EVIDENCE SUMMARY
The treatment of choice for people with opioid use disorder (OUD) is opioid agonist therapy (OAT), ideally, though not necessarily, in combination with psychosocial interventions such as counseling, contingency management, and/or peer support. The main options for OAT include buprenorphine/naloxone (Suboxone) and methadone, with Sustained Release Oral Morphine (SROM) as a third line option. Novel long-acting formulations of buprenorphine are also available.
# First-line Treatment
Due to its comparable effectiveness and an enhanced safety and side-effect profile, buprenorphine/naloxone is the preferred first-line treatment for OUD. For the majority of people with OUD, it should be used preferentially. Further reasons to strongly consider buprenorphine/naloxone as the optimal pharmacologic treatment include significant alcohol, benzodiazepine, or other sedative/hypnotic use, or significant respiratory disease.
Consideration for methadone as an alternative agent may be appropriate in the presence of: Significant cirrhosis (where activity of the naloxone component is enhanced due to reduced first pass effect, causing problematic withdrawal symptoms), Previous failed treatment with buprenorphine/naloxone, or Very high opioid tolerance unlikely to stabilize on a partial opioid agonist.
Personal preference should also be considered, though it is important to ensure that people understand the risks and benefits of the various OAT medications and make an informed choice.
In rare situations, a third-line option such as SROM or injectable OAT (iOAT) may be appropriate, in consultation with an addiction medicine specialist. Please see Alternative Treatment Approaches for OUD Including SROM (Kadian®) for detailed recommendations.
# Opioid Antagonists
Alternative pharmacologic options that have been studied include opioid antagonists. While there is emerging evidence to support sustained release injectable naltrexone as an alternative to OAT in some populations, it is not currently available in Canada.
Oral naltrexone is available but is not supported by the evidence. However, in people who decline OAT in favour of abstinence-based treatment, oral naltrexone may be considered as an adjunct to reduce risk of overdose in the event of resumption of opioid use.
# Detox NOT Recommended
Withdrawal management, or detox, without transition to OAT and long-term treatment is specifically NOT recommended as it has been associated with increased morbidity, such as HIV transmission, and mortality secondary to overdose.
If people decline OAT despite the risks, a slow outpatient taper of opioids is a safer approach than admission to a hospital or residential detox setting. Other considerations to improve safety include the use of oral naltrexone for overdose protection, take-home naloxone for overdose treatment, and enrolment in intensive psychosocial interventions including long-term residential treatment or recovery housing. Please refer to Alternative Treatment Approaches for OUD for further considerations around home-based withdrawal management.
# Harm-Reduction is Paramount
Finally, there is ample evidence to support harm-reduction interventions for all people who use opioids, including those engaged in OAT or other treatment.
# In Summary
For the treatment of opioid use disorder, the evidence suggests:
OAT with buprenorphine is the preferred first-line treatment.
OAT with methadone is an alternative first-line treatment.
OAT with SROM or injectable options are specialist-led approaches for severe or complex disease.
Oral naltrexone is not recommended as primary treatment. It may be used to reduce the risk of overdose if OAT is refused.
Withdrawal management (i.e., detox), without immediate transition to OAT and longterm treatment, is NOT recommended.
Harm reduction interventions, including supply distribution, supervised consumption, and take-home-naloxone training should be widely available, promoted, and considered standard of care for all people at risk of opioid related harms. | None | None |
ea7d3321ebdf9cfbbc9b55e3eebe85832c16e319 | cma | None | # Introduction
Castration-resistant prostate cancer (CRPC) is defined by disease progression despite castrate levels of testosterone and may present as either a continuous rise in serum prostatespecific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases.
Advanced prostate cancer has been known under a few names over the years, including hormone-resistant prostate cancer (HRPC) and androgen-insensitive prostate cancer (AIPC). Most recently, the terms castration-resistant prostate cancer or castration-recurrent prostate cancer were introduced with the realization that extra-testicular androgen production plays a significant role in the resistance of prostate cancer cells to medical or surgical castration therapy. 1 In their second publication, the Prostate Cancer Working Group defined CRPC as a continuum on the basis of whether metastases are detectable (clinically or by imaging) and whether the serum testosterone is in the castrate range by surgical orchidectomy or medical therapy. 2 This definition creates a clinical-states model, where patients can be classified. The rising PSA states (castrate and non-castrate) signify that no detectable (measurable or non-measurable) disease has ever been found. The clinical metastases states (castrate and non-castrate) signify that disease was detectable at some point in the past, regardless of whether it is detectable now. 3 Prognosis is associated with several factors that go beyond PSA levels. These include performance status, presence of visceral metastases, presence of bone pain, extent of disease on bone scan, and serum lactate dehydrogenase and alkaline phosphatase levels. Bone metastases will occur in 90% of men with CRPC and can produce significant morbidity, including pain, pathological fractures, spinal cord compression, and bone marrow failure. Paraneoplastic effects, including anemia, weight loss, fatigue, hypercoagulability, and increased susceptibility to infection, are also common.
CRPC includes patients without metastases or symptoms with rising PSA levels despite androgen deprivation therapy (ADT) to patients with metastases and significant debilitation due to cancer symptoms.
# Management of CRPC
# ADT and first-generation androgen receptor antagonists
Because the androgen receptor remains active in most patients who have developed castration-resistant disease, it is recommended that ADT be continued for the remainder of a patient's life (Level 3,Weak recommendation).
In patients who develop CRPC, the addition or change of first-generation androgen receptor antagonists may be considered (Level 3, Weak recommendation).
To date, no study using first-generation androgen receptor antagonists, when introduced in the CRPC setting, has shown survival benefits; most trials have been small, were not designed to evaluate overall survival (OS), and were heavily confounded by future treatments used. In patients treated with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist monotherapy or those who have had an orchidectomy, the addition of androgen receptor antagonists, such as bicalutamide, can offer modest PSA responses that are short-lived in 30-35% of patients. 4 For patients who have undergone total androgen blockade (TAB), the anti-androgen (AA) should be discontinued to test for an anti-androgen withdrawal response (AAWD). Changing AA or using corticosteroids with or without ketoconazole have been noted to cause transient PSA reductions in about 30% of patients but have not been shown to improve any of the clinically meaningful outcome measures.
# Detection of metastases and imaging in untreated patients
For patients who progress on ADT without evidence of distant metastases, it is suggested to screen for bone metastases with bone scans and monitor for lymph node and visceral metastases/progression with imaging of the abdomen/pelvis and chest.
Patients with a rapid PSADT (20) are at high risk for developing metastases earlier. 3 Imaging in these patients should be performed every 3-6 months. Patients with a slower PSADT (>10 months) should be screened every 6-12 months (Expert opinion). Imaging techniques most commonly used include nuclear bone scans and abdominal/pelvic CT and chest X-ray. The role of positronemission tomography (PET), such as prostate specific membrane antigen (PSMA)-PET are still unclear and the benefits unknown.
If and when metastases are detected, patients should be treated according to guidelines for metastatic CRPC (mCRPC). How patients are treated in the mCRPC state will depend on what they received prior to becoming mCRPC.
# Non-metastatic CRPC (nmCRPC)
Men with high-risk nmCRPC, defined as a PSA doubling time (PSADT) of less than 10 months, with an estimated life expectancy of greater than five years should be offered apalutamide, enzalutamide, or darolutamide (Level 1,
# Strong recommendation).
Until 2018, there was no standard of care and no approved regimen for the nmCRPC state. The risk of progression to clinical metastases or death is linked to PSADT. PSADT of less than 10 months has been correlated with worse outcome and has been used in recent clinical trials as the definition for highrisk nmCRPC. Patients in these studies were randomized to treatment + ADT vs. placebo + ADT until the appearance of metastases on conventional imaging (bone scan and computed tomography /magnetic resonance imaging of the abdomen/chest). The three studies used second-generation androgen receptor (AR)-targeted therapies (apalutamide, enzalutamide, and darolutamide) and reported similar results in significantly improving the primary endpoint of metastasesfree survival (MFS). At the first report of results for the three trials, median OS, a secondary endpoint, was not reached but at interim analysis, there was a non-significant improvement in OS for men receiving the AR-targeted therapies. At final analysis, the three agents demonstrated statistically significant improvements in OS. The phase 3 studies have led to Health Canada approvals of apalutamide, enzalutamide, and darolutamide for the treatment of high-risk nmCRPC.
# Summary of results
# Apalutamide
Apalutamide is a second-generation AR ligand-binding domain inhibitor. This agent was tested in combination with standard ADT in patients with nmCRPC at high risk for progression (PSADT of ≤10 months). 5 The median MFS was 40.5 months with apalutamide and 16.2 months with placebo (hazard ratio for metastasis or death 0.28; 95% confidence interval 0.23-0.35; p<0.001). Secondary endpoints analyzed, including progression-free survival (PFS) (local and distant), time to PSA progression, and time to subsequent therapy, were all statistically significantly improved. 5 Although more adverse events were reported in patients receiving ADT + apalutamide vs. ADT + placebo, patient-reported health-related quality of life was similar between both groups. 8 At final survival analysis, median followup time was 52.0 months. Median treatment duration was 32.9 months for apalutamide and 11.5 months for the placebo group. Median OS was significantly longer with apalutamide + ADT compared to placebo + ADT (73.9 months vs. 59.9 months, respectively; HR 0.784; p=0.0161) The trial regimen was discontinued in 42.7% of the treatment group and 73.9% of the placebo group due to progressive disease, and 15.2% vs. 8.4% due to adverse events. The survival benefit was observed even though more than 85% of the patients Guideline: CRPC management in the placebo group received subsequent treatment. The SPARTAN trial concluded that apalutamide reduced the risk of metastasis or death and the MFS and OS benefit was consistent across all subgroups, including all age groups, local or regional nodal disease, and those with shorter or longer PSADT. 9
# Enzalutamide
Enzalutamide is a second-generation AR ligand-binding domain inhibitor. This agent was tested in combination with standard ADT in patients with nmCRPC at high risk for progression (PSADT of ≤10 months). 6 The median MFS was 36.6 months with enzalutamide and 14.7 months with placebo (HR for metastasis or death 0.29; 95% CI 0.24-0.35; p<0.001). Secondary endpoints analyzed, including PFS (local and distant), time to PSA progression, and time to subsequent therapy, were all statistically significantly improved. Although more adverse events were reported in patients receiving ADT + enzalutamide vs. ADT + placebo, patient-reported health-related quality of life was similar between both groups. 10 At final analysis, median follow-up was 48 months. At the time of cutoff, 31% of patients in the enzalutamide cohort and 38% of patients within the placebo group had died. In the enzalutamide cohort, 19% of deaths were from prostate cancer and 12% were not from prostate cancer. In the placebo group, 29% were from prostate cancer and 9% were not from prostate cancer. Median OS was 67 months (95% CI 64-not reached) in the enzalutamide group and 56.3 months (95% CI 54.4-63.0) in the placebo group. Enzalutamide + ADT was associated a 27% lower risk of death than placebo + ADT (HR 0.73; 95% CI 0.61-0.89; p=0.001). 11
# Darolutamide
Daroutamide is a second-generation AR ligand-binding domain inhibitor. This agent was tested in combination with standard ADT in patients with nmCRPC at high risk for progression (PSADT of ≤10 months). 7 The median MFS was 40.4 months with darolutamide and 18.4 months with placebo (HR for metastasis or death 0.41; 95% CI 0.34-0.50; p<0.001). Secondary endpoints analyzed, including PFS (local and distant), time to PSA progression, and time to subsequent therapy, were all statistically significantly improved. 7 Although more adverse events were reported in patients receiving ADT + darolutamide vs. ADT + placebo, patient-reported healthrelated quality of life was similar between both groups. 7 Final analysis was conducted after 254 deaths were observed (15.5% of darolutamide group and 19.1% of placebo control group). Darolutamide had a statistically significant 31% reduction in the risk of death. After a median followup time of 29 months, the median survival rate at three years was 83% in the darolutamide cohort and 77% in the placebo group (HR 0.69; 95% CI 0.53-0.88; p=0.003). The survival benefit was observed even though more than half of the patients in the placebo group received subsequent darolutamide treatment. 12 Apalutamide, enzalutamide, and darolutamide have received Health Canada approval for use in high-risk nmCRPC.
# Treatment of mCRPC
Since mCRPC is generally associated with a high risk of morbidity and cancer-related mortality, patients with mCRPC detected on conventional imaging should be considered for systemic therapy with demonstrated survival benefits. Patients with mCRPC should optimally receive multidisciplinary care to maximize survival and quality of life. Because any treatment for advanced disease remains non-curative, patients with advanced prostate cancer should be encouraged to participate in clinical trials.
# I. AR signaling therapeutic options
In men with CRPC, phase 3 clinical trials have evaluated the role of abiraterone acetate and enzalutamide in both the chemo-naive and post-chemotherapy settings.
# Abiraterone acetate
Abiraterone acetate is a potent and irreversible inhibitor of CYP-17, a critical enzyme in androgen biosynthesis.
In the chemo-naive setting: Abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily is recommended for first-line therapy for asymptomatic or minimally symptomatic mCRPC (Level 1, Strong recommendation).
In asymptomatic or minimally symptomatic patients (defined as pain that is relieved by acetaminophen or a nonsteroidal anti-inflammatory) without visceral metastases, abiraterone acetate significantly improved radiographic PFS (16.5 vs. 8.3 months) (HR 0.53; 95% CI 0.45-0.62; p<0.001) and had a statistically significant 4.4-month improvement in OS (HR 0.81; p=0.0033). 13,14 Abiraterone also significantly delayed time to pain progression, time to chemotherapy initiation, time to opiate initiation, and deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status.
In the post-docetaxel setting: Abiraterone acetate 1000 mg per day plus prednisone 5 mg twice daily is recommended in patients progressing on or after docetaxel-based chemotherapy (Level 1, Strong recommendation).
In the post-docetaxel setting, abiraterone-prednisone compared to placebo-prednisone significantly prolonged median OS by 4.6 months (15.8 vs. 11.2 months; HR 0.74; p=0.0001) in patients with mCRPC who had progressed after docetaxel treatment. Moreover, all secondary endpoints provided support for the superiority of abiraterone over placebo: median time to PSA progression (8.5 vs. 6.6 months; HR 0.63; p<0.0001), radiographic PFS (5.6 vs. 3.6 months; HR 0.66; p<0.0001), confirmed PSA response rate defined as ≥50% reduction in PSA from the pretreatment baseline PSA (29% vs. 5.5%; p<0.0001), and objective response by Response Evaluation Criteria in Solid Tumors (RECIST) (14.8% vs. 3.3%; p<0.0001). 15
# Enzalutamide
Enzalutamide is a potent multi-targeted androgen signalling pathway inhibitor.
In the chemo-naive setting: Enzalutamide 160 mg per day is recommended as first-line therapy for asymptomatic or minimally symptomatic mCRPC (Level 1, Strong recommendation).
In asymptomatic or minimally symptomatic patients (defined as pain that is relieved by acetaminophen or a nonsteroidal anti-inflammatory), enzalutamide decreased the risk of radiographic progression or death by 81% (HR 0.19; 95% CI 0.15-0.23; p<0.001) and the risk of death by 29% (HR 0.71; 95% CI 0.60-0.84; p<0.001) as compared to placebo. The benefit of enzalutamide was demonstrated for all secondary endpoints, including time to initiation of cytotoxic chemotherapy, time to first skeletal-related event (SRE), best overall soft tissue response (59% vs. 5%; p<0.001), time to PSA progression (HR 0.17; p<0.001), and ≥50% PSA decline rate (78% vs. 4%; p<0.001). Enzalutamide also significantly delayed time to pain progression, time to opiate initiation, and deterioration of the ECOG performance status. 16,17 In the post-docetaxel setting: Enzalutamide 160 mg per day is recommended in patients progressing on or after docetaxelbased chemotherapy (Level 1, Strong recommendation).
In patients previously treated with docetaxel, the trial compared enzalutamide and placebo. The study demonstrated a significant advantage in OS of 4.8 months (18.4 vs. 13.6 months; HR 0.62; p<0.0001) and in all secondary endpoints, including confirmed PSA response rate (54% vs. 2%; p<0.001), soft-tissue response rate (29% vs. 4%; p<0.001), time to PSA progression (8.3 vs. 3.0 months; HR 0.25; p<0.001), radiographic PFS (8.3 vs. 2.9 months; HR 0.40; p<0.001), and the time to the first SRE (16.7 vs. 13.3 months; HR 0.69; p<0.001). 18 NOTE: The studies in the chemo-naive setting did not include patients with moderate or severe symptoms; however, abiraterone and enzalutamide may be potential therapeutic options in patients who are deemed chemotherapyineligible or refuse chemotherapy (Expert opinion).
# II. Chemotherapy
# First-line systemic chemotherapy
# Docetaxel
# Docetaxel 75 mg/m 2 intravenous (IV) every three weeks with 5 mg oral prednisone twice daily is recommended for patients with mCRPC (Level 1, Strong recommendation).
The TAX-327 study randomized 1006 patients to one of three treatment arms: 1) docetaxel 75 mg/m 2 IV every three weeks; 2) docetaxel 30 mg/m 2 weekly for five of six weeks; or 3) control therapy with mitoxantrone. 19 The study reported improved survival with docetaxel (every three weeks) compared with mitoxantrone-prednisone (median survival 18.9 vs. 16.5 months; HR 0.76; 95% CI 0.62-0.94; twosided p=0.009). No OS benefit was observed with docetaxel given on a weekly schedule (HR 0.91; 95% CI 0.75-1.11; two-sided p=0.36). Significantly, more patients treated with docetaxel (every three weeks) achieved a pain response compared with patients receiving mitoxantrone (35% vs. 22%; p=0.01). Quality of life response, defined as a sustained 16-point or greater improvement from baseline on Guideline: CRPC management two consecutive measurements, was higher with docetaxel given every three weeks (22% vs. 13%; p=0.009) or weekly (23% vs. 13%; p=0.005) compared with mitoxantrone. PSA response rates were also statistically significantly higher with docetaxel compared to mitoxantrone. 19 Although patients received up to 10 cycles of treatment if no progression and no prohibitive toxicities were noted, the duration of therapy should be based on the assessment of benefit and toxicities. Rising PSA alone should not be used as the sole criteria for progression; assessment of response should incorporate clinical and radiographic criteria.
# Alternative therapies that have not demonstrated improvement in OS but can provide disease control, palliation, and improve quality of life include weekly docetaxel plus prednisone, and mitoxantrone plus prednisone (Level 2, Weak recommendation).
The
# timing of docetaxel therapy in men with evidence of metastases but without symptoms should be discussed with patients, and therapy should be individualized based on patients' clinical status and preferences (Level 3, Weak recommendation).
Patients who do not respond to first-line ADT or who progress clinically or radiologically without significant PSA elevations may have neuroendocrine differentiation. Biopsy of accessible lesions should be considered to identify these patients; these patients should then be treated with combination chemotherapy, such as cisplatin/etoposide or carboplatin/etoposide (Level 3, Weak recommendation).
# Second-line systemic chemotherapy
# Cabazitaxel
# Cabazitaxel is recommended for mCRPC patients progressing on or following docetaxel (Level 1, Strong recommendation).
A phase 3 study comparing cabazitaxel to mitoxantrone in patients previously treated with docetaxel has shown a statistically significant survival advantage. 20 This randomized, placebo-controlled trial recruited 755 docetaxel-pretreated CRPC patients. OS was the primary endpoint of the study. Patients were randomized to receive prednisone 10 mg/day with three times weekly mitoxantrone 12 mg/m 2 or cabazitaxel 25 mg/m 2 . An advantage in survival emerged in favor of the cabazitaxel group, with a median survival of 15.1 months compared with 12.7 months in the mitoxantrone group (HR 0.70; 95% CI 0.59, 0.83; p<0.0001). 20 A recent phase 3 study comparing cabazitaxel 25 mg/m 2 vs. 20 mg/m 2 resulted in non-inferiority for cabazitaxel 20 mg/m 2 with less adverse events. Of note, in the subgroup analysis of patients who had received both docetaxel and abiraterone/enzalutamide, results appeared to favor a higher dose of cabazitaxel. 21
# Other options
For patients who have had a good response to first-line docetaxel, re-treatment with docetaxel can be considered (Expert opinion, Weak recommendation). 22,23 Mitoxantrone has not shown any survival advantage but may provide symptomatic relief. Mitoxantrone may be considered a therapeutic option in symptomatic patients with mCRPC in the first-or second-line setting (Expert opinion, Weak recommendation).
# III. Bone-targeted therapy
# Life-prolonging therapy
# Radium-223
# Radium-223 every four weeks for six cycles is recommended in patients with pain due to bone metastases and who do not have visceral metastases (Level 1, Strong recommendation).
Radium-223 (previously known as alpharadin) is an intravenous alpha-emitting agent that mimics calcium, preferentially targeting bone metastases. In a randomized, phase 3 study, radium-223 given every four weeks for six cycles was compared to placebo. 20 Radium-223 demonstrated a significant improvement in OS and symptomatic SREs. OS was improved by 3.6 months (HR 0.7; p<0.0001) and symptomatic SREs were delayed by 5.8 months (p<0.0001). The study included patients with symptomatic bone metastases who were post-docetaxel or ineligible for docetaxel. 24 The study excluded patients with visceral metastases or lymph node metastases greater than 3 cm. PSA measurements while receiving radium-223 cannot provide evidence of whether patients are benefitting or not. Given the mechanism of action of the drug, alkaline phosphatase appears to be better marker of activity. A phase 3 study in the first-line mCRPC setting compared radium-223 in combination with abiraterone/prednisone vs. abiraterone/prednisone alone and demonstrated no advantage and an increased risk of fractures. 25 Radium-223 should not be combined with abiraterone. A bone-supportive agent (denosumab or zoledronic acid) should always be used when using radium-223 (Level 1, Strong recommendation).
# Patients with homologous recombination repair (HRR) mutations
# Olaparib
# Olaparib 300 mg twice daily is recommended for patients with mCPRC and HRR mutation who have progressed on a previous androgen receptor-axis-targeted therapy (ARAT) (Level 1, Strong recommendation).
# Saad et al
HRR gene mutations occur in approximately 20-30% of prostate cancers from patients with metastatic disease, with the most common altered gene being BRCA2. Defective HRR renders a cancer susceptible to poly (ADP-ribose) polymerase (PARP) inhibition in a form of synthetic lethality. A randomized, phase 3 trial (PROfound) compared the PARP inhibitor, olaparib 300 mg BID, with physician's choice enzalutamide/abiraterone in patients with mCRPC with HRR mutations. Patients with HRR mutations and progression on prior enzalutamide and/or abiraterone with or without prior exposure to a taxane (docetaxel, cabazitaxel) were eligible. The primary endpoint of the study was radiographic PFS in patients with BRCA1/2 or ATM mutations. Results favored olaparib (7.39 vs. 3.44 months 20.86, 95% CI 4.18, 379.18, p<0.001) and delay in pain progression (HR 0.44, 95% CI 0.22, 0.91, p=0.0192). Adverse events were more common in the olaparib arm (anemia, fatigue, nausea, diarrhea), however, patients reported health-related quality of life was improved in the olaparib arm of the study.
The Health Canada approval of olaparib is for patients with deleterious or suspected deleterious germline or somatic BRCA1/2 or ATM mutations who have progressed following prior treatment with enzalutamide or abiraterone. The U.S. Food and Drug Administration has approved olaparib for prostate cancers harboring a broader spectrum of 11 additional genes that are directly or indirectly involved in HRR (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L), which comprised an additional cohort in the PROfound study. The European regulatory authority has approved olaparib only for BRCA1/2 alterations. Further study is required to define optimal biomarker selection criteria to select patients with mCRPC with the highest potential for benefit from PARP inhibitors, as well as timing around taxane chemotherapy.
# Supportive agents
# Denosumab and zoledronic acid
In men with CRPC and bone metastases, denosumab (120 mg subcutaneous ) or zoledronic acid (4 mg IV) every four weeks are recommended to prevent disease-related SREs, including pathological fractures, spinal cord com-pression, surgery, or radiation therapy to bone (Level 1, Strong recommendation).
Bone loss associated with ADT has been shown to increase the risk of fracture. Moreover, about 90% of patients with mCRPC will develop bone metastases, which cause local decreases in bone integrity. Patients are at significant risk of SREs that include pathological fractures, debilitating bone pain requiring palliative radiation therapy, and spinal cord compression. Quality of life is affected by these complications.
Zoledronic acid is a third-generation nitrogen containing bisphosphonate. Bisphosphonates other than zoledronic acid are not known to be effective to prevent disease-related SREs. In the placebo-controlled zoledronic acid study, fewer men receiving zoledronic acid had SREs (38% vs. 49%; p=0.02). 31 Zoledronic acid also increased the median time to first SRE (488 vs. 321 days; p=0.01). There was an overall 36% reduction in the rate of SREs in treated patients. 31 Treatment with zoledronic acid should not be used in men with baseline creatinine clearance <30 mL/min.
Denosumab is a fully humanized monoclonal antibody against RANK ligand. It has been shown to be effective in preventing bone loss and new vertebral fractures due to ADT. 30 In the setting of mCRPC, denosumab (120 mg SC every four weeks) compared to zoledronic acid (4 mg IV every four weeks) has shown significant improvement in the time to the first SRE (20.7 vs. 17.1 months; p<0.001 for non-inferiority; p=0.008 for superiority), while OS and PFS were not different. 32 No dose modification for renal function is necessary in the case of denosumab; however, the risk of hypocalcemia is increased and calcium monitoring and supplementation (with calcium and vitamin D) is recommended for both denosumab and zoledronic acid. Denosumab has not been studied, however, in patients with severe renal impairment (glomerular filtration rate <30 ml/min).
Good oral hygiene, baseline dental evaluation for high-risk individuals, and avoidance of invasive dental surgery during therapy are recommended to reduce risk of osteonecrosis of the jaw (ONJ) for patients treated with bone-targeted therapies (Expert opinion). Zoledronic acid and denosumab have been used in combination with all the agents presently in use for the treatment of mCRPC. To date, there have been no additional safety issues of concern that have been reported.
The optimal duration of zoledronic acid and denosumab in men with CRPC and bone metastases is undefined. The risk of ONJ appears to be related to time on bone-targeted therapy, therefore, caution should be taken in using these agents beyond two years (Level 3, Weak recommendation).
Denosumab and zoledronic acid are not approved and not indicated for SRE prevention in the treatment of metastatic castration-sensitive prostate cancer or for bone metastases prevention.
# Guideline: CRPC management
# IV. Other supportive care therapies
# Systemic corticosteroid therapy
Corticosteroid therapy with low-dose prednisone or dexamethasone may also offer improvements in PSA values and/ or palliative outcomes in up to 30% of patients in both symptomatic and asymptomatic men. Steroids may also exert an anti-neoplastic effect on prostate cancer (Level 3, Weak recommendation). 33
# Palliative radiation
Bone metastases from prostate cancer are often radiosensitive and most men will experience partial or complete pain relief from external beam radiation to a specific lesion. 34 Studies have shown that a single fraction of standard palliative radiotherapy (RT) is as effective as five or more fractions in providing palliation. However, more patients require retreatment for pain recurrence with single fraction radia- Palliative radiation therapy should be considered in patients with pain 1. The optimal sequence of available options remains unknown. In general, it is felt that changing therapeutic mechanism of action with each line of therapy is likely to lead to better and longer-lasting response (Expert opinion).
- Patients who have had little or no response to hormonal agents OR who progress with minimal change in PSA OR with significant visceral metastases should be considered for early chemotherapeutic options.
- Radium-223 is not approved for patients with visceral metastases.
# Summary
Health Canada-approved agents that have shown improvements in survival in mCRPC now include abiraterone, enzalutamide, docetaxel, cabazitaxel, and radium-223. Health Canada-approved agents that have shown improvements in delaying metastases in high-risk nmCRPC include apalutamide, enzalutamide, and darolutamide. Bone-supportive agents and palliative radiation continue to play an important role in the overall management of mCRPC. Given the complexity, variety, and importance of optimizing the use of these agents, a multidisciplinary team approach is highly recommended.
Saad et al tion. Stereotactic body RT (SBRT) is a more precise and may be a more effective form of palliation delivered in five or fewer treatments and may also be considered, particularly for oligometastatic disease where high-dose RT is currently being studied for improved oncological outcomes.
Malignant spinal cord compression is an oncological emergency that requires immediate diagnosis with an MRI if suspected. Options for treatment are debulking surgery + RT, vertebrectomy with stabilization and RT, or RT + steroids (Level 1, Strong recommendation).
# Conclusions
Advances in treatment for men with CRPC have improved survival and quality of life, but most, if not all, patients eventually succumb to their disease and better treatments are required. Several new agents are being studied in all states of CRPC and an increase in options is likely in the near future. Because CRPC remains an incurable and ultimately fatal illness, inclusion of patients in clinical trials remains paramount.
A summary on the recommended treatment of CRPC is shown in Fig. 1.
Competing interests: Dr. Saad has been an advisory board member for and has received payment/ honoraria from Abbvie, Amgen, Astellas, Bayer, Janssen, and Sanofi; and has participated in clinical trials supported by Amgen, Astellas, Bayer, Janssen, and Sanofi. Dr. Aprikian has been an advisory board member for Abbvie, Astellas, and Bayer; and has received grants from Abbvie, Astellas Bayer, Sanofi, and TerSera. Dr. Finelli has been an advisory board member for Abbvie, Astellas, Bayer, Janssen, Ipsen, Sanofi, and TerSera; and has participated in clinical trials supported by Astellas, Bayer, and Janssen. Dr. Fleshner has been a consultant or advisory board member for Abbvie, Amgen, Astellas, Bayer, Ferring, Hybridyne Health, Janssen, and Sanofi; and has participated in clinical trials supported by Astellas, Bavarian Nordic, Bayer, Ferring, Janssen, Medivalion, Nucleix, Progenics Pharmaceutical, Sanofi, and Spectracure AB. Dr. Gleave has been a consultant for and has received honoraria/grants from Abbvie, Amgen, Astellas, Bayer, GDx, Janssen, MDX, Pfizer, and Sanofi; and is founder/holds a patent with OncoGenex. Dr. Kapoor has been an advisory board member for BMS, Eisai, Ipsen, Merck, Novartis, Pfizer, and Roche; a speakers' bureau member for Eisai, Ipsen, Novartis, and Roche; and has received grants/honoraria from BMS, Eisai, Ipsen, Merck, Novartis, Pfizer, and Roche. Dr. Niazi has received research grants and honoraria from Abbvie, Amgen, Astellas, Astra Zeneca, Bayer, Janssen, and Sanofi; and has participated in clinical trials supported by Astellas, Ferring, Janssen, and Sanofi. Dr. North has been an advisory board member for Astellas, has received honoraria from Astra Zeneca, Astellas, Janssen, Merck, Roche, and Sanofi; and has participated in clinical trials supported by Astra Zeneca, Merck, Roche, and Sanofi. Dr. Pouliot has been an advisory board member for Amgen, Astellas, Bayer , and Janssen; has received payment from Abbott, Amgen, Astellas, Astra Zeneca, Bayer, Ferring, Janssen, and Sanofi; has received grants from Astra Zeneca and Sanofi; and has participated in clinical trials supported by Astellas, Bayer, Ferring, and Janssen. Dr. Rendon has been an advisory board and speakers' bureau member for and has received honoraria from Abbvie, Amgen, Astellas, Astra Zeneca, Bayer, Ferring, Jansen, and Sanofi. Dr. Shayegan has been an advisory board member for Astellas, Bayer, and Janssen; and has received a research grant from Janssen. Dr. Sridhar has been an advisory board member for Astellas, AstraZeneca, Bayer, Janssen, Merck, and Roche; and has participated in several pharma-supported clinical trials. Dr. So has been an advisory board member for Abbvie, Amgen, Astellas, Bayer, Janssen, Ferring, and TerSera; and has participated in clinical trials supported by Astellas, Ferring, and Janssen. Dr. Usmani has been an advisory board member for Amgen, Astellas, and Bayer; and has received grants from Best Medical and Concure Oncology Canada. Dr. Vigneault has been an advisory board member for Abbvie, Bayer, Ferring, and Sanofi. Dr. Chi has received honoraria from Astellas, Bayer, Janssen, and Sanofi; and has participated in clinical trials supported by Astellas, Astra Zeneca, Bayer, Eli Lilly, Essa, Janssen, Merck, Novartis, Pfizer, Roche, and Sanofi.
Prior to original publication, this guideline underwent review by the CUA Guidelines Committee, CUA members at large, the CUAJ Editorial Board, and the CUA Executive Board. 2020 updates were approved by the CUA Guidelines Committee.
# CUA-CUOG CRPC guideline summary
Castration-resistant prostate cancer (CRPC) includes a wide range of disease types: from patients without metastases or symptoms with rising prostate-specific antigen (PSA) levels despite androgen deprivation therapy (ADT) to patients with metastases and significant debilitation due to cancer symptoms.
# Androgen deprivation therapy
Because androgen receptor remains active in most patients who have developed castration-resistant disease, it is recommended that ADT be continued for the remainder of a patient's life (Strong recommendation).
# I. Rising | # Introduction
Castration-resistant prostate cancer (CRPC) is defined by disease progression despite castrate levels of testosterone and may present as either a continuous rise in serum prostatespecific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases.
Advanced prostate cancer has been known under a few names over the years, including hormone-resistant prostate cancer (HRPC) and androgen-insensitive prostate cancer (AIPC). Most recently, the terms castration-resistant prostate cancer or castration-recurrent prostate cancer were introduced with the realization that extra-testicular androgen production plays a significant role in the resistance of prostate cancer cells to medical or surgical castration therapy. 1 In their second publication, the Prostate Cancer Working Group defined CRPC as a continuum on the basis of whether metastases are detectable (clinically or by imaging) and whether the serum testosterone is in the castrate range by surgical orchidectomy or medical therapy. 2 This definition creates a clinical-states model, where patients can be classified. The rising PSA states (castrate and non-castrate) signify that no detectable (measurable or non-measurable) disease has ever been found. The clinical metastases states (castrate and non-castrate) signify that disease was detectable at some point in the past, regardless of whether it is detectable now. 3 Prognosis is associated with several factors that go beyond PSA levels. These include performance status, presence of visceral metastases, presence of bone pain, extent of disease on bone scan, and serum lactate dehydrogenase and alkaline phosphatase levels. Bone metastases will occur in 90% of men with CRPC and can produce significant morbidity, including pain, pathological fractures, spinal cord compression, and bone marrow failure. Paraneoplastic effects, including anemia, weight loss, fatigue, hypercoagulability, and increased susceptibility to infection, are also common.
CRPC includes patients without metastases or symptoms with rising PSA levels despite androgen deprivation therapy (ADT) to patients with metastases and significant debilitation due to cancer symptoms.
# Management of CRPC
# ADT and first-generation androgen receptor antagonists
Because the androgen receptor remains active in most patients who have developed castration-resistant disease, it is recommended that ADT be continued for the remainder of a patient's life (Level 3,Weak recommendation).
In patients who develop CRPC, the addition or change of first-generation androgen receptor antagonists may be considered (Level 3, Weak recommendation).
To date, no study using first-generation androgen receptor antagonists, when introduced in the CRPC setting, has shown survival benefits; most trials have been small, were not designed to evaluate overall survival (OS), and were heavily confounded by future treatments used. In patients treated with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist monotherapy or those who have had an orchidectomy, the addition of androgen receptor antagonists, such as bicalutamide, can offer modest PSA responses that are short-lived in 30-35% of patients. 4 For patients who have undergone total androgen blockade (TAB), the anti-androgen (AA) should be discontinued to test for an anti-androgen withdrawal response (AAWD). Changing AA or using corticosteroids with or without ketoconazole have been noted to cause transient PSA reductions in about 30% of patients but have not been shown to improve any of the clinically meaningful outcome measures.
# Detection of metastases and imaging in untreated patients
For patients who progress on ADT without evidence of distant metastases, it is suggested to screen for bone metastases with bone scans and monitor for lymph node and visceral metastases/progression with imaging of the abdomen/pelvis and chest.
Patients with a rapid PSADT (<10 months) or elevated PSA levels (>20) are at high risk for developing metastases earlier. 3 Imaging in these patients should be performed every 3-6 months. Patients with a slower PSADT (>10 months) should be screened every 6-12 months (Expert opinion). Imaging techniques most commonly used include nuclear bone scans and abdominal/pelvic CT and chest X-ray. The role of positronemission tomography (PET), such as prostate specific membrane antigen (PSMA)-PET are still unclear and the benefits unknown.
If and when metastases are detected, patients should be treated according to guidelines for metastatic CRPC (mCRPC). How patients are treated in the mCRPC state will depend on what they received prior to becoming mCRPC.
# Non-metastatic CRPC (nmCRPC)
Men with high-risk nmCRPC, defined as a PSA doubling time (PSADT) of less than 10 months, with an estimated life expectancy of greater than five years should be offered apalutamide, enzalutamide, or darolutamide (Level 1,
# Strong recommendation).
Until 2018, there was no standard of care and no approved regimen for the nmCRPC state. The risk of progression to clinical metastases or death is linked to PSADT. PSADT of less than 10 months has been correlated with worse outcome and has been used in recent clinical trials as the definition for highrisk nmCRPC. Patients in these studies were randomized to treatment + ADT vs. placebo + ADT until the appearance of metastases on conventional imaging (bone scan and computed tomography [CT]/magnetic resonance imaging [MRI] of the abdomen/chest). The three studies used second-generation androgen receptor (AR)-targeted therapies (apalutamide, enzalutamide, and darolutamide) and reported similar results in significantly improving the primary endpoint of metastasesfree survival (MFS). At the first report of results for the three trials, median OS, a secondary endpoint, was not reached but at interim analysis, there was a non-significant improvement in OS for men receiving the AR-targeted therapies. [5][6][7] At final analysis, the three agents demonstrated statistically significant improvements in OS. The phase 3 studies have led to Health Canada approvals of apalutamide, enzalutamide, and darolutamide for the treatment of high-risk nmCRPC.
# Summary of results
# Apalutamide
Apalutamide is a second-generation AR ligand-binding domain inhibitor. This agent was tested in combination with standard ADT in patients with nmCRPC at high risk for progression (PSADT of ≤10 months). 5 The median MFS was 40.5 months with apalutamide and 16.2 months with placebo (hazard ratio [HR] for metastasis or death 0.28; 95% confidence interval [CI] 0.23-0.35; p<0.001). Secondary endpoints analyzed, including progression-free survival (PFS) (local and distant), time to PSA progression, and time to subsequent therapy, were all statistically significantly improved. 5 Although more adverse events were reported in patients receiving ADT + apalutamide vs. ADT + placebo, patient-reported health-related quality of life was similar between both groups. 8 At final survival analysis, median followup time was 52.0 months. Median treatment duration was 32.9 months for apalutamide and 11.5 months for the placebo group. Median OS was significantly longer with apalutamide + ADT compared to placebo + ADT (73.9 months vs. 59.9 months, respectively; HR 0.784; p=0.0161) The trial regimen was discontinued in 42.7% of the treatment group and 73.9% of the placebo group due to progressive disease, and 15.2% vs. 8.4% due to adverse events. The survival benefit was observed even though more than 85% of the patients Guideline: CRPC management in the placebo group received subsequent treatment. The SPARTAN trial concluded that apalutamide reduced the risk of metastasis or death and the MFS and OS benefit was consistent across all subgroups, including all age groups, local or regional nodal disease, and those with shorter or longer PSADT. 9
# Enzalutamide
Enzalutamide is a second-generation AR ligand-binding domain inhibitor. This agent was tested in combination with standard ADT in patients with nmCRPC at high risk for progression (PSADT of ≤10 months). 6 The median MFS was 36.6 months with enzalutamide and 14.7 months with placebo (HR for metastasis or death 0.29; 95% CI 0.24-0.35; p<0.001). Secondary endpoints analyzed, including PFS (local and distant), time to PSA progression, and time to subsequent therapy, were all statistically significantly improved. Although more adverse events were reported in patients receiving ADT + enzalutamide vs. ADT + placebo, patient-reported health-related quality of life was similar between both groups. 10 At final analysis, median follow-up was 48 months. At the time of cutoff, 31% of patients in the enzalutamide cohort and 38% of patients within the placebo group had died. In the enzalutamide cohort, 19% of deaths were from prostate cancer and 12% were not from prostate cancer. In the placebo group, 29% were from prostate cancer and 9% were not from prostate cancer. Median OS was 67 months (95% CI 64-not reached) in the enzalutamide group and 56.3 months (95% CI 54.4-63.0) in the placebo group. Enzalutamide + ADT was associated a 27% lower risk of death than placebo + ADT (HR 0.73; 95% CI 0.61-0.89; p=0.001). 11
# Darolutamide
Daroutamide is a second-generation AR ligand-binding domain inhibitor. This agent was tested in combination with standard ADT in patients with nmCRPC at high risk for progression (PSADT of ≤10 months). 7 The median MFS was 40.4 months with darolutamide and 18.4 months with placebo (HR for metastasis or death 0.41; 95% CI 0.34-0.50; p<0.001). Secondary endpoints analyzed, including PFS (local and distant), time to PSA progression, and time to subsequent therapy, were all statistically significantly improved. 7 Although more adverse events were reported in patients receiving ADT + darolutamide vs. ADT + placebo, patient-reported healthrelated quality of life was similar between both groups. 7 Final analysis was conducted after 254 deaths were observed (15.5% of darolutamide group and 19.1% of placebo control group). Darolutamide had a statistically significant 31% reduction in the risk of death. After a median followup time of 29 months, the median survival rate at three years was 83% in the darolutamide cohort and 77% in the placebo group (HR 0.69; 95% CI 0.53-0.88; p=0.003). The survival benefit was observed even though more than half of the patients in the placebo group received subsequent darolutamide treatment. 12 Apalutamide, enzalutamide, and darolutamide have received Health Canada approval for use in high-risk nmCRPC.
# Treatment of mCRPC
Since mCRPC is generally associated with a high risk of morbidity and cancer-related mortality, patients with mCRPC detected on conventional imaging should be considered for systemic therapy with demonstrated survival benefits. Patients with mCRPC should optimally receive multidisciplinary care to maximize survival and quality of life. Because any treatment for advanced disease remains non-curative, patients with advanced prostate cancer should be encouraged to participate in clinical trials.
# I. AR signaling therapeutic options
In men with CRPC, phase 3 clinical trials have evaluated the role of abiraterone acetate and enzalutamide in both the chemo-naive and post-chemotherapy settings.
# Abiraterone acetate
Abiraterone acetate is a potent and irreversible inhibitor of CYP-17, a critical enzyme in androgen biosynthesis.
In the chemo-naive setting: Abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily is recommended for first-line therapy for asymptomatic or minimally symptomatic mCRPC (Level 1, Strong recommendation).
In asymptomatic or minimally symptomatic patients (defined as pain that is relieved by acetaminophen or a nonsteroidal anti-inflammatory) without visceral metastases, abiraterone acetate significantly improved radiographic PFS (16.5 vs. 8.3 months) (HR 0.53; 95% CI 0.45-0.62; p<0.001) and had a statistically significant 4.4-month improvement in OS (HR 0.81; p=0.0033). 13,14 Abiraterone also significantly delayed time to pain progression, time to chemotherapy initiation, time to opiate initiation, and deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status.
In the post-docetaxel setting: Abiraterone acetate 1000 mg per day plus prednisone 5 mg twice daily is recommended in patients progressing on or after docetaxel-based chemotherapy (Level 1, Strong recommendation).
In the post-docetaxel setting, abiraterone-prednisone compared to placebo-prednisone significantly prolonged median OS by 4.6 months (15.8 vs. 11.2 months; HR 0.74; p=0.0001) in patients with mCRPC who had progressed after docetaxel treatment. Moreover, all secondary endpoints provided support for the superiority of abiraterone over placebo: median time to PSA progression (8.5 vs. 6.6 months; HR 0.63; p<0.0001), radiographic PFS (5.6 vs. 3.6 months; HR 0.66; p<0.0001), confirmed PSA response rate defined as ≥50% reduction in PSA from the pretreatment baseline PSA (29% vs. 5.5%; p<0.0001), and objective response by Response Evaluation Criteria in Solid Tumors (RECIST) (14.8% vs. 3.3%; p<0.0001). 15
# Enzalutamide
Enzalutamide is a potent multi-targeted androgen signalling pathway inhibitor.
In the chemo-naive setting: Enzalutamide 160 mg per day is recommended as first-line therapy for asymptomatic or minimally symptomatic mCRPC (Level 1, Strong recommendation).
In asymptomatic or minimally symptomatic patients (defined as pain that is relieved by acetaminophen or a nonsteroidal anti-inflammatory), enzalutamide decreased the risk of radiographic progression or death by 81% (HR 0.19; 95% CI 0.15-0.23; p<0.001) and the risk of death by 29% (HR 0.71; 95% CI 0.60-0.84; p<0.001) as compared to placebo. The benefit of enzalutamide was demonstrated for all secondary endpoints, including time to initiation of cytotoxic chemotherapy, time to first skeletal-related event (SRE), best overall soft tissue response (59% vs. 5%; p<0.001), time to PSA progression (HR 0.17; p<0.001), and ≥50% PSA decline rate (78% vs. 4%; p<0.001). Enzalutamide also significantly delayed time to pain progression, time to opiate initiation, and deterioration of the ECOG performance status. 16,17 In the post-docetaxel setting: Enzalutamide 160 mg per day is recommended in patients progressing on or after docetaxelbased chemotherapy (Level 1, Strong recommendation).
In patients previously treated with docetaxel, the trial compared enzalutamide and placebo. The study demonstrated a significant advantage in OS of 4.8 months (18.4 vs. 13.6 months; HR 0.62; p<0.0001) and in all secondary endpoints, including confirmed PSA response rate (54% vs. 2%; p<0.001), soft-tissue response rate (29% vs. 4%; p<0.001), time to PSA progression (8.3 vs. 3.0 months; HR 0.25; p<0.001), radiographic PFS (8.3 vs. 2.9 months; HR 0.40; p<0.001), and the time to the first SRE (16.7 vs. 13.3 months; HR 0.69; p<0.001). 18 NOTE: The studies in the chemo-naive setting did not include patients with moderate or severe symptoms; however, abiraterone and enzalutamide may be potential therapeutic options in patients who are deemed chemotherapyineligible or refuse chemotherapy (Expert opinion).
# II. Chemotherapy
# First-line systemic chemotherapy
# Docetaxel
# Docetaxel 75 mg/m 2 intravenous (IV) every three weeks with 5 mg oral prednisone twice daily is recommended for patients with mCRPC (Level 1, Strong recommendation).
The TAX-327 study randomized 1006 patients to one of three treatment arms: 1) docetaxel 75 mg/m 2 IV every three weeks; 2) docetaxel 30 mg/m 2 weekly for five of six weeks; or 3) control therapy with mitoxantrone. 19 The study reported improved survival with docetaxel (every three weeks) compared with mitoxantrone-prednisone (median survival 18.9 vs. 16.5 months; HR 0.76; 95% CI 0.62-0.94; twosided p=0.009). No OS benefit was observed with docetaxel given on a weekly schedule (HR 0.91; 95% CI 0.75-1.11; two-sided p=0.36). Significantly, more patients treated with docetaxel (every three weeks) achieved a pain response compared with patients receiving mitoxantrone (35% vs. 22%; p=0.01). Quality of life response, defined as a sustained 16-point or greater improvement from baseline on Guideline: CRPC management two consecutive measurements, was higher with docetaxel given every three weeks (22% vs. 13%; p=0.009) or weekly (23% vs. 13%; p=0.005) compared with mitoxantrone. PSA response rates were also statistically significantly higher with docetaxel compared to mitoxantrone. 19 Although patients received up to 10 cycles of treatment if no progression and no prohibitive toxicities were noted, the duration of therapy should be based on the assessment of benefit and toxicities. Rising PSA alone should not be used as the sole criteria for progression; assessment of response should incorporate clinical and radiographic criteria.
# Alternative therapies that have not demonstrated improvement in OS but can provide disease control, palliation, and improve quality of life include weekly docetaxel plus prednisone, and mitoxantrone plus prednisone (Level 2, Weak recommendation).
The
# timing of docetaxel therapy in men with evidence of metastases but without symptoms should be discussed with patients, and therapy should be individualized based on patients' clinical status and preferences (Level 3, Weak recommendation).
Patients who do not respond to first-line ADT or who progress clinically or radiologically without significant PSA elevations may have neuroendocrine differentiation. Biopsy of accessible lesions should be considered to identify these patients; these patients should then be treated with combination chemotherapy, such as cisplatin/etoposide or carboplatin/etoposide (Level 3, Weak recommendation).
# Second-line systemic chemotherapy
# Cabazitaxel
# Cabazitaxel is recommended for mCRPC patients progressing on or following docetaxel (Level 1, Strong recommendation).
A phase 3 study comparing cabazitaxel to mitoxantrone in patients previously treated with docetaxel has shown a statistically significant survival advantage. 20 This randomized, placebo-controlled trial recruited 755 docetaxel-pretreated CRPC patients. OS was the primary endpoint of the study. Patients were randomized to receive prednisone 10 mg/day with three times weekly mitoxantrone 12 mg/m 2 or cabazitaxel 25 mg/m 2 . An advantage in survival emerged in favor of the cabazitaxel group, with a median survival of 15.1 months compared with 12.7 months in the mitoxantrone group (HR 0.70; 95% CI 0.59, 0.83; p<0.0001). 20 A recent phase 3 study comparing cabazitaxel 25 mg/m 2 vs. 20 mg/m 2 resulted in non-inferiority for cabazitaxel 20 mg/m 2 with less adverse events. Of note, in the subgroup analysis of patients who had received both docetaxel and abiraterone/enzalutamide, results appeared to favor a higher dose of cabazitaxel. 21
# Other options
For patients who have had a good response to first-line docetaxel, re-treatment with docetaxel can be considered (Expert opinion, Weak recommendation). 22,23 Mitoxantrone has not shown any survival advantage but may provide symptomatic relief. Mitoxantrone may be considered a therapeutic option in symptomatic patients with mCRPC in the first-or second-line setting (Expert opinion, Weak recommendation).
# III. Bone-targeted therapy
# Life-prolonging therapy
# Radium-223
# Radium-223 every four weeks for six cycles is recommended in patients with pain due to bone metastases and who do not have visceral metastases (Level 1, Strong recommendation).
Radium-223 (previously known as alpharadin) is an intravenous alpha-emitting agent that mimics calcium, preferentially targeting bone metastases. In a randomized, phase 3 study, radium-223 given every four weeks for six cycles was compared to placebo. 20 Radium-223 demonstrated a significant improvement in OS and symptomatic SREs. OS was improved by 3.6 months (HR 0.7; p<0.0001) and symptomatic SREs were delayed by 5.8 months (p<0.0001). The study included patients with symptomatic bone metastases who were post-docetaxel or ineligible for docetaxel. 24 The study excluded patients with visceral metastases or lymph node metastases greater than 3 cm. PSA measurements while receiving radium-223 cannot provide evidence of whether patients are benefitting or not. Given the mechanism of action of the drug, alkaline phosphatase appears to be better marker of activity. A phase 3 study in the first-line mCRPC setting compared radium-223 in combination with abiraterone/prednisone vs. abiraterone/prednisone alone and demonstrated no advantage and an increased risk of fractures. 25 Radium-223 should not be combined with abiraterone. A bone-supportive agent (denosumab or zoledronic acid) should always be used when using radium-223 (Level 1, Strong recommendation).
# Patients with homologous recombination repair (HRR) mutations
# Olaparib
# Olaparib 300 mg twice daily is recommended for patients with mCPRC and HRR mutation who have progressed on a previous androgen receptor-axis-targeted therapy (ARAT) (Level 1, Strong recommendation).
# Saad et al
HRR gene mutations occur in approximately 20-30% of prostate cancers from patients with metastatic disease, with the most common altered gene being BRCA2. Defective HRR renders a cancer susceptible to poly (ADP-ribose) polymerase (PARP) inhibition in a form of synthetic lethality. A randomized, phase 3 trial (PROfound) compared the PARP inhibitor, olaparib 300 mg BID, with physician's choice enzalutamide/abiraterone in patients with mCRPC with HRR mutations. Patients with HRR mutations and progression on prior enzalutamide and/or abiraterone with or without prior exposure to a taxane (docetaxel, cabazitaxel) were eligible. The primary endpoint of the study was radiographic PFS in patients with BRCA1/2 or ATM mutations. Results favored olaparib (7.39 vs. 3.44 months [HR 0.34, 95% CI (0.25, 0.47 p<0.001). The final results for OS also demonstrated a significant improvement among men with BRCA1/2 or ATM mutations, with a median OS of 19.1 vs. 14.7 months (HR 0.69, 95% CI 0.50, 0.97, p=0.02). Of note, from patients in the physician's choice of enzalutamide/abiraterone arm who progressed, 67% crossed over to receive olaparib. Adjusting for crossover results in a HR 0.42 (95% CI 0.19, 0.91). Other key secondary endpoints include significant improvements in overall measurable response rates of 33.3% vs. 2.3% (odds ratio [OR] 20.86, 95% CI 4.18, 379.18, p<0.001) and delay in pain progression (HR 0.44, 95% CI 0.22, 0.91, p=0.0192). Adverse events were more common in the olaparib arm (anemia, fatigue, nausea, diarrhea), however, patients reported health-related quality of life was improved in the olaparib arm of the study.
The Health Canada approval of olaparib is for patients with deleterious or suspected deleterious germline or somatic BRCA1/2 or ATM mutations who have progressed following prior treatment with enzalutamide or abiraterone. The U.S. Food and Drug Administration has approved olaparib for prostate cancers harboring a broader spectrum of 11 additional genes that are directly or indirectly involved in HRR (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L), which comprised an additional cohort in the PROfound study. The European regulatory authority has approved olaparib only for BRCA1/2 alterations. Further study is required to define optimal biomarker selection criteria to select patients with mCRPC with the highest potential for benefit from PARP inhibitors, as well as timing around taxane chemotherapy.
# Supportive agents
# Denosumab and zoledronic acid
In men with CRPC and bone metastases, denosumab (120 mg subcutaneous [SC]) or zoledronic acid (4 mg IV) every four weeks are recommended to prevent disease-related SREs, including pathological fractures, spinal cord com-pression, surgery, or radiation therapy to bone (Level 1, Strong recommendation).
Bone loss associated with ADT has been shown to increase the risk of fracture. [26][27][28][29][30] Moreover, about 90% of patients with mCRPC will develop bone metastases, which cause local decreases in bone integrity. Patients are at significant risk of SREs that include pathological fractures, debilitating bone pain requiring palliative radiation therapy, and spinal cord compression. Quality of life is affected by these complications.
Zoledronic acid is a third-generation nitrogen containing bisphosphonate. Bisphosphonates other than zoledronic acid are not known to be effective to prevent disease-related SREs. In the placebo-controlled zoledronic acid study, fewer men receiving zoledronic acid had SREs (38% vs. 49%; p=0.02). 31 Zoledronic acid also increased the median time to first SRE (488 vs. 321 days; p=0.01). There was an overall 36% reduction in the rate of SREs in treated patients. 31 Treatment with zoledronic acid should not be used in men with baseline creatinine clearance <30 mL/min.
Denosumab is a fully humanized monoclonal antibody against RANK ligand. It has been shown to be effective in preventing bone loss and new vertebral fractures due to ADT. 30 In the setting of mCRPC, denosumab (120 mg SC every four weeks) compared to zoledronic acid (4 mg IV every four weeks) has shown significant improvement in the time to the first SRE (20.7 vs. 17.1 months; p<0.001 for non-inferiority; p=0.008 for superiority), while OS and PFS were not different. 32 No dose modification for renal function is necessary in the case of denosumab; however, the risk of hypocalcemia is increased and calcium monitoring and supplementation (with calcium and vitamin D) is recommended for both denosumab and zoledronic acid. Denosumab has not been studied, however, in patients with severe renal impairment (glomerular filtration rate <30 ml/min).
Good oral hygiene, baseline dental evaluation for high-risk individuals, and avoidance of invasive dental surgery during therapy are recommended to reduce risk of osteonecrosis of the jaw (ONJ) for patients treated with bone-targeted therapies (Expert opinion). Zoledronic acid and denosumab have been used in combination with all the agents presently in use for the treatment of mCRPC. To date, there have been no additional safety issues of concern that have been reported.
The optimal duration of zoledronic acid and denosumab in men with CRPC and bone metastases is undefined. The risk of ONJ appears to be related to time on bone-targeted therapy, therefore, caution should be taken in using these agents beyond two years (Level 3, Weak recommendation).
Denosumab and zoledronic acid are not approved and not indicated for SRE prevention in the treatment of metastatic castration-sensitive prostate cancer or for bone metastases prevention.
# Guideline: CRPC management
# IV. Other supportive care therapies
# Systemic corticosteroid therapy
Corticosteroid therapy with low-dose prednisone or dexamethasone may also offer improvements in PSA values and/ or palliative outcomes in up to 30% of patients in both symptomatic and asymptomatic men. Steroids may also exert an anti-neoplastic effect on prostate cancer (Level 3, Weak recommendation). 33
# Palliative radiation
Bone metastases from prostate cancer are often radiosensitive and most men will experience partial or complete pain relief from external beam radiation to a specific lesion. 34 Studies have shown that a single fraction of standard palliative radiotherapy (RT) is as effective as five or more fractions in providing palliation. However, more patients require retreatment for pain recurrence with single fraction radia- Palliative radiation therapy should be considered in patients with pain 1. The optimal sequence of available options remains unknown. In general, it is felt that changing therapeutic mechanism of action with each line of therapy is likely to lead to better and longer-lasting response (Expert opinion).
2. Patients who have had little or no response to hormonal agents OR who progress with minimal change in PSA OR with significant visceral metastases should be considered for early chemotherapeutic options.
3. Radium-223 is not approved for patients with visceral metastases.
# Summary
Health Canada-approved agents that have shown improvements in survival in mCRPC now include abiraterone, enzalutamide, docetaxel, cabazitaxel, and radium-223. Health Canada-approved agents that have shown improvements in delaying metastases in high-risk nmCRPC include apalutamide, enzalutamide, and darolutamide. Bone-supportive agents and palliative radiation continue to play an important role in the overall management of mCRPC. Given the complexity, variety, and importance of optimizing the use of these agents, a multidisciplinary team approach is highly recommended.
#
Saad et al tion. Stereotactic body RT (SBRT) is a more precise and may be a more effective form of palliation delivered in five or fewer treatments and may also be considered, particularly for oligometastatic disease where high-dose RT is currently being studied for improved oncological outcomes.
Malignant spinal cord compression is an oncological emergency that requires immediate diagnosis with an MRI if suspected. Options for treatment are debulking surgery + RT, vertebrectomy with stabilization and RT, or RT + steroids (Level 1, Strong recommendation).
# Conclusions
Advances in treatment for men with CRPC have improved survival and quality of life, but most, if not all, patients eventually succumb to their disease and better treatments are required. Several new agents are being studied in all states of CRPC and an increase in options is likely in the near future. Because CRPC remains an incurable and ultimately fatal illness, inclusion of patients in clinical trials remains paramount.
A summary on the recommended treatment of CRPC is shown in Fig. 1.
Competing interests: Dr. Saad has been an advisory board member for and has received payment/ honoraria from Abbvie, Amgen, Astellas, Bayer, Janssen, and Sanofi; and has participated in clinical trials supported by Amgen, Astellas, Bayer, Janssen, and Sanofi. Dr. Aprikian has been an advisory board member for Abbvie, Astellas, and Bayer; and has received grants from Abbvie, Astellas Bayer, Sanofi, and TerSera. Dr. Finelli has been an advisory board member for Abbvie, Astellas, Bayer, Janssen, Ipsen, Sanofi, and TerSera; and has participated in clinical trials supported by Astellas, Bayer, and Janssen. Dr. Fleshner has been a consultant or advisory board member for Abbvie, Amgen, Astellas, Bayer, Ferring, Hybridyne Health, Janssen, and Sanofi; and has participated in clinical trials supported by Astellas, Bavarian Nordic, Bayer, Ferring, Janssen, Medivalion, Nucleix, Progenics Pharmaceutical, Sanofi, and Spectracure AB. Dr. Gleave has been a consultant for and has received honoraria/grants from Abbvie, Amgen, Astellas, Bayer, GDx, Janssen, MDX, Pfizer, and Sanofi; and is founder/holds a patent with OncoGenex. Dr. Kapoor has been an advisory board member for BMS, Eisai, Ipsen, Merck, Novartis, Pfizer, and Roche; a speakers' bureau member for Eisai, Ipsen, Novartis, and Roche; and has received grants/honoraria from BMS, Eisai, Ipsen, Merck, Novartis, Pfizer, and Roche. Dr. Niazi has received research grants and honoraria from Abbvie, Amgen, Astellas, Astra Zeneca, Bayer, Janssen, and Sanofi; and has participated in clinical trials supported by Astellas, Ferring, Janssen, and Sanofi. Dr. North has been an advisory board member for Astellas, has received honoraria from Astra Zeneca, Astellas, Janssen, Merck, Roche, and Sanofi; and has participated in clinical trials supported by Astra Zeneca, Merck, Roche, and Sanofi. Dr. Pouliot has been an advisory board member for Amgen, Astellas, Bayer , and Janssen; has received payment from Abbott, Amgen, Astellas, Astra Zeneca, Bayer, Ferring, Janssen, and Sanofi; has received grants from Astra Zeneca and Sanofi; and has participated in clinical trials supported by Astellas, Bayer, Ferring, and Janssen. Dr. Rendon has been an advisory board and speakers' bureau member for and has received honoraria from Abbvie, Amgen, Astellas, Astra Zeneca, Bayer, Ferring, Jansen, and Sanofi. Dr. Shayegan has been an advisory board member for Astellas, Bayer, and Janssen; and has received a research grant from Janssen. Dr. Sridhar has been an advisory board member for Astellas, AstraZeneca, Bayer, Janssen, Merck, and Roche; and has participated in several pharma-supported clinical trials. Dr. So has been an advisory board member for Abbvie, Amgen, Astellas, Bayer, Janssen, Ferring, and TerSera; and has participated in clinical trials supported by Astellas, Ferring, and Janssen. Dr. Usmani has been an advisory board member for Amgen, Astellas, and Bayer; and has received grants from Best Medical and Concure Oncology Canada. Dr. Vigneault has been an advisory board member for Abbvie, Bayer, Ferring, and Sanofi. Dr. Chi has received honoraria from Astellas, Bayer, Janssen, and Sanofi; and has participated in clinical trials supported by Astellas, Astra Zeneca, Bayer, Eli Lilly, Essa, Janssen, Merck, Novartis, Pfizer, Roche, and Sanofi.
Prior to original publication, this guideline underwent review by the CUA Guidelines Committee, CUA members at large, the CUAJ Editorial Board, and the CUA Executive Board. 2020 updates were approved by the CUA Guidelines Committee.
# CUA-CUOG CRPC guideline summary
Castration-resistant prostate cancer (CRPC) includes a wide range of disease types: from patients without metastases or symptoms with rising prostate-specific antigen (PSA) levels despite androgen deprivation therapy (ADT) to patients with metastases and significant debilitation due to cancer symptoms.
# Androgen deprivation therapy
Because androgen receptor remains active in most patients who have developed castration-resistant disease, it is recommended that ADT be continued for the remainder of a patient's life (Strong recommendation).
# I. Rising
| None | None |
1545506977b41c3e04e935034b1ebd44c4605c4e | cma | None | Topics covered: 1. Background: Cardiac Complications of COVID-19 2. Long COVID-19 3. Potential Long COVID-19 Scenarios Warranting Consultation with Cardiac Specialists 4. Suggested Cardiac Investigations# Background
# Cardiac Complications of COVID-19
As of March 2, 2021, an estimated 870,000 Canadians have been infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), including over 22,000 known deaths. 1 Cardiac injury, defined as an elevation in serum troponin, has been documented in up to 45% of inpatients with COVID-19 2 and has been linked to worse outcomes. 3 It is also postulated that this type of injury may be linked to symptoms that persist following resolution of acute infection, as part of the syndrome commonly referred to as "Long COVID-19". The purpose of this document is to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of Long COVID-19. It must be recognized that this is an evolving area with little data, at present, to guide management. March 12, 2021 Several potential mechanisms for myocardial injury secondary to SARS-CoV-2 infection have been proposed, including: i) myocarditis from either direct viral toxicity and/or bystander immune damage; ii) myocardial ischemia from microvascular thrombosis; and/or iii) COVID-19-related hypoxemia. 4 More recently, histopathological data from COVID-19 patients undergoing endomyocardial biopsy or autopsy suggest that myocarditis is present in only 4.5%. 5 However, it is unclear if any of these cardiac manifestations during acute COVID-19 lead to significant long-term consequences.
Small cohort studies of recovered patients utilizing cardiac MRI have reported conflicting results, further highlighting the need to better elucidate potential long-term cardiac sequelae of COVID-19, especially as it pertains to patient symptoms and functional impairments. Furthermore, no data presently exist to support or refute the cardiovascular impact of COVID-19 in patients with or without pre-existing cardiac conditions.
# Long COVID-19 (also known as COVID-19 long-haulers; chronic COVID-19)
It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. National survey data from the United Kingdom reported 21% of respondents with COVID-19 exhibit symptoms for longer than 5 weeks and 10% exhibit symptoms for greater than 12 weeks. 9 The term "Long COVID-19" is used to define any patient with persistent symptoms after acute COVID-19 (i.e. after 4 weeks) (Table 1). There is a lack of high-quality data on the prevalence of symptom subtypes in patients with Long COVID-19. Fatigue and shortness of breath are commonly reported, affecting up to 98% and 85% of patients respectively, among other multisystem symptoms. 10 Chest pain or palpitations have been reported in 10-44% of cases and are potentially more common at 4-12 weeks post COVID-19 infection. 10,11 A growing awareness of the impact of COVID-19 infections has led to the formation of several online patient-initiated Long COVID-19 support groups and, more recently, ambulatory clinics specializing in the care of these patients. Generally, cardiac
# Definition
Duration of Sign or Symptoms Acute COVID-19
- lasting up to 4 weeks Ongoing symptomatic COVID-19
- lasting 4 to 12 weeks Post COVID-19
- starting during or after the illness, but lasting more than 12 weeks specialists have either been integrated into these clinics or have provided consultation on an ad hoc basis. Thus, the following recommendations are largely based on expert opinion and the current collective experience.
# Potential Long COVID-19 Scenarios Warranting Consultation with Cardiac Specialists
Patients with diagnosed COVID-19 illness >4 weeks ago and:
(1) Persistent or new unexplained chest pain. A cardiac etiology is more likely with multiple cardiac risk factors, documented cardiac injury and/or new Q waves or ST-T wave abnormalities on ECG, during or after initial COVID-19 illness.
(2) Shortness of breath. A cardiac etiology is more likely with elevated BNP, left ventricular dysfunction on imaging and/or radiographic evidence of pulmonary edema.
(3) Frequent palpitations. A cardiac etiology is more likely if associated with presyncope or syncope and/or a significant arrhythmia is detected on Holter or other cardiac monitoring device. For patients with persistent sinus tachycardia, consider a cardiac etiology in the absence of systemic causes (e.g. fever, anemia and hypoxia).
(4) Postural light headedness. A cardiovascular etiology is more likely if orthostatic hypotension is documented.
# Suggested Cardiac Investigations
The Canadian Cardiovascular Society Rapid Response Team has placed an emphasis on physical examination and non-invasive assessment utilising local expertise and continued close surveillance, especially among those with pre-existing cardiac conditions or multi-system disease (Table 2).
# Recommended Treatment
Although there are no specific recommendations for managing cardiac symptoms in Long COVID-19 patients, there is considerable support for maintaining guideline-based goal-directed therapy in patients with pre-existing cardiovascular disease. Patients with new cardiac findings or symptoms should be managed using contemporary treatments, similar to patients without a history of COVID-19 infection (Table 3).
# Multidisciplinary Care of Patients with Long COVID-19
After careful investigations to identify and treat cardiac and/or pulmonary causes of patient symptoms, many may remain symptomatic with chronic fatigue and tiredness.
Although in some individuals these symptoms may be attributed to the slow nature of their recovery following a critical illness, in others it may result from deconditioning and other unrecognised factors. There is no clear relationship between chronicity of symptoms and severity of initial COVID-19 illness. Long COVID-19 patients often report less energy than pre-illness, and everyday situations requiring physical, cognitive and/or emotional stamina may be exhausting in a waxing and waning pattern.
In many patients, a tailored return to exercise can be a useful adjunctive therapy. This requires a multidisciplinary team rehabilitation service consisting of nurses, physiotherapists, physiatrists, exercise specialists, neurologists, psychiatrists, respirologists, rehabilitation experts and cardiologists to co-ordinate an individualised plan. Additional considerations should include baseline health, premorbid function, biomechanical assessments, exercise prescription and a holistic patient review. The Long COVID-19 patient care map illustrated below enables a cycle of "learn-teach and modify" to further refine interventions.
# Figure 1. Long COVID-19 patient care map
Return to exercise is often regarded as an important milestone of recovering from COVID-19, resulting in post-exertional malaise (PEM). Many with this syndrome experience a cycle of "push and crash" (Figure 2).
# Figure 2. Push and crash cycle
The symptoms of PEM resemble myalgic encephalitis or chronic fatigue syndrome, and typically occur 24-72h post trigger, potentially lasting for several days. The opposite of "push and crash" is pacing. This further emphasizes the importance of early involvement of a multidisciplinary approach to prevent and support "push and crash" candidates to a path of pacing, with reduced suffering, improved sense of control and well-being.
Pacing involves:
- Finding the individual's envelope -paying attention to the level of triggers, which may be physical, emotional or cognitive - The individual adapting to their envelope -learning to control triggers - Expanding their envelope -gradual progression and adaptation
The management strategies proposed above for Long COVID-19 have not yet been evaluated in clinical trials. However, these recommendations appear reasonable given current knowledge and experience. Future work on COVID-19 should continue to assess knowledge gaps and evaluate the long-term cardiovascular effects and potential impact on patient wellness and survival. Furthermore, long-term outcomes should also be studied in asymptomatic, recovered COVID-19 patients to determine any potential links to latent cardiovascular disease.
- Avoid use of CCS logos or trademarks on slides, tools or publications that are not the property of the CCS o Do not modify the slide content and, the layout and CCS branding on the Guideline-related slides o Guideline recommendations must be reproduced exactly as published
- For an industry supported or involved program, permissions are required:
- If content is published in the Canadian Journal of Cardiology, permissions must be sought through our publisher Elsevier (www.onlinecjc.com)
If content is property of the CCS, contact [email protected] | Topics covered: 1. Background: Cardiac Complications of COVID-19 2. Long COVID-19 3. Potential Long COVID-19 Scenarios Warranting Consultation with Cardiac Specialists 4. Suggested Cardiac Investigations# Background
# Cardiac Complications of COVID-19
As of March 2, 2021, an estimated 870,000 Canadians have been infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), including over 22,000 known deaths. 1 Cardiac injury, defined as an elevation in serum troponin, has been documented in up to 45% of inpatients with COVID-19 2 and has been linked to worse outcomes. 3 It is also postulated that this type of injury may be linked to symptoms that persist following resolution of acute infection, as part of the syndrome commonly referred to as "Long COVID-19". The purpose of this document is to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of Long COVID-19. It must be recognized that this is an evolving area with little data, at present, to guide management. March 12, 2021 Several potential mechanisms for myocardial injury secondary to SARS-CoV-2 infection have been proposed, including: i) myocarditis from either direct viral toxicity and/or bystander immune damage; ii) myocardial ischemia from microvascular thrombosis; and/or iii) COVID-19-related hypoxemia. 4 More recently, histopathological data from COVID-19 patients undergoing endomyocardial biopsy or autopsy suggest that myocarditis is present in only 4.5%. 5 However, it is unclear if any of these cardiac manifestations during acute COVID-19 lead to significant long-term consequences.
Small cohort studies of recovered patients utilizing cardiac MRI have reported conflicting results, [6][7][8] further highlighting the need to better elucidate potential long-term cardiac sequelae of COVID-19, especially as it pertains to patient symptoms and functional impairments. Furthermore, no data presently exist to support or refute the cardiovascular impact of COVID-19 in patients with or without pre-existing cardiac conditions.
# Long COVID-19 (also known as COVID-19 long-haulers; chronic COVID-19)
It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. National survey data from the United Kingdom reported 21% of respondents with COVID-19 exhibit symptoms for longer than 5 weeks and 10% exhibit symptoms for greater than 12 weeks. 9 The term "Long COVID-19" is used to define any patient with persistent symptoms after acute COVID-19 (i.e. after 4 weeks) (Table 1). There is a lack of high-quality data on the prevalence of symptom subtypes in patients with Long COVID-19. Fatigue and shortness of breath are commonly reported, affecting up to 98% and 85% of patients respectively, among other multisystem symptoms. 10 Chest pain or palpitations have been reported in 10-44% of cases and are potentially more common at 4-12 weeks post COVID-19 infection. 10,11 A growing awareness of the impact of COVID-19 infections has led to the formation of several online patient-initiated Long COVID-19 support groups and, more recently, ambulatory clinics specializing in the care of these patients. Generally, cardiac
# Definition
Duration of Sign or Symptoms Acute COVID-19
• lasting up to 4 weeks Ongoing symptomatic COVID-19
• lasting 4 to 12 weeks Post COVID-19
• starting during or after the illness, but lasting more than 12 weeks specialists have either been integrated into these clinics or have provided consultation on an ad hoc basis. Thus, the following recommendations are largely based on expert opinion and the current collective experience.
# Potential Long COVID-19 Scenarios Warranting Consultation with Cardiac Specialists
Patients with diagnosed COVID-19 illness >4 weeks ago and:
(1) Persistent or new unexplained chest pain. A cardiac etiology is more likely with multiple cardiac risk factors, documented cardiac injury and/or new Q waves or ST-T wave abnormalities on ECG, during or after initial COVID-19 illness.
(2) Shortness of breath. A cardiac etiology is more likely with elevated BNP, left ventricular dysfunction on imaging and/or radiographic evidence of pulmonary edema.
(3) Frequent palpitations. A cardiac etiology is more likely if associated with presyncope or syncope and/or a significant arrhythmia is detected on Holter or other cardiac monitoring device. For patients with persistent sinus tachycardia, consider a cardiac etiology in the absence of systemic causes (e.g. fever, anemia and hypoxia).
(4) Postural light headedness. A cardiovascular etiology is more likely if orthostatic hypotension is documented.
# Suggested Cardiac Investigations
The Canadian Cardiovascular Society Rapid Response Team has placed an emphasis on physical examination and non-invasive assessment utilising local expertise and continued close surveillance, especially among those with pre-existing cardiac conditions or multi-system disease (Table 2).
# Recommended Treatment
Although there are no specific recommendations for managing cardiac symptoms in Long COVID-19 patients, there is considerable support for maintaining guideline-based goal-directed therapy in patients with pre-existing cardiovascular disease. Patients with new cardiac findings or symptoms should be managed using contemporary treatments, similar to patients without a history of COVID-19 infection (Table 3).
# Multidisciplinary Care of Patients with Long COVID-19
After careful investigations to identify and treat cardiac and/or pulmonary causes of patient symptoms, many may remain symptomatic with chronic fatigue and tiredness.
Although in some individuals these symptoms may be attributed to the slow nature of their recovery following a critical illness, in others it may result from deconditioning and other unrecognised factors. There is no clear relationship between chronicity of symptoms and severity of initial COVID-19 illness. Long COVID-19 patients often report less energy than pre-illness, and everyday situations requiring physical, cognitive and/or emotional stamina may be exhausting in a waxing and waning pattern.
In many patients, a tailored return to exercise can be a useful adjunctive therapy. This requires a multidisciplinary team rehabilitation service consisting of nurses, physiotherapists, physiatrists, exercise specialists, neurologists, psychiatrists, respirologists, rehabilitation experts and cardiologists to co-ordinate an individualised plan. Additional considerations should include baseline health, premorbid function, biomechanical assessments, exercise prescription and a holistic patient review. The Long COVID-19 patient care map illustrated below enables a cycle of "learn-teach and modify" to further refine interventions.
# Figure 1. Long COVID-19 patient care map
Return to exercise is often regarded as an important milestone of recovering from COVID-19, resulting in post-exertional malaise (PEM). Many with this syndrome experience a cycle of "push and crash" (Figure 2).
# Figure 2. Push and crash cycle
The symptoms of PEM resemble myalgic encephalitis or chronic fatigue syndrome, and typically occur 24-72h post trigger, potentially lasting for several days. The opposite of "push and crash" is pacing. This further emphasizes the importance of early involvement of a multidisciplinary approach to prevent and support "push and crash" candidates to a path of pacing, with reduced suffering, improved sense of control and well-being.
Pacing involves:
• Finding the individual's envelope -paying attention to the level of triggers, which may be physical, emotional or cognitive • The individual adapting to their envelope -learning to control triggers • Expanding their envelope -gradual progression and adaptation
The management strategies proposed above for Long COVID-19 have not yet been evaluated in clinical trials. However, these recommendations appear reasonable given current knowledge and experience. Future work on COVID-19 should continue to assess knowledge gaps and evaluate the long-term cardiovascular effects and potential impact on patient wellness and survival. Furthermore, long-term outcomes should also be studied in asymptomatic, recovered COVID-19 patients to determine any potential links to latent cardiovascular disease.
o Avoid use of CCS logos or trademarks on slides, tools or publications that are not the property of the CCS o Do not modify the slide content and, the layout and CCS branding on the Guideline-related slides o Guideline recommendations must be reproduced exactly as published
• For an industry supported or involved program, permissions are required:
o If content is published in the Canadian Journal of Cardiology, permissions must be sought through our publisher Elsevier (www.onlinecjc.com)
o
If content is property of the CCS, contact [email protected]
# Disclaimer (for reuse purposes)
The Canadian Cardiovascular Society (CCS) welcomes reuse of our Guideline educational slide decks. | None | None |
edbb52fb0c7c8d5a91cef50afe277adecc342b94 | cma | None | # Background
The recognized risks factors for gastric cancer include male gender, older age, chronic inflammation (e.g.: Helicobacter pylori infection, intestinal metaplasia, pernicious anemia), cigarette smoking, obesity, and certain hereditary conditions (e.g. familial adenomatous polyposis).
Prognosis depends upon the stage at diagnosis; that is, prognosis is better with less penetration of tumour into the stomach wall, fewer involved regional lymph nodes, and no evidence of metastatic disease.
A multidisciplinary team is required to define and provide the optimal care for a patient with gastric carcinoma. It should be composed of thoracic and general surgeons, gastroenterologists, and oncologists.
Early involvement of a dietician is recommended to complete a nutritional assessment and to optimize the patient's nutritional status.
This guideline was developed to outline the management recommendations for adult patients with gastric cancer.
Guideline Questions
# Target Population
Adult (≥18 years of age) patients with a confirmed or suspected diagnosis of gastric cancer.
# Recommendations
Suggested Diagnostic Work-Up i. A complete endoscopic and radiologic evaluation is required to allow the multidisciplinary team to define the optimal management plan. ii. Esophagogastroduodenoscopy helps to distinguish between a gastric cancer that extends into esophagus and an esophageal cancer that extends into stomach. It also obtains a biopsy of the intraluminal mass to confirm the histologic diagnosis.
iii. CT scan of the thorax abdomen, and pelvis should be performed at baseline and should be repeated prior to surgery if patients receive neoadjuvant therapy. iv. For gastric cancer patients, a PET CT can be considered for locally advanced cancers (for example node positive). PET CT may have limited utility in mucinous or diffuse tumours and does not replace a laparoscopic assessment for peritoneal disease. 40 v. If no metastases are seen on baseline imaging, a laparoscopic evaluation for peritoneal metastasis should be considered prior to surgical resection. Laparoscopic evaluation can alter management in up to 44% of cases. 1 vi. Bone scans can be done for patients suspected of having bone metastases, CT head or MRI for patients suspected of having brain metastases. vii. For patients on palliative systemic treatment, CT chest, abdomen, pelvis should be done every 2-3 months. viii. Individualized discussion regarding imaging after definitive chemoRT or after surgical resection for non-metastatic patients. ix. Perioperative chemotherapy should be considered for curative intent cases. Surgical resection should be with oncologic principles. A minimum D1 resection by an experienced surgeon with a goal of 16 or more lymph nodes examined should be performed.
x. Mismatch repair (MMR) or microsatellite instability (MSI) testing should be considered for curative intent cases. Retrospective analyses, and an individual patient meta-analysis of 1156 patients from 4 randomized trials (MAGIC, CLASSIC, ARTIST, and ITACA-S), identified 121 (7.8%) patients that were MSI high. MSI-high patients had better 5 year DFS (71.8 vs 52.3%, HR 1.88, 95% CI 1.28-2.76, p<0.01) and OS (77.5 vs 59.3%, HR 1.78, 95% CI 1.17-2.73, p 0.008), and did not seem to benefit from chemotherapy with 5 year DFS 70 vs 77% HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12). 2 MMR status may influence decisions regarding adjuvant and neoadjuvant chemotherapy for gastric cancer. Currently, the preferred neoadjuvant regimen is FLOT. A retrospective review of 101 patients, including 5 MSI-H patients treated with FLOT, demonstrated a relatively poor histological response to neoadjuvant therapy but a significantly superior overall survival for MSI-H versus MSS tumors. 3 Given the limited data available using the FLOT regimen, the applicability of using MSI testing is less clear.
xi. Early involvement with a registered dietician, experienced with gastric cancer is recommended to support the unique nutritional needs of this patient population, particularly in the setting of surgery and/or significant >10% weight loss.
# Stage Information:
# Note:
Tumors involving the esophagogastric junction (EGJ) with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal rather than gastric cancers (refer to esophageal cancer guideline). In contrast, EGJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach cancers. As described above N3a-3b As described above M0 Absent Stage IV Tany As described above N1-3 As described above M1 Present - A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified as T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified as T4. The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. *Intramural extension to the duodenum or esophagus is not considered invasion of an adjacent structure, but is classified using the depth of the greatest invasion in any of these sites.
# Goals of Therapy
To render the patient free of disease, delay or prevent recurrence, and to improve or prolong survival. In patients that cannot be rendered disease free, prolong survival, palliate symptoms and maximize quality of life.
# Treatment Recommendations
Consider treatment on a clinical trial, if available.
See the Treatment Flow Chart found here: Stage Ia i. Perform surgical resection with oncologic principles (minimum D1 resection by an experienced surgeon with a goal of 16 or more lymph nodes). ii. No adjuvant local or systemic therapy is indicated.
Stage Ib-IIIc i. Surgery should be performed with oncologic principles (minimum D1 resection by an experienced surgeon with a goal of 16 or more lymph nodes examined).
Peri-operative chemotherapy should be considered in patients with clinical T2 or node positive disease prior to surgical resection (see below).
Peri-Operative Chemotherapy: 11 Note: According to the CRITICS trial, in patients who have received pre-operative chemotherapy, there is no evidence to suggest that further intensification of post-operative treatment with chemoradiation has any benefit. 4 Preferred FLOT was shown to be superior to ECF/ECX in preliminary reports from the FLOT4-AIO phase III trial in terms of median overall survival (50 months vs. 35 months, HR:0.77, p=0.012), and progressionfree survival (30 months vs 18 months, HR:0.75, p=0.004), and should therefore be considered standard of care. 12 i. Prophylactic GCSF should be considered for patients undergoing FLOT, as grade 3/4 neutropenia occurs at a higher rate than ECF/ECX.
# Alternative Protocols (ECX/ECF/MAGIC): for patients not eligible for FLOT
i. When compared to surgery alone in patients with good performance status (ECOG ≤1) and T2-4N0-3M0 adenocarcinoma of the distal third of the esophagus, gastro-esophageal junction, or stomach, peri-operative chemotherapy improves the five-year progression-free (HR 0.66, CI95% 0.53-0.81, p < 0.001) and overall survival (from 23.0% to 36.3%, HR 0.74, CI95% 0.59-0.93, p = 0.008). 14 ii. Similarly, peri-operative Cisplatin + Fluorouracil the five-year disease-free survival (34% versus 19%, HR 0.65, CI95% 0.48-0.89, p = 0.003), overall survival (38% versus 24%, HR 0.69, CI95% 0.50-0.95, p = 0.02), and rate of curative resection (84% versus 73%, p = 0.04). 15 iii. These regimens require placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port. iv. For patients who decline a central line, based on extrapolation from the ST03 trial, 16 ECX would be a reasonable option. Consideration should be made to substitute infusional 5-Fluorouracil for the capecitabine component in patients with impaired gastric acid production (eg. post gastrectomy, proton pump inhibitor)
# For patients not suitable for peri-operative chemotherapy:
In patients who have not had pre-operative chemotherapy, treatment options include adjuvant chemoradiation or chemotherapy. The decision between the two approaches benefits from multidisciplinary discussion.(see below).
Adjuvant Chemoradiation: 5 i.Leucovorin followed by 5-Fluororuacil combined with radiotherapy. 6 Improves five-year relapse-free survival from 22% to 40% (HR 1.51, CI95% 1.25-1.83, p < 0.001) and five-year overall survival from 26% to 40% (HR 1.32, CI95% 1.10-1.60, p = 0.0046) when compared with surgery alone. Stage IV (First Line) i. Palliative maneuvers to maintain and/or improve quality of life are indicated (e.g.: stent placement or radiotherapy to relieve dysphagia, pain, obstruction, or bleeding). ii. Palliative chemotherapy regimens 17,18 are generally continued as long as tumour shrinkage or stability is confirmed, as long as the side effects remain manageable, as long as the patient wishes to continue, and as long as the treatment remains medically reasonable. iii. Consider an early referral to palliative care . iv. In those patients with unresectable disease, consider early referral to dietician and psychosocial oncology. 45
# HER2 Normal: Preferred Oxaliplatin/fluoropyrimidine or FOLFIRI
i. A network meta-analysis of systemic therapy for advanced gastric cancer demonstrated that anthracycline triplet chemotherapy and docetaxel, cisplatin, fluorouracil (5FU) triplets showed no benefit over fluoropyrimidine (FP: 5-fluorouracil (5FU) or capecitabine) doublets for overall survival (OS) or progression-free survival (PFS), and increased toxicity was noted. 19 ii. A fluoropyrimidine doublet containing oxaliplatin or irinotecan significantly improved overall survival compared with a fluoropyrimidine plus cisplatin (for a fluoropyrimidine plus irinotecan, the HR for death was 0.85, 95% CI 0.71-0.99; for a fluoropyrimidine plus oxaliplatin, the HR was 0.83, 95% CI 0.71-0.98). The cisplatin-fluoropyrimidine doublet was also associated with more grade 3 or 4 toxicity.
# FOLFOX/CAPOX
Four phase III trials have compared oxaliplatin to cisplatin based regimens (including ECF) suggesting similar efficacy. A meta-analysis of the REAL-2 trial and two randomized phase II trials - Nivolumab is Health Canada approved, but not funded in Alberta for this indication.
Subsequent lines of therapy comparing oxaliplatin to cisplatin based regimens demonstrated that oxaliplatin was associated with significant improvements in PFS (HR 0.88, 95% CI 0.80-0.98) and overall survival (HR for death 0.88, 95% CI 0.78-0.99), and with less neutropenia, anemia, alopecia, and thromboembolic events, but with more neurotoxicity and diarrhea. FOLFIRI i. Suitable first or second line regimen for patients with an ECOG of 0-2: Irinotecan (180 mg/m2 IV over ninety minutes) and Leucovorin (400 mg/m2 IV over two hours) followed by 5-Fluorouracil (2400 mg/m2 as 46 hour infusion) every 2 weeks.
ii. FOLFIRI followed by ECX was compared to the reverse sequence in the first line setting of metastatic GE junction/gastric adenocarcinoma. 25 The dosing and duration of Capecitabine in the ECX arm (oral Capecitabine 1g/m2 twice per day from day 2 to day 15 every 3 weeks) was different than in the REAL-2 trial.
iii. FOLFIRI followed by ECX was superior to the reverse strategy for the primary endpoint of time to treatment failure (5.08 months versus 4.24 months, HR 0.77, CI95% 0.63-0.83, p = 0.008), however, OS (9.5 months versus 9.7 months; p=0.95) and PFS (5.3 months versus 5.8 months; p=0.96) were similar between the two sequences. iv. Patients who received first line ECX had higher rates of grade 3/4 toxicities, especially hematological ones.
# Nivolumab with FOLFOX/CAPOX CPS≥5
i. In the ATTRACTION-4 study 41 patients in Japan, Korea or Taiwan were randomized to nivolumab or placebo with chemotherapy (SOX or CapeOx). In this study with dual primary endpoints, the nivolumab + chemotherapy patients had improved progression free survival (median PFS 10.45 months versus 8.34 months with chemotherapy alone (HR: 0.68, 95%CI: 0.51-0.90, p<0.001).
However, there was no improvement in overall survival.
ii. The Checkmate 649 study 42 study was an international trial (including poppulations from Asia, North America and the rest of the world) which randomized patients to nivolumab with chemotherapy (Nivolumab + XELOX or Nivolumab + FOLFOX) or chemotherapy alone (XELOX or FOLFOX). This study demonstrated a statistically significant improvement in overall survival in patients with the addition of nivolumab in the PD-L1 CPS≥5 (median OS 14.4 months versus 11.1 months in the chemotherapy alone arm; HR: 0.71, 95%CI: 0.59-0.86, p<0.001). Furthermore, OS benefit was also seen in the secondary endpoints analyzing patients with PD-L1 CPS≥1 as well as in all randomized patients. Similarly, benefits were seen in PFS, overall responses and duration of response in the patients receiving nivolumab † .
# Pembrolizumab i.
In the phase III KEYNOTE-062 trial, 763 patients with previously untreated advanced gastric or GE junction adenocarcinoma patients with a CPS > 1 were randomized to pembrolizumab, chemotherapy (cisplatin plus a fluoropyrimidine) or combined therapy. Pembrolizumab was non-inferior to chemotherapy alone for overall survival. In an exploratory analysis of patients with a CPS > 10, there was a clinically meaningful improvement in median overall survival with pembrolizumab compared to chemotherapy alone (17.4 vs 10.8 months, HR 0.69, 95% CI 0.49-0.97). Pembrolizumab is not currently funded.
ii. At this time, the addition of pembrolizumab to chemotherapy has not demonstrated sufficient improvement in outcomes to justify the associated toxicities. 43 Palliative ii. Oxaliplatin is the preferred platinum as it reduces the risk of death (HR 0.88, CI95% 0.78-0.99, p = 0.04), progression (HR 0.88, CI95% 0.80-0.98, p = 0.02), and thromboembolism. 23,27 HER2 Positive: i. HER2 over-expression can be demonstrated in 16% of gastric cancers. The addition of Trastuzumab to Cisplatin plus either Capecitabine or 5-Fluorouracil was associated with a superior progression-free (6.7 months versus 5.5 months, HR 0.71, CI95% 0.59-0.85, p = 0.0002) and overall survival (13.8 months versus 11.1 months, HR 0.74, CI95% 0.60-0.91, p = 0.0046). 28 In a preplanned exploratory analysis, the subset of patients with high-level HER2 expression (immunohistochemistry scores (IHC) of 2+ with FISH positivity or IHC3+) achieved a median overall survival of 16.0 months. In the updated survival analysis, the median overall survival for the addition of trastuzumab was 13.1 months as compared to 11.7 months for the chemotherapy alone arm (HR 0.80, CI95% 0.67-0.91). In the updated pre-planned analysis, only the patients in the IHC3+ subgroup showed a statistically significant survival benefit (18.0 months vs 13.2 months, HR 0.66 (CI95% 0.50-0.87)).
# Contraindications to platinum/fluoropyrimidine or FOLFIRI
In patients who have a contraindication to a platinum/fluoropyrimidine combination, or FOLFIRI, the following regimen may be considered as an alternative but it does not have the same degree of survival benefit: a. ELF 29 Stage IV (Second Line) Combination Systemic Therapy: i. In patients with a preserved performance status, modest benefits have been achieved with secondline chemotherapy. For patients who are fit enough, combination systemic therapy should be considered. Options include: a. Paclitaxel + Ramucirumab 1. Compared to Paclitaxel alone, in patients with ECOG 0-1 the addition of Ramucirumab significantly improved overall survival (7.6 months versus 9.6 months, HR 0.807, CI95% 0.678-0.962, p = 0.017) 30 2. Similar time to deterioration in performance status was reported in the paclitaxel arm and the paclitaxel plus ramucirumab arm (p=0.0941) according to QLQ-C30 scales. EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. 25,31 b. FOLFIRI as above can be considered in the second line setting, after a fluoropyrimide/platinum combination. 25 It is unclear as to whether the addition of 5-fluouracil to irinotecan confers additional benefit and consideration can be single agent irinotecan (see below). c. A fluoropyrimidine/platinum combination such as FOLFOX or CAPOX can be considered in the second line setting after FOLFIRI. 25 While combinations like ECX, EOX, ECF or EOF have more direct evidence in this setting, it is reasonable to omit the anthracycline in the second line setting due to the added toxicities and lack of increased efficacy observed in the first line setting. 19,25 a. This improved overall survival when compared to best supportive care (5.2 versus 3.8 months, multivariable HR 0.774, CI95% 0.605-0.991, p = 0.042) with no difference in quality of life scores at 6 weeks. 36 Patients enrolled in the study had an ECOG 0-1 and Ramucirumab was also associated with a delay to median time to deterioration of performance status. Ramicirumab is not currently funded for single agent use. In patients with an ECOG 0-1 who had received 2 or more lines of systemic therapy, TAS-102 demonstrated an improvement in median overall survival to 5.7 months from 3.6 months, compared to placebo (HR 0.69, CI95% 0.56-0.85, p = 0.00029, two-sided p=0.00058). 37 c. Higher rates of grade 3 or higher were observed with TAS-102 in terms of neutropenia (n=114, 35=4%) and anemia (n=64, 19%), while with placebo abdominal pain (n=15, 9%) and general deterioration of physical health (n=15, 9%) were more common. No differences were seen in quality of life between patients treated with TAS-102 and placebo. ‡ ii. Nivolumab § a. The ATTRACTION-2 44 study randomized patients with advanced gastric or GEJ cancer who were refractory or intolerant to two or more previous lines of chemotherapy and naive to PD-1 therapy or other pharmacotherapies for the regulation of T-cells to randomly receive nivolumab or placebo. Median overall survival was improved in the nivolumab group as compared to the placebo group (5.26 months versus 4.14 months, HR 0.63, 95%CI: 0.51-0.78, p<0.001). b. Nivolumab is not currently available on the Alberta CancerCare Drug Benefit List for this indication c. At this time, the Alberta GI Tumour Group does not support the routine use of nivolumab in this setting. At this point the clinical benefit may not outweigh the associated toxicities.
# Stage IV (Third or Greater
# Appendix A: Chemotherapy Regimens Regimen Description
Perioperative FLOT 4-cycles prior to surgery, with a further 4 cycles post-surgery. Each cycle lasts 14 days and consists of 5-FU 2600 mg/m2 (24 h) day 1 and leucovorin 200 mg/m2 (2h), day 1 and oxaliplatin 85 mg/m2 (2 h) day 1 and docetaxel 50 mg/m2 (1 h), every 2 weeks. Perioperative ECX/ECF/MAGIC 3-cycles prior to surgery, with a further 3 cycles post-surgery. three-week cycles of Epirubicin 50 mg/m2 and Cisplatin 60 mg/m2 IV on day one plus a continuous IV infusion of 5-Fluorouracil 200 mg/m2/day over twenty-one days. Perioperative Cisplatin + Fluorouracil Six four-week peri-operative cycles of Cisplatin 100 mg/m2 IV on day one plus 5-Fluorouracil 800 mg/m2/day over days one through five days Adjuvant Leucovorin + 5-Fluorouracil + RT Five four-week cycles where Leucovorin (20 mg/m2 IV) followed by 5-Fluorouracil (425 mg/m2 IV) is administered daily on the first five consecutive days of cycles one, four, and five. During cycles two and three, radiotherapy is administered on weekdays for twenty-five fractions (180 cGy per fraction). Leucovorin (20 mg/m2 IV) followed by 5-Fluorouracil (400 mg/m2 IV) is administered daily on the first four and last three days of radiotherapy (see grid below). Adjuvant Leucovorin + 5-Fluorouracil (de Gramont) Nine cycles of Leucovorin 100 mg/m2 IV over 2 hours on days 1-2 and 5-Fluorouracil 400 mg/m2 as bolus followed by daily 22 hour infusion of 600 mg/m2 every 14 days
Six cycles of the Capecitabine 1,000 mg/m2 twice daily on days 1 to 14 and Cisplatin 60 mg/m2 on day 1 every 3 weeks Adjuvant Capecitabine + Oxaliplatin (CLASSIC) Eight cycles of Capecitabine 1,000 mg/m2 twice daily on days 1 to 14 and Oxaliplatin 130 mg/m2 on day 1 every 3 weeks Adjuvant Capecitabine + Cisplatin + RT (ARTIST) Two cycles of Capecitabine/Cisplatin followed by 45-Gy chemoradiation with capecitabine 1,650 mg/m2 per day for 5 weeks, followed by two more cycles of Capecitabine/Cisplatin Nivolumab + SOX (ATTRACTION-4) Nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) Nivolumab + CapeOx (ATTRACTION-4) Nivolumab (360 mg intravenously every 3 weeks) plus CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) Nivolumab + XELOX (Checkmate 649) Nivolumab 360mg IV + XELOX (intravenous oxaliplatin 130 mg/m(2) (day 1) followed by oral capecitabine 1,000 mg/m(2) twice daily (day 1, evening, to day 15, morning)q 3 weekly Nivolumab + FOLFOX (Checkmate 649) Nivolumab 240mg + FOLFOX (oxaliplatin 85 mg/m2 IV infusion on day 1, then leucovorin 400 mg/m2 IV infusion, plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2 d (total 2400 mg/m2 over 46-48 h) q2 weekly ECX Epirubicin (50 mg/m2 IV over twenty minutes) and Cisplatin (60 mg/m2 IV over one hour) are administered on day one, and Trastuzumab (Initial loading dose 8 mg/kg i.v. infusion on Day 1 of cycle, followed by 6 mg/kg i.v. infusion every 3 weeks until disease progression) added to six three-week cycles of Cisplatin 80 mg/m2 IV on day one plus Capecitabine 1,000 mg/m2 po BID for fourteen days Trastuzumab + Cisplatin + 5-Fluorouracil (ToGA) Trastuzumab (Initial loading dose 8 mg/kg i.v. infusion on Day 1 of cycle, followed by 6 mg/kg i.v. infusion every 3 weeks until disease progression) added to six three-week cycles of Cisplatin 80 mg/m2 IV on day one plus 5-Fluorouracil 800 mg/m2 continuous IV infusion on days one through five
# Single Agent Nivolumab
Nivolumab (3mg/kg IV q 2 weekly) FOLFIRI Irinotecan (180 mg/m2 IV over 90 minutes) concurrently with folinic acid (400 mg/m2 IV over 120 minutes) followed by fluorouracil (400-500 mg/m2 IV bolus) then fluorouracil (2400-3000 mg/m2 intravenous infusion over 46 hours) FOLFOX FOLFOX (oxaliplatin 85 mg/m2 IV infusion on day 1, then leucovorin 400 mg/m2 IV infusion, plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2 d (total 2400 mg/m2 over 46-48 h) q2 weekly
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta GI Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010.
# Levels of Evidence | # Background
The recognized risks factors for gastric cancer include male gender, older age, chronic inflammation (e.g.: Helicobacter pylori infection, intestinal metaplasia, pernicious anemia), cigarette smoking, obesity, and certain hereditary conditions (e.g. familial adenomatous polyposis).
Prognosis depends upon the stage at diagnosis; that is, prognosis is better with less penetration of tumour into the stomach wall, fewer involved regional lymph nodes, and no evidence of metastatic disease.
A multidisciplinary team is required to define and provide the optimal care for a patient with gastric carcinoma. It should be composed of thoracic and general surgeons, gastroenterologists, and oncologists.
Early involvement of a dietician is recommended to complete a nutritional assessment and to optimize the patient's nutritional status.
This guideline was developed to outline the management recommendations for adult patients with gastric cancer.
Guideline Questions
# Target Population
Adult (≥18 years of age) patients with a confirmed or suspected diagnosis of gastric cancer.
# Recommendations
Suggested Diagnostic Work-Up i. A complete endoscopic and radiologic evaluation is required to allow the multidisciplinary team to define the optimal management plan. ii. Esophagogastroduodenoscopy helps to distinguish between a gastric cancer that extends into esophagus and an esophageal cancer that extends into stomach. It also obtains a biopsy of the intraluminal mass to confirm the histologic diagnosis.
iii. CT scan of the thorax abdomen, and pelvis should be performed at baseline and should be repeated prior to surgery if patients receive neoadjuvant therapy. iv. For gastric cancer patients, a PET CT can be considered for locally advanced cancers (for example node positive). PET CT may have limited utility in mucinous or diffuse tumours and does not replace a laparoscopic assessment for peritoneal disease. 40 v. If no metastases are seen on baseline imaging, a laparoscopic evaluation for peritoneal metastasis should be considered prior to surgical resection. Laparoscopic evaluation can alter management in up to 44% of cases. 1 vi. Bone scans can be done for patients suspected of having bone metastases, CT head or MRI for patients suspected of having brain metastases. vii. For patients on palliative systemic treatment, CT chest, abdomen, pelvis should be done every 2-3 months. viii. Individualized discussion regarding imaging after definitive chemoRT or after surgical resection for non-metastatic patients. ix. Perioperative chemotherapy should be considered for curative intent cases. Surgical resection should be with oncologic principles. A minimum D1 resection by an experienced surgeon with a goal of 16 or more lymph nodes examined should be performed.
x. Mismatch repair (MMR) or microsatellite instability (MSI) testing should be considered for curative intent cases. Retrospective analyses, and an individual patient meta-analysis of 1156 patients from 4 randomized trials (MAGIC, CLASSIC, ARTIST, and ITACA-S), identified 121 (7.8%) patients that were MSI high. MSI-high patients had better 5 year DFS (71.8 vs 52.3%, HR 1.88, 95% CI 1.28-2.76, p<0.01) and OS (77.5 vs 59.3%, HR 1.78, 95% CI 1.17-2.73, p 0.008), and did not seem to benefit from chemotherapy with 5 year DFS 70 vs 77% HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12). 2 MMR status may influence decisions regarding adjuvant and neoadjuvant chemotherapy for gastric cancer. Currently, the preferred neoadjuvant regimen is FLOT. A retrospective review of 101 patients, including 5 MSI-H patients treated with FLOT, demonstrated a relatively poor histological response to neoadjuvant therapy but a significantly superior overall survival for MSI-H versus MSS tumors. 3 Given the limited data available using the FLOT regimen, the applicability of using MSI testing is less clear.
xi. Early involvement with a registered dietician, experienced with gastric cancer is recommended to support the unique nutritional needs of this patient population, particularly in the setting of surgery and/or significant >10% weight loss.
# Stage Information:
# Note:
Tumors involving the esophagogastric junction (EGJ) with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal rather than gastric cancers (refer to esophageal cancer guideline). In contrast, EGJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach cancers. As described above N3a-3b As described above M0 Absent Stage IV Tany As described above N1-3 As described above M1 Present * A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified as T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified as T4. **The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. ***Intramural extension to the duodenum or esophagus is not considered invasion of an adjacent structure, but is classified using the depth of the greatest invasion in any of these sites.
# Goals of Therapy
To render the patient free of disease, delay or prevent recurrence, and to improve or prolong survival. In patients that cannot be rendered disease free, prolong survival, palliate symptoms and maximize quality of life.
# Treatment Recommendations
Consider treatment on a clinical trial, if available.
See the Treatment Flow Chart found here: https://www.albertahealthservices.ca/info/cancerguidelines.aspx Stage Ia i. Perform surgical resection with oncologic principles (minimum D1 resection by an experienced surgeon with a goal of 16 or more lymph nodes). ii. No adjuvant local or systemic therapy is indicated.
Stage Ib-IIIc i. Surgery should be performed with oncologic principles (minimum D1 resection by an experienced surgeon with a goal of 16 or more lymph nodes examined).
Peri-operative chemotherapy should be considered in patients with clinical T2 or node positive disease prior to surgical resection (see below).
Peri-Operative Chemotherapy: 11 Note: According to the CRITICS trial, in patients who have received pre-operative chemotherapy, there is no evidence to suggest that further intensification of post-operative treatment with chemoradiation has any benefit. 4 Preferred FLOT was shown to be superior to ECF/ECX in preliminary reports from the FLOT4-AIO phase III trial in terms of median overall survival (50 months vs. 35 months, HR:0.77, p=0.012), and progressionfree survival (30 months vs 18 months, HR:0.75, p=0.004), and should therefore be considered standard of care. 12 [Level of evidence: I] i. Prophylactic GCSF should be considered for patients undergoing FLOT, as grade 3/4 neutropenia occurs at a higher rate than ECF/ECX.
# Alternative Protocols (ECX/ECF/MAGIC): for patients not eligible for FLOT
i. When compared to surgery alone in patients with good performance status (ECOG ≤1) and T2-4N0-3M0 adenocarcinoma of the distal third of the esophagus, gastro-esophageal junction, or stomach, peri-operative chemotherapy improves the five-year progression-free (HR 0.66, CI95% 0.53-0.81, p < 0.001) and overall survival (from 23.0% to 36.3%, HR 0.74, CI95% 0.59-0.93, p = 0.008). 14 [Level of evidence: I] ii. Similarly, peri-operative Cisplatin + Fluorouracil the five-year disease-free survival (34% versus 19%, HR 0.65, CI95% 0.48-0.89, p = 0.003), overall survival (38% versus 24%, HR 0.69, CI95% 0.50-0.95, p = 0.02), and rate of curative resection (84% versus 73%, p = 0.04). 15 iii. These regimens require placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port. iv. For patients who decline a central line, based on extrapolation from the ST03 trial, 16 ECX would be a reasonable option. Consideration should be made to substitute infusional 5-Fluorouracil for the capecitabine component in patients with impaired gastric acid production (eg. post gastrectomy, proton pump inhibitor)
# For patients not suitable for peri-operative chemotherapy:
In patients who have not had pre-operative chemotherapy, treatment options include adjuvant chemoradiation or chemotherapy. The decision between the two approaches benefits from multidisciplinary discussion.(see below).
Adjuvant Chemoradiation: 5 i.Leucovorin followed by 5-Fluororuacil combined with radiotherapy. 6 [Level of evidence: I] Improves five-year relapse-free survival from 22% to 40% (HR 1.51, CI95% 1.25-1.83, p < 0.001) and five-year overall survival from 26% to 40% (HR 1.32, CI95% 1.10-1.60, p = 0.0046) when compared with surgery alone. Stage IV (First Line) i. Palliative maneuvers to maintain and/or improve quality of life are indicated (e.g.: stent placement or radiotherapy to relieve dysphagia, pain, obstruction, or bleeding). ii. Palliative chemotherapy regimens 17,18 are generally continued as long as tumour shrinkage or stability is confirmed, as long as the side effects remain manageable, as long as the patient wishes to continue, and as long as the treatment remains medically reasonable. iii. Consider an early referral to palliative care [link]. iv. In those patients with unresectable disease, consider early referral to dietician and psychosocial oncology. 45
# HER2 Normal: Preferred Oxaliplatin/fluoropyrimidine or FOLFIRI [Level of evidence: I]
i. A network meta-analysis of systemic therapy for advanced gastric cancer demonstrated that anthracycline triplet chemotherapy and docetaxel, cisplatin, fluorouracil (5FU) triplets showed no benefit over fluoropyrimidine (FP: 5-fluorouracil (5FU) or capecitabine) doublets for overall survival (OS) or progression-free survival (PFS), and increased toxicity was noted. 19 ii. A fluoropyrimidine doublet containing oxaliplatin or irinotecan significantly improved overall survival compared with a fluoropyrimidine plus cisplatin (for a fluoropyrimidine plus irinotecan, the HR for death was 0.85, 95% CI 0.71-0.99; for a fluoropyrimidine plus oxaliplatin, the HR was 0.83, 95% CI 0.71-0.98). The cisplatin-fluoropyrimidine doublet was also associated with more grade 3 or 4 toxicity.
# FOLFOX/CAPOX
Four phase III trials have compared oxaliplatin to cisplatin based regimens (including ECF) suggesting similar efficacy. A meta-analysis of the REAL-2 trial and two randomized phase II trials * Nivolumab is Health Canada approved, but not funded in Alberta for this indication.
Subsequent lines of therapy comparing oxaliplatin to cisplatin based regimens demonstrated that oxaliplatin was associated with significant improvements in PFS (HR 0.88, 95% CI 0.80-0.98) and overall survival (HR for death 0.88, 95% CI 0.78-0.99), and with less neutropenia, anemia, alopecia, and thromboembolic events, but with more neurotoxicity and diarrhea. [20][21][22][23][24] FOLFIRI i. Suitable first or second line regimen for patients with an ECOG of 0-2: Irinotecan (180 mg/m2 IV over ninety minutes) and Leucovorin (400 mg/m2 IV over two hours) followed by 5-Fluorouracil (2400 mg/m2 as 46 hour infusion) every 2 weeks.
ii. FOLFIRI followed by ECX was compared to the reverse sequence in the first line setting of metastatic GE junction/gastric adenocarcinoma. 25 The dosing and duration of Capecitabine in the ECX arm (oral Capecitabine 1g/m2 twice per day from day 2 to day 15 every 3 weeks) was different than in the REAL-2 trial.
iii. FOLFIRI followed by ECX was superior to the reverse strategy for the primary endpoint of time to treatment failure (5.08 months versus 4.24 months, HR 0.77, CI95% 0.63-0.83, p = 0.008), however, OS (9.5 months versus 9.7 months; p=0.95) and PFS (5.3 months versus 5.8 months; p=0.96) were similar between the two sequences. iv. Patients who received first line ECX had higher rates of grade 3/4 toxicities, especially hematological ones.
# Nivolumab with FOLFOX/CAPOX CPS≥5
i. In the ATTRACTION-4 study 41 patients in Japan, Korea or Taiwan were randomized to nivolumab or placebo with chemotherapy (SOX or CapeOx). In this study with dual primary endpoints, the nivolumab + chemotherapy patients had improved progression free survival (median PFS 10.45 months versus 8.34 months with chemotherapy alone (HR: 0.68, 95%CI: 0.51-0.90, p<0.001).
However, there was no improvement in overall survival.
ii. The Checkmate 649 study 42 study was an international trial (including poppulations from Asia, North America and the rest of the world) which randomized patients to nivolumab with chemotherapy (Nivolumab + XELOX or Nivolumab + FOLFOX) or chemotherapy alone (XELOX or FOLFOX). This study demonstrated a statistically significant improvement in overall survival in patients with the addition of nivolumab in the PD-L1 CPS≥5 (median OS 14.4 months versus 11.1 months in the chemotherapy alone arm; HR: 0.71, 95%CI: 0.59-0.86, p<0.001). Furthermore, OS benefit was also seen in the secondary endpoints analyzing patients with PD-L1 CPS≥1 as well as in all randomized patients. Similarly, benefits were seen in PFS, overall responses and duration of response in the patients receiving nivolumab † .
# Pembrolizumab i.
In the phase III KEYNOTE-062 trial, 763 patients with previously untreated advanced gastric or GE junction adenocarcinoma patients with a CPS > 1 were randomized to pembrolizumab, chemotherapy (cisplatin plus a fluoropyrimidine) or combined therapy. Pembrolizumab was non-inferior to chemotherapy alone for overall survival. In an exploratory analysis of patients with a CPS > 10, there was a clinically meaningful improvement in median overall survival with pembrolizumab compared to chemotherapy alone (17.4 vs 10.8 months, HR 0.69, 95% CI 0.49-0.97). Pembrolizumab is not currently funded.
ii. At this time, the addition of pembrolizumab to chemotherapy has not demonstrated sufficient improvement in outcomes to justify the associated toxicities. 43 Palliative ii. Oxaliplatin is the preferred platinum as it reduces the risk of death (HR 0.88, CI95% 0.78-0.99, p = 0.04), progression (HR 0.88, CI95% 0.80-0.98, p = 0.02), and thromboembolism. 23,27 HER2 Positive: i. HER2 over-expression can be demonstrated in 16% of gastric cancers. The addition of Trastuzumab to Cisplatin plus either Capecitabine or 5-Fluorouracil was associated with a superior progression-free (6.7 months versus 5.5 months, HR 0.71, CI95% 0.59-0.85, p = 0.0002) and overall survival (13.8 months versus 11.1 months, HR 0.74, CI95% 0.60-0.91, p = 0.0046). 28 In a preplanned exploratory analysis, the subset of patients with high-level HER2 expression (immunohistochemistry scores (IHC) of 2+ with FISH positivity or IHC3+) achieved a median overall survival of 16.0 months. [Level of evidence: I] In the updated survival analysis, the median overall survival for the addition of trastuzumab was 13.1 months as compared to 11.7 months for the chemotherapy alone arm (HR 0.80, CI95% 0.67-0.91). In the updated pre-planned analysis[link], only the patients in the IHC3+ subgroup showed a statistically significant survival benefit (18.0 months vs 13.2 months, HR 0.66 (CI95% 0.50-0.87)). [Level of evidence:1]
# Contraindications to platinum/fluoropyrimidine or FOLFIRI
In patients who have a contraindication to a platinum/fluoropyrimidine combination, or FOLFIRI, the following regimen may be considered as an alternative but it does not have the same degree of survival benefit: a. ELF 29 Stage IV (Second Line) Combination Systemic Therapy: i. In patients with a preserved performance status, modest benefits have been achieved with secondline chemotherapy. For patients who are fit enough, combination systemic therapy should be considered. Options include: a. Paclitaxel + Ramucirumab 1. Compared to Paclitaxel alone, in patients with ECOG 0-1 the addition of Ramucirumab significantly improved overall survival (7.6 months versus 9.6 months, HR 0.807, CI95% 0.678-0.962, p = 0.017) 30 [Level of evidence: I] 2. Similar time to deterioration in performance status was reported in the paclitaxel arm and the paclitaxel plus ramucirumab arm (p=0.0941) according to QLQ-C30 scales. EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. 25,31 b. FOLFIRI as above can be considered in the second line setting, after a fluoropyrimide/platinum combination. 25 It is unclear as to whether the addition of 5-fluouracil to irinotecan confers additional benefit and consideration can be single agent irinotecan (see below). c. A fluoropyrimidine/platinum combination such as FOLFOX or CAPOX can be considered in the second line setting after FOLFIRI. 25 While combinations like ECX, EOX, ECF or EOF have more direct evidence in this setting, it is reasonable to omit the anthracycline in the second line setting due to the added toxicities and lack of increased efficacy observed in the first line setting. 19,25 a. This improved overall survival when compared to best supportive care (5.2 versus 3.8 months, multivariable HR 0.774, CI95% 0.605-0.991, p = 0.042) with no difference in quality of life scores at 6 weeks. 36 Patients enrolled in the study had an ECOG 0-1 and Ramucirumab was also associated with a delay to median time to deterioration of performance status. Ramicirumab is not currently funded for single agent use. In patients with an ECOG 0-1 who had received 2 or more lines of systemic therapy, TAS-102 demonstrated an improvement in median overall survival to 5.7 months from 3.6 months, compared to placebo (HR 0.69, CI95% 0.56-0.85, p = 0.00029, two-sided p=0.00058). 37 c. Higher rates of grade 3 or higher were observed with TAS-102 in terms of neutropenia (n=114, 35=4%) and anemia (n=64, 19%), while with placebo abdominal pain (n=15, 9%) and general deterioration of physical health (n=15, 9%) were more common. No differences were seen in quality of life between patients treated with TAS-102 and placebo. ‡ ii. Nivolumab § a. The ATTRACTION-2 44 study randomized patients with advanced gastric or GEJ cancer who were refractory or intolerant to two or more previous lines of chemotherapy and naive to PD-1 therapy or other pharmacotherapies for the regulation of T-cells to randomly receive nivolumab or placebo. Median overall survival was improved in the nivolumab group as compared to the placebo group (5.26 months versus 4.14 months, HR 0.63, 95%CI: 0.51-0.78, p<0.001). b. Nivolumab is not currently available on the Alberta CancerCare Drug Benefit List for this indication c. At this time, the Alberta GI Tumour Group does not support the routine use of nivolumab in this setting. At this point the clinical benefit may not outweigh the associated toxicities.
# Stage IV (Third or Greater
# Appendix A: Chemotherapy Regimens Regimen Description
Perioperative FLOT 4-cycles prior to surgery, with a further 4 cycles post-surgery. Each cycle lasts 14 days and consists of 5-FU 2600 mg/m2 (24 h) day 1 and leucovorin 200 mg/m2 (2h), day 1 and oxaliplatin 85 mg/m2 (2 h) day 1 and docetaxel 50 mg/m2 (1 h), every 2 weeks. Perioperative ECX/ECF/MAGIC 3-cycles prior to surgery, with a further 3 cycles post-surgery. three-week cycles of Epirubicin 50 mg/m2 and Cisplatin 60 mg/m2 IV on day one plus a continuous IV infusion of 5-Fluorouracil 200 mg/m2/day over twenty-one days. Perioperative Cisplatin + Fluorouracil Six four-week peri-operative cycles of Cisplatin 100 mg/m2 IV on day one plus 5-Fluorouracil 800 mg/m2/day over days one through five days Adjuvant Leucovorin + 5-Fluorouracil + RT Five four-week cycles where Leucovorin (20 mg/m2 IV) followed by 5-Fluorouracil (425 mg/m2 IV) is administered daily on the first five consecutive days of cycles one, four, and five. During cycles two and three, radiotherapy is administered on weekdays for twenty-five fractions (180 cGy per fraction). Leucovorin (20 mg/m2 IV) followed by 5-Fluorouracil (400 mg/m2 IV) is administered daily on the first four and last three days of radiotherapy (see grid below). Adjuvant Leucovorin + 5-Fluorouracil (de Gramont) Nine cycles of Leucovorin 100 mg/m2 IV over 2 hours on days 1-2 and 5-Fluorouracil 400 mg/m2 as bolus followed by daily 22 hour infusion of 600 mg/m2 every 14 days
Six cycles of the Capecitabine 1,000 mg/m2 twice daily on days 1 to 14 and Cisplatin 60 mg/m2 on day 1 every 3 weeks Adjuvant Capecitabine + Oxaliplatin (CLASSIC) Eight cycles of Capecitabine 1,000 mg/m2 twice daily on days 1 to 14 and Oxaliplatin 130 mg/m2 on day 1 every 3 weeks Adjuvant Capecitabine + Cisplatin + RT (ARTIST) Two cycles of Capecitabine/Cisplatin followed by 45-Gy chemoradiation with capecitabine 1,650 mg/m2 per day for 5 weeks, followed by two more cycles of Capecitabine/Cisplatin Nivolumab + SOX (ATTRACTION-4) Nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) Nivolumab + CapeOx (ATTRACTION-4) Nivolumab (360 mg intravenously every 3 weeks) plus CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) Nivolumab + XELOX (Checkmate 649) Nivolumab 360mg IV + XELOX (intravenous oxaliplatin 130 mg/m(2) (day 1) followed by oral capecitabine 1,000 mg/m(2) twice daily (day 1, evening, to day 15, morning)q 3 weekly Nivolumab + FOLFOX (Checkmate 649) Nivolumab 240mg + FOLFOX (oxaliplatin 85 mg/m2 IV infusion on day 1, then leucovorin 400 mg/m2 IV infusion, plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2 d (total 2400 mg/m2 over 46-48 h) q2 weekly ECX Epirubicin (50 mg/m2 IV over twenty minutes) and Cisplatin (60 mg/m2 IV over one hour) are administered on day one, and Trastuzumab (Initial loading dose 8 mg/kg i.v. infusion on Day 1 of cycle, followed by 6 mg/kg i.v. infusion every 3 weeks until disease progression) added to six three-week cycles of Cisplatin 80 mg/m2 IV on day one plus Capecitabine 1,000 mg/m2 po BID for fourteen days Trastuzumab + Cisplatin + 5-Fluorouracil (ToGA) Trastuzumab (Initial loading dose 8 mg/kg i.v. infusion on Day 1 of cycle, followed by 6 mg/kg i.v. infusion every 3 weeks until disease progression) added to six three-week cycles of Cisplatin 80 mg/m2 IV on day one plus 5-Fluorouracil 800 mg/m2 continuous IV infusion on days one through five
# Single Agent Nivolumab
Nivolumab (3mg/kg IV q 2 weekly) FOLFIRI Irinotecan (180 mg/m2 IV over 90 minutes) concurrently with folinic acid (400 mg/m2 [or 2 x 250 mg/m2] IV over 120 minutes) followed by fluorouracil (400-500 mg/m2 IV bolus) then fluorouracil (2400-3000 mg/m2 intravenous infusion over 46 hours) FOLFOX FOLFOX (oxaliplatin 85 mg/m2 IV infusion on day 1, then leucovorin 400 mg/m2 IV infusion, plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2 d (total 2400 mg/m2 over 46-48 h) q2 weekly
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta GI Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010.
# Levels of Evidence
# Funding Source
Financial support for the development of CancerCare Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerCare Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Oliver Bathe has nothing to disclose.
Dr. Richard Lee-Ying reports grants from Sanofi, Jansen, Roche, Celgene, and Taiho. Dr. Karen Mulder reports grants from Blueprint Medicines Corporation, Deciphera Pharmaceuticals, AstraZeneca, and Eisai Canada. Dr. Andrew Scarfe has nothing to disclose. Dr. Patricia Tang reports grants from Pfizer, Roche, Amgen, Taiho, AstraZeneca, and Genomic Health.
Derek Tilley has nothing to disclose. | None | None |
1b0dae328cadb00b6ec1c3d98e6af9f49c6247e3 | cma | None | Canadian Journal of Diabetes j o u r n a l h o m e p a g e : w w w . c a n a d ia n j o u r n a l o f d i a b e t e s . c o m 1499-2671/Ó 2021 Canadian Diabetes Association. The Canadian Diabetes Association is the registered owner of the name Diabetes Canada.# Introduction
The Diabetes Canada Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada (CPG) were last published in 2018 (1). Rapid uptake of new monitoring technologies by persons living with diabetes and uncertainty among healthcare professionals prompted a review of evidence emerging since our previous recommendations for "Monitoring Glycemic Control" (2). We have updated the title for this topic to align with Diabetes Canada's position statement on "Language Matters" (3).
# Methods
A consolidated search strategy (for adults, children and pregnant women) was developed by modifying and updating PICO (population, intervention, comparison and outcome) questions used for the 2018 CPG (chapters 9, 34,35,36). A systematic search of the literature for relevant articles published from November 1, 2017 to October 28, 2020 was performed by the health science librarians at the McMaster Evidence Review and Synthesis Team (MERST). The MERST team reviewed all relevant citations at title, abstract and full-text levels. Relevant citations were abstracted and critically reviewed by a methodologist from MERST. All MERST staff (librarians and methodologists) were without financial or intellectual conflict. The full-text citations and critical appraisal reports were provided to the expert working group. Members of the expert working group were selected by the CPG Steering Committee with the goal of ensuring representation of diverse perspectives (across disciplines, and academic and community settings), appropriate content and methodologic expertise, while limiting the potential of financial conflict, as much as possible. Diabetes Canada has a formal policy to manage conflict of interest for the CPG Steering Committee.
The expert working group reviewed the citations, graded the evidence, drafted the revised recommendations and created the initial draft of the preamble document to accompany the revised recommendations. For this update, the CPG Steering Committee reviewed the cited evidence independently and suggested revisions to the draft recommendations and the text. The grading of recommendations was reviewed independently by the Independent Methods Review Co-Chair (D.R.). The finalized recommendations were unanimously approved by the CPG Steering Committee.
# Change in Terminology
Glucose monitoring remains a cornerstone of diabetes management. It allows people living with diabetes and their health-care providers to assess glycemic status and adverse effects, and to determine the effectiveness of glucose lowering therapies. Testing of glycated hemoglobin (A1C) continues to be the primary modality to ensure that glycemic goals are being met and the recommended frequency of testing remains unchanged. However, A1C is a measure of chronic glycemic levels over months and does not provide information that can inform immediate/short-term decisions. To measure glucose levels in real time, different modalities exist currently and new technologies are being studied. To address this expanding field, the terminology used to describe the different modalities needs to adapt to allow for future growth and has been updated in Table 1.
# Strength of Wording
To maintain consistency with other chapters in the 2018 CPG, the language within the recommendations has been modified, such that interventions supported by Grade A, Level 1 evidence, and confirmed as appropriate through clinical experience, are now written as "should be used" in place of the previous language of "may be offered." The population, intervention and expected outcome benefit is clearly indicated in each recommendation and the action language should reflect the confidence in the evidence provided.
# Real-Time Continuous Glucose Monitoring (rtCGM)
For people living with type 1 diabetes who use basal-bolus injection therapy or continuous subcutaneous insulin infusion (CSII), rtCGM has been shown to reduce A1C (4e9) and increase glucose time in range (TIR) (5,7,8,10), while simultaneously reducing duration and incidence of hypoglycemia (5,7e11) in adults and children. These glycemic benefits of rtCGM have been demonstrated in trials recruiting adults and children with A1C at target (<7.5%) (6) or above target (4e6,9); and in trials which included adults at or above target (8). As well as reducing biochemical (i.e. not necessarily symptomatic) hypoglycemia, rtCGM has been shown to reduce episodes of severe hypoglycemia in adults with a history of severe hypoglycemia or impaired awareness of hypoglycemia using multiple daily injections (MDI) (11). rtCGM has also been shown to improve quality of life and hypoglycemia distress in adults with type 1 diabetes (11e13).
For people living with type 2 diabetes using basal-bolus injection therapy, a randomized controlled trial of 158 subjects demonstrated that the use of rtCGM reduced A1C to a greater extent than usual care, with more time spent in the target range and less time spent above range at 24 weeks (14). Therefore, it is now recommended that rtCGM may be used to improve glycemic levels in those with type 2 diabetes on basal-bolus injection therapy, with a reminder that successful use of rtCGM is dependent on the duration of time it is used, along with the importance of providing it in association with structured education and therapeutic programs (see section Importance of Diabetes Self-Management Education).
# Intermittently-Scanned Continuous Glucose Monitoring (isCGM)
The use of isCGM has been shown to be beneficial for people living with type 1 or type 2 diabetes using insulin therapy to decrease time spent in hypoglycemia (15e17). Randomized controlled trials of isCGM compared to capillary blood glucose (CBG) testing in type 1 and type 2 diabetes have not consistently demonstrated differences in A1C (18). However, in a recent health technology assessment, other glucose parameters have been shown to improve. Compared with CBG testing, people using isCGM spent, on average, 1 hour more in target glucose range (95% confidence interval 0.41e1.59) and 22 minutes less in a high glucose range (95% CI À0.69 to À0.05) per day and less glucose variability among those with type 1 diabetes (19). A meta-regression, which included clinical trials and observational studies (which are subject to a number of biases) in type 1 and type 2 diabetes, suggested isCGM could reduce A1C by 0.55%, with the magnitude of A1C reduction being proportional to baseline A1C (20). However, as is true with any form of glucose monitoring, the act of monitoring may not of itself improve glucose levels, but, rather, provide data that permits users and providers to take actions to impact glucose levels underlying the importance of diabetes self-management education (see below).
# Comparison of rtCGM and isCGM in People With Type 1 Diabetes
Two studies have directly compared rtCGM with isCGM in adults with type 1 diabetes. rtCGM users spent more TIR and less time below range (TBR) than isCGM users in a 5-week randomized study in adults with normal awareness of hypoglycemia using MDI or CSII (21). In an 8-week study of individuals with impaired awareness of, or recent severe hypoglycemia using MDI, rtCGM reduced time in hypoglycemia and fear of hypoglycemia, which was not seen with isCGM (22). Superiority of rtCGM to protect from hypoglycemia in this high-risk population was supported in the extension phase of this study, where switching to rtCGM was associated with significant reduction in TBR in subjects originally randomized to isCGM (23).
# Masked Continuous Glucose Monitoring
A pragmatic, open-label 12-month study of the use of masked CGM every 3 months, for 5 to 14 days before their clinical visit, compared to usual clinical care among those with type 2 diabetes in general practice, showed no difference in the primary endpoint of A1C at 12 months (24), but there was an increase in TIR at 12 months and lower A1C at 6 months. Similarly, a randomized study of 148 people living with type 2 diabetes treated with insulin compared the effects of masked CGM and usual care with CBG testing in primary and secondary care settings and did not show a difference in the primary endpoint of TIR but did show a greater reduction in A1C with no increase in hypoglycemia (25). Given the conflicting data regarding the effects of the use of masked CGM, no recommendation can be made at this time.
# Glucose Monitoring in Women With Diabetes During Pregnancy
Accuracy of rtCGM and isCGM in pregnancy
In a study of the performance of rtCGM (Dexcom G6) in 32 pregnant women with diabetes (type 1, type 2 and gestational diabetes) across sensor wear sites, accuracy of rtCGM was acceptable (overall mean absolute relative difference was 10.3%) when compared to venous glucose measures, which were taken during a period of 6 hours when participants were allowed to eat freely. rtCGM was also found to be acceptably accurate in the hypoglycemic range (<3.8 mmol/L), with a mean absolute difference of 0.5 mmol/L between 3-3.8 mmol/L and 0.35 mmol/L at glucose levels of 2.2-3.0 mmol/L. Comparing different sites, the posterior upper arm was found to be most accurate, with a MARD of 8.7%, followed by the buttock (11.2%) and the abdomen (11.5%) (26).
The use of isCGM in pregnant women with diabetes has also been studied for accuracy and safety. In a study of 74 pregnant women with type 1, type 2 or gestational diabetes, isCGM was found to have good agreement with CBG (overall MARD 11.8%), with high levels of user satisfaction (27).
# Glucose monitoring in pregnant women with type 1 and type 2 diabetes
The Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy (CONCEPTT) trial randomized 325 women (215 pregnant and 110 planning pregnancy) with type 1 diabetes, to rtCGM, in addition to CBG testing or CBG testing alone (28). Pregnant rtCGM users spent more time in the target range of 3.5 to 7.8 mmol/L (68% vs 61%, p¼0.0034) and less time above the range (>7.8 mmol/L) (27% vs 32%, p¼0.0279) than did pregnant participants using CBG testing alone, with comparable severe hypoglycemic episodes and time spent with hypoglycemia. Neonatal health outcomes were significantly improved, with a lower incidence of large for gestational age (LGA) infants (OR 0.51, 95% CI 0.28e0.90, p¼0.021), fewer neonatal intensive care unit (NICU) admissions lasting more than 24 hours (OR 0.48, 95% CI 0.26e0.86, p¼0.0157), and a lower risk of neonatal hypoglycemia (OR 0.45; 95% CI 0.22e0.89, p¼0.025). No benefit was observed for women planning a pregnancy (28). A budget impact model, where the National Health Service in England was used, estimated the total cost of pregnancy and delivery in women with type 1 diabetes using CBG testing with or without rtCGM. The potential annual cost savings of using rtCGM was estimated to be approximately £9.5 million, with the principal driver being reduced need for NICU and reduced duration of stay in NICU (29). Taken together, these data support updating the recommendation that rtCGM should be used in women with type 1 diabetes during pregnancy to improve blood glucose levels, and to reduce the risk for LGA infants, neonatal hypoglycemia and NICU admissions >24 hours.
To date, there have been no randomized trials using isCGM in pregnant women with type 1 or type 2 diabetes. In an observational cohort study of 186 women with type 1 diabetes attending pregnancy care at 2 tertiary care antenatal clinics in Sweden (92 women used rtCGM and 94 women used isCGM), TIR (3.5 to 7.8 mmol/L) was similar in the 2 groups, although time spent in hypoglycemia was higher in the isCGM group. Pregnancy outcomes were associated with CGM metrics and the incidence of LGA was similar in the 2 groups (52% rtCGM vs 53% isCGM) (30). The TIR achieved in this observational study (reaching 60% in the third trimester) was similar to the control arm, but lower than the intervention arm of CONCEPTT. While isCGM has not yet been shown to reduce neonatal morbidity in women with type 1 diabetes, these data are reassuring, but these observational data are not sufficient to conclude non-inferiority. Achieving optimal glycemic targets is more important than the technology employed. The effectiveness of rtCGM or isCGM for glycemic or fetal outcomes has not yet been studied in pregnant women with type 2 diabetes.
# Glucose monitoring in pregnant women with gestational diabetes
Frequent CBG testing is essential to guide management of gestational diabetes (31). Both fasting and postprandial testing are recommended to guide therapy in order to improve fetal outcomes (32). In a randomized trial of 293 women with newly diagnosed gestational diabetes, after 1 week of daily CBG testing (4 times per day: fasting and 2 hours postprandial), women who did not require pharmacotherapy were randomized to testing (4 times per day), either daily or every other day (33). The alternate day approach was non-inferior for birthweight and there were no differences in the need for medical therapy, gestational age of delivery, rate of LGA or preeclampsia. Consistent use of CBG testing was found to be higher in the every-other-day group (89% compared with 92%, p¼0.01). It is, therefore, reasonable to reduce testing to every other day after 1 week of testing daily, if glucose levels do not indicate the need for pharmacotherapy.
There have been no new randomized trials or cohort studies using rtCGM or isCGM in women with gestational diabetes since 2018. More studies are needed to assess the benefits of rtCGM or isCGM in women with gestational diabetes.
# Glucose Monitoring in Children and Adolescents With Diabetes
# CBG testing
Among children and adolescents with type 1 diabetes, frequent CBG testing (4 or more tests per day) was associated with lower A1C (34,35). In youth with type 2 diabetes on noninsulin antihyperglycemic therapy or insulin, low frequency of CBG testing was associated with higher A1C (36). rtCGM Two of 3 randomized controlled trials which included children as young as 6 years, comparing rtCGM to CBG testing, showed lower A1C and less TBR in both adults and children (7,9), but this was not seen in pediatric participants in the other study, which had very low use of rtCGM and was under-powered to detect differences in hypoglycemia (37). Lower A1C with rtCGM in children may depend on time spent using CGM since further analysis of pediatric subjects in this latter trial showed use of rtCGM for 6 or more days per week improved A1C by -0.8 AE 0.6% at 12 months (38). Characteristics, such as younger age and higher frequency of CBG testing prior to rtCGM, may help predict those who are more likely to use rtCGM consistently (39). Another study in younger children (ages 4 to 10 years) did not show any change or differences in A1C or CGM parameters between groups, although the use of rtCGM was associated with a high degree of parental satisfaction with rtCGM (40). These findings underscore a fear of hypoglycemia which is reflected in more conservative recommended glucose targets. In randomized controlled trials (37,40) and observational studies (41,42) of rtCGM, the rates of severe hypoglycemia were low, making it difficult to assess the effect of rtCGM on rates of severe hypoglycemia.
# isCGM
An open label study of isCGM in 76 children aged 4 to 17 years with type 1 diabetes using CSII or MDI showed lower A1C and more TIR, with no change in TBR (which was low at baseline) (43). A randomized trial of isCGM in adolescents (ages 13 to 20 years) with A1C >9% at baseline showed no advantage to reduce A1C but was associated with increased frequency of blood glucose monitoring and greater treatment satisfaction (44). Switching from CBG testing to isCGM among children and adolescents with type 1 diabetes was associated with a reduction in severe hypoglycemia but no reduction in A1C in a Belgian observational study (45). Of note, 15.8% of those who switched to isCGM reverted back to CBG testing after a median use of 5.3 months. A small, 2-week camp study showed isCGM was non-inferior to CBG testing in children aged 6 to 15 with type 1 diabetes using CSII (46). A meta-regression including trials and observational data suggested that isCGM may be associated with a mean reduction in A1C of 0.54% in the pediatric subgroup (20).
# Hypoglycemia in children with type 1 diabetes
Avoidance of severe hypoglycemia in children is of particular concern for families and providers. Safety is a primary concern in trial design and, fortunately, severe hypoglycemia during clinical trials is a rare event and, therefore, difficult to study. Although a definitive statement regarding the effectiveness of rtCGM to reduce severe hypoglycemia in children is not possible, observations of reductions in severe hypoglycemia in adults and less TBR in children suggest inference of the potential for benefit is plausible.
# Type 2 diabetes
No studies have examined the effectiveness of either rtCGM or isCGM in children and/or adolescents with type 2 diabetes. CGM could be offered, as an alternative to CBG testing, if preferred by the individual as part of training, education and support in selfmanagement.
# Glucose Metrics
When continuous glucose data are captured, it is possible to generate glucose metrics, including TIR, time above range (TAR), TBR and glycemic variability (standard deviation or coefficient of variation), which may be summarized along with the ambulatory glucose profile (see Table 2) (47). These metrics provide additional complementary glycemic data to assess blood glucose levels and identify potential areas for intervention. As the use of technologies allowing for CGM increases, clinicians will need to become more comfortable with the interpretation of these glucose metrics and international consensus groups have provided guidance and proposed targets (see Tables 2-4) (45,47e49).
# Importance of Diabetes Self-Management Education
The importance of diabetes self-management education when introducing or using newer glucose monitoring technologies has been clearly illustrated in recent trials. A randomized controlled trial Table 2 Glucose metrics that can be derived from continuous glucose monitoring- (47,48) and recommended targets from the International Consensus Report for most individuals with type 1 or type 2 diabetes (excluding pregnancy, children/adolescents, and older/high-risk groups) (49)
# Glucose metric
Recommended targets (for most individuals with type 1 or type 2 diabetes)
# Comments
Glucose Management Indicator (GMI) Approximate A1C level based on the average glucose levels from CGM readings for 14 or more days 7.0% GMI may differ from measured A1C as it is reflective of glucose values during the period being assessed during CGM interpretation (last 14 days, last 30 days)
# Glycemic Variability
Reported as % coefficient of variation (%CV) ¼ Standard Deviation/Mean Glucose 36% Lower %CV has been associated with reduced rates of hypoglycemia Time In Range (TIR) % of values between 3.9-10.0 mmol/L >70% 70% TIR equates to an A1C of about 7.0%. Each 10% TIR equates to about 0.5% change in A1C Time Below Range (TBR) - Recommended to use CGM regularly (>70% of a 14-day period).
# Table 3
Recommended CGM targets for older/higher risk individuals (excluding pregnancy, children/adolescents) (49)
Glucose metric Older/High-risk individuals Comments Time In Range (TIR) % of values between 3.9-10.0 mmol/L >50% 50% TIR equates to an A1C of about 8.0%. Each 10% TIR equates to about 0.5-0.8% change in A1C Time Below Range (TBR) Level 1 and 2: % of values <3.9 mmol/L <1.0%
In older/high-risk individuals using insulin or sulfonylureas, avoidance of hypoglycemia is a priority - Time Above Range (TAR) Level 1: % of values 10.1-13.9 mmol/L n/a Some glucose values between 10.1-13.9 mmol/L are acceptable. Minimizing time higher than this is preferred Level 2: % of values >13.9 mmol/L <10% A1C, glycated hemoglobin; CGM, continuous glucose monitoring.
- In individuals NOT using insulin or sulfonylureas, CGM values <3.9 mmol/L may not indicate true or clinically significant hypoglycemia.
-f a structured educational program conducted in 216 people on basal-bolus injection therapy for type 1 or type 2 diabetes who were using or starting isCGM demonstrated that structured education resulted in greater A1C reduction, TIR and reduced diabetes-related distress, compared to usual care (50). The structured program was designed to increase understanding and use of the available glucose information by the individual to optimize diabetes treatment. It emphasized principles of isCGM, analysis of glucose values and trends, recognition of glucose patterns, therapy adjustments based on those glucose patterns, and psychosocial impact of isCGM.
In the high-risk setting of impaired awareness of hypoglycemia or history of severe hypoglycemia, structured education per se was effective to restore hypoglycemia awareness and to reduce frequency of severe hypoglycemia whether CBG testing or rtCGM were used (51). The trial may have underestimated the value of rtCGM which was used only 57% of the time, and greater use of rtCGM was associated with less time in hypoglycemia (TBR) (51 see Supp Table 6). In the Hypo-DE study, where sensors were used 90% of the time, rtCGM reduced incidence and duration of hypoglycemia events (11).
More guidance around self-management education and selfmanagement support is provided in the 2018 CPG (52).
Table 4 Recommended CGM targets for pregnancy (48). Note limited evidence.
# Author Disclosures
A.C. reports consulting and/or speaking honoraria from Abbott, Astra Zeneca, Bausch, Bayer, Boehringer Ingelheim, Dexcom, Eisai, Eli Lilly, HLS Therapeutics, Insulet, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Sanofi, and Takeda, as well as clinical trials with Applied Therapeutics, Boehringer Ingelheim, and Sanofi. D.F. reports funds from Novo Nordisk as part of an expert panel for a randomized trial, outside of the submitted work. R.S. reports consulting and/or speaking honoraria from CCRN, ICEBM, Ensemble-IQ, PPME, MdBriefcase, Pear Healthcare, Antibody, Lifescan, Abbott, Novo Nordisk, Sanofi, HLS Therapeutics, Merck, Dexcom, Astra Zeneca, Lilly, Janssen, and Amgen. J.H. has no conflicts to disclose. For more information, visit www.prisma-statement.org. | Canadian Journal of Diabetes j o u r n a l h o m e p a g e : w w w . c a n a d ia n j o u r n a l o f d i a b e t e s . c o m 1499-2671/Ó 2021 Canadian Diabetes Association. The Canadian Diabetes Association is the registered owner of the name Diabetes Canada.# Introduction
The Diabetes Canada Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada (CPG) were last published in 2018 (1). Rapid uptake of new monitoring technologies by persons living with diabetes and uncertainty among healthcare professionals prompted a review of evidence emerging since our previous recommendations for "Monitoring Glycemic Control" (2). We have updated the title for this topic to align with Diabetes Canada's position statement on "Language Matters" (3).
# Methods
A consolidated search strategy (for adults, children and pregnant women) was developed by modifying and updating PICO (population, intervention, comparison and outcome) questions used for the 2018 CPG (chapters 9, 34,35,36). A systematic search of the literature for relevant articles published from November 1, 2017 to October 28, 2020 was performed by the health science librarians at the McMaster Evidence Review and Synthesis Team (MERST). The MERST team reviewed all relevant citations at title, abstract and full-text levels. Relevant citations were abstracted and critically reviewed by a methodologist from MERST. All MERST staff (librarians and methodologists) were without financial or intellectual conflict. The full-text citations and critical appraisal reports were provided to the expert working group. Members of the expert working group were selected by the CPG Steering Committee with the goal of ensuring representation of diverse perspectives (across disciplines, and academic and community settings), appropriate content and methodologic expertise, while limiting the potential of financial conflict, as much as possible. Diabetes Canada has a formal policy to manage conflict of interest for the CPG Steering Committee.
The expert working group reviewed the citations, graded the evidence, drafted the revised recommendations and created the initial draft of the preamble document to accompany the revised recommendations. For this update, the CPG Steering Committee reviewed the cited evidence independently and suggested revisions to the draft recommendations and the text. The grading of recommendations was reviewed independently by the Independent Methods Review Co-Chair (D.R.). The finalized recommendations were unanimously approved by the CPG Steering Committee.
# Change in Terminology
Glucose monitoring remains a cornerstone of diabetes management. It allows people living with diabetes and their health-care providers to assess glycemic status and adverse effects, and to determine the effectiveness of glucose lowering therapies. Testing of glycated hemoglobin (A1C) continues to be the primary modality to ensure that glycemic goals are being met and the recommended frequency of testing remains unchanged. However, A1C is a measure of chronic glycemic levels over months and does not provide information that can inform immediate/short-term decisions. To measure glucose levels in real time, different modalities exist currently and new technologies are being studied. To address this expanding field, the terminology used to describe the different modalities needs to adapt to allow for future growth and has been updated in Table 1.
# Strength of Wording
To maintain consistency with other chapters in the 2018 CPG, the language within the recommendations has been modified, such that interventions supported by Grade A, Level 1 evidence, and confirmed as appropriate through clinical experience, are now written as "should be used" in place of the previous language of "may be offered." The population, intervention and expected outcome benefit is clearly indicated in each recommendation and the action language should reflect the confidence in the evidence provided.
# Real-Time Continuous Glucose Monitoring (rtCGM)
For people living with type 1 diabetes who use basal-bolus injection therapy or continuous subcutaneous insulin infusion (CSII), rtCGM has been shown to reduce A1C (4e9) and increase glucose time in range (TIR) (5,7,8,10), while simultaneously reducing duration and incidence of hypoglycemia (5,7e11) in adults and children. These glycemic benefits of rtCGM have been demonstrated in trials recruiting adults and children with A1C at target (<7.5%) (6) or above target (4e6,9); and in trials which included adults at or above target (8). As well as reducing biochemical (i.e. not necessarily symptomatic) hypoglycemia, rtCGM has been shown to reduce episodes of severe hypoglycemia in adults with a history of severe hypoglycemia or impaired awareness of hypoglycemia using multiple daily injections (MDI) (11). rtCGM has also been shown to improve quality of life and hypoglycemia distress in adults with type 1 diabetes (11e13).
For people living with type 2 diabetes using basal-bolus injection therapy, a randomized controlled trial of 158 subjects demonstrated that the use of rtCGM reduced A1C to a greater extent than usual care, with more time spent in the target range and less time spent above range at 24 weeks (14). Therefore, it is now recommended that rtCGM may be used to improve glycemic levels in those with type 2 diabetes on basal-bolus injection therapy, with a reminder that successful use of rtCGM is dependent on the duration of time it is used, along with the importance of providing it in association with structured education and therapeutic programs (see section Importance of Diabetes Self-Management Education).
# Intermittently-Scanned Continuous Glucose Monitoring (isCGM)
The use of isCGM has been shown to be beneficial for people living with type 1 or type 2 diabetes using insulin therapy to decrease time spent in hypoglycemia (15e17). Randomized controlled trials of isCGM compared to capillary blood glucose (CBG) testing in type 1 and type 2 diabetes have not consistently demonstrated differences in A1C (18). However, in a recent health technology assessment, other glucose parameters have been shown to improve. Compared with CBG testing, people using isCGM spent, on average, 1 hour more in target glucose range (95% confidence interval [CI] 0.41e1.59) and 22 minutes less in a high glucose range (95% CI À0.69 to À0.05) per day and less glucose variability among those with type 1 diabetes (19). A meta-regression, which included clinical trials and observational studies (which are subject to a number of biases) in type 1 and type 2 diabetes, suggested isCGM could reduce A1C by 0.55%, with the magnitude of A1C reduction being proportional to baseline A1C (20). However, as is true with any form of glucose monitoring, the act of monitoring may not of itself improve glucose levels, but, rather, provide data that permits users and providers to take actions to impact glucose levels underlying the importance of diabetes self-management education (see below).
# Comparison of rtCGM and isCGM in People With Type 1 Diabetes
Two studies have directly compared rtCGM with isCGM in adults with type 1 diabetes. rtCGM users spent more TIR and less time below range (TBR) than isCGM users in a 5-week randomized study in adults with normal awareness of hypoglycemia using MDI or CSII (21). In an 8-week study of individuals with impaired awareness of, or recent severe hypoglycemia using MDI, rtCGM reduced time in hypoglycemia and fear of hypoglycemia, which was not seen with isCGM (22). Superiority of rtCGM to protect from hypoglycemia in this high-risk population was supported in the extension phase of this study, where switching to rtCGM was associated with significant reduction in TBR in subjects originally randomized to isCGM (23).
# Masked Continuous Glucose Monitoring
A pragmatic, open-label 12-month study of the use of masked CGM every 3 months, for 5 to 14 days before their clinical visit, compared to usual clinical care among those with type 2 diabetes in general practice, showed no difference in the primary endpoint of A1C at 12 months (24), but there was an increase in TIR at 12 months and lower A1C at 6 months. Similarly, a randomized study of 148 people living with type 2 diabetes treated with insulin compared the effects of masked CGM and usual care with CBG testing in primary and secondary care settings and did not show a difference in the primary endpoint of TIR but did show a greater reduction in A1C with no increase in hypoglycemia (25). Given the conflicting data regarding the effects of the use of masked CGM, no recommendation can be made at this time.
# Glucose Monitoring in Women With Diabetes During Pregnancy
Accuracy of rtCGM and isCGM in pregnancy
In a study of the performance of rtCGM (Dexcom G6) in 32 pregnant women with diabetes (type 1, type 2 and gestational diabetes) across sensor wear sites, accuracy of rtCGM was acceptable (overall mean absolute relative difference [MARD] was 10.3%) when compared to venous glucose measures, which were taken during a period of 6 hours when participants were allowed to eat freely. rtCGM was also found to be acceptably accurate in the hypoglycemic range (<3.8 mmol/L), with a mean absolute difference of 0.5 mmol/L between 3-3.8 mmol/L and 0.35 mmol/L at glucose levels of 2.2-3.0 mmol/L. Comparing different sites, the posterior upper arm was found to be most accurate, with a MARD of 8.7%, followed by the buttock (11.2%) and the abdomen (11.5%) (26).
The use of isCGM in pregnant women with diabetes has also been studied for accuracy and safety. In a study of 74 pregnant women with type 1, type 2 or gestational diabetes, isCGM was found to have good agreement with CBG (overall MARD 11.8%), with high levels of user satisfaction (27).
# Glucose monitoring in pregnant women with type 1 and type 2 diabetes
The Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy (CONCEPTT) trial randomized 325 women (215 pregnant and 110 planning pregnancy) with type 1 diabetes, to rtCGM, in addition to CBG testing or CBG testing alone (28). Pregnant rtCGM users spent more time in the target range of 3.5 to 7.8 mmol/L (68% vs 61%, p¼0.0034) and less time above the range (>7.8 mmol/L) (27% vs 32%, p¼0.0279) than did pregnant participants using CBG testing alone, with comparable severe hypoglycemic episodes and time spent with hypoglycemia. Neonatal health outcomes were significantly improved, with a lower incidence of large for gestational age (LGA) infants (OR 0.51, 95% CI 0.28e0.90, p¼0.021), fewer neonatal intensive care unit (NICU) admissions lasting more than 24 hours (OR 0.48, 95% CI 0.26e0.86, p¼0.0157), and a lower risk of neonatal hypoglycemia (OR 0.45; 95% CI 0.22e0.89, p¼0.025). No benefit was observed for women planning a pregnancy (28). A budget impact model, where the National Health Service in England was used, estimated the total cost of pregnancy and delivery in women with type 1 diabetes using CBG testing with or without rtCGM. The potential annual cost savings of using rtCGM was estimated to be approximately £9.5 million, with the principal driver being reduced need for NICU and reduced duration of stay in NICU (29). Taken together, these data support updating the recommendation that rtCGM should be used in women with type 1 diabetes during pregnancy to improve blood glucose levels, and to reduce the risk for LGA infants, neonatal hypoglycemia and NICU admissions >24 hours.
To date, there have been no randomized trials using isCGM in pregnant women with type 1 or type 2 diabetes. In an observational cohort study of 186 women with type 1 diabetes attending pregnancy care at 2 tertiary care antenatal clinics in Sweden (92 women used rtCGM and 94 women used isCGM), TIR (3.5 to 7.8 mmol/L) was similar in the 2 groups, although time spent in hypoglycemia was higher in the isCGM group. Pregnancy outcomes were associated with CGM metrics and the incidence of LGA was similar in the 2 groups (52% rtCGM vs 53% isCGM) (30). The TIR achieved in this observational study (reaching 60% in the third trimester) was similar to the control arm, but lower than the intervention arm of CONCEPTT. While isCGM has not yet been shown to reduce neonatal morbidity in women with type 1 diabetes, these data are reassuring, but these observational data are not sufficient to conclude non-inferiority. Achieving optimal glycemic targets is more important than the technology employed. The effectiveness of rtCGM or isCGM for glycemic or fetal outcomes has not yet been studied in pregnant women with type 2 diabetes.
# Glucose monitoring in pregnant women with gestational diabetes
Frequent CBG testing is essential to guide management of gestational diabetes (31). Both fasting and postprandial testing are recommended to guide therapy in order to improve fetal outcomes (32). In a randomized trial of 293 women with newly diagnosed gestational diabetes, after 1 week of daily CBG testing (4 times per day: fasting and 2 hours postprandial), women who did not require pharmacotherapy were randomized to testing (4 times per day), either daily or every other day (33). The alternate day approach was non-inferior for birthweight and there were no differences in the need for medical therapy, gestational age of delivery, rate of LGA or preeclampsia. Consistent use of CBG testing was found to be higher in the every-other-day group (89% compared with 92%, p¼0.01). It is, therefore, reasonable to reduce testing to every other day after 1 week of testing daily, if glucose levels do not indicate the need for pharmacotherapy.
There have been no new randomized trials or cohort studies using rtCGM or isCGM in women with gestational diabetes since 2018. More studies are needed to assess the benefits of rtCGM or isCGM in women with gestational diabetes.
# Glucose Monitoring in Children and Adolescents With Diabetes
# CBG testing
Among children and adolescents with type 1 diabetes, frequent CBG testing (4 or more tests per day) was associated with lower A1C (34,35). In youth with type 2 diabetes on noninsulin antihyperglycemic therapy or insulin, low frequency of CBG testing was associated with higher A1C (36). rtCGM Two of 3 randomized controlled trials which included children as young as 6 years, comparing rtCGM to CBG testing, showed lower A1C and less TBR in both adults and children (7,9), but this was not seen in pediatric participants in the other study, which had very low use of rtCGM and was under-powered to detect differences in hypoglycemia (37). Lower A1C with rtCGM in children may depend on time spent using CGM since further analysis of pediatric subjects in this latter trial showed use of rtCGM for 6 or more days per week improved A1C by -0.8 AE 0.6% at 12 months (38). Characteristics, such as younger age and higher frequency of CBG testing prior to rtCGM, may help predict those who are more likely to use rtCGM consistently (39). Another study in younger children (ages 4 to 10 years) did not show any change or differences in A1C or CGM parameters between groups, although the use of rtCGM was associated with a high degree of parental satisfaction with rtCGM (40). These findings underscore a fear of hypoglycemia which is reflected in more conservative recommended glucose targets. In randomized controlled trials (37,40) and observational studies (41,42) of rtCGM, the rates of severe hypoglycemia were low, making it difficult to assess the effect of rtCGM on rates of severe hypoglycemia.
# isCGM
An open label study of isCGM in 76 children aged 4 to 17 years with type 1 diabetes using CSII or MDI showed lower A1C and more TIR, with no change in TBR (which was low at baseline) (43). A randomized trial of isCGM in adolescents (ages 13 to 20 years) with A1C >9% at baseline showed no advantage to reduce A1C but was associated with increased frequency of blood glucose monitoring and greater treatment satisfaction (44). Switching from CBG testing to isCGM among children and adolescents with type 1 diabetes was associated with a reduction in severe hypoglycemia but no reduction in A1C in a Belgian observational study (45). Of note, 15.8% of those who switched to isCGM reverted back to CBG testing after a median use of 5.3 months. A small, 2-week camp study showed isCGM was non-inferior to CBG testing in children aged 6 to 15 with type 1 diabetes using CSII (46). A meta-regression including trials and observational data suggested that isCGM may be associated with a mean reduction in A1C of 0.54% in the pediatric subgroup (20).
# Hypoglycemia in children with type 1 diabetes
Avoidance of severe hypoglycemia in children is of particular concern for families and providers. Safety is a primary concern in trial design and, fortunately, severe hypoglycemia during clinical trials is a rare event and, therefore, difficult to study. Although a definitive statement regarding the effectiveness of rtCGM to reduce severe hypoglycemia in children is not possible, observations of reductions in severe hypoglycemia in adults and less TBR in children suggest inference of the potential for benefit is plausible.
# Type 2 diabetes
No studies have examined the effectiveness of either rtCGM or isCGM in children and/or adolescents with type 2 diabetes. CGM could be offered, as an alternative to CBG testing, if preferred by the individual as part of training, education and support in selfmanagement.
# Glucose Metrics
When continuous glucose data are captured, it is possible to generate glucose metrics, including TIR, time above range (TAR), TBR and glycemic variability (standard deviation or coefficient of variation), which may be summarized along with the ambulatory glucose profile (see Table 2) (47). These metrics provide additional complementary glycemic data to assess blood glucose levels and identify potential areas for intervention. As the use of technologies allowing for CGM increases, clinicians will need to become more comfortable with the interpretation of these glucose metrics and international consensus groups have provided guidance and proposed targets (see Tables 2-4) (45,47e49).
# Importance of Diabetes Self-Management Education
The importance of diabetes self-management education when introducing or using newer glucose monitoring technologies has been clearly illustrated in recent trials. A randomized controlled trial Table 2 Glucose metrics that can be derived from continuous glucose monitoring* (47,48) and recommended targets from the International Consensus Report for most individuals with type 1 or type 2 diabetes (excluding pregnancy, children/adolescents, and older/high-risk groups) (49)
# Glucose metric
Recommended targets (for most individuals with type 1 or type 2 diabetes)
# Comments
Glucose Management Indicator (GMI) Approximate A1C level based on the average glucose levels from CGM readings for 14 or more days 7.0% GMI may differ from measured A1C as it is reflective of glucose values during the period being assessed during CGM interpretation (last 14 days, last 30 days)
# Glycemic Variability
Reported as % coefficient of variation (%CV) ¼ Standard Deviation/Mean Glucose 36% Lower %CV has been associated with reduced rates of hypoglycemia Time In Range (TIR) % of values between 3.9-10.0 mmol/L >70% 70% TIR equates to an A1C of about 7.0%. Each 10% TIR equates to about 0.5% change in A1C Time Below Range (TBR) * Recommended to use CGM regularly (>70% of a 14-day period).
# Table 3
Recommended CGM targets for older/higher risk individuals (excluding pregnancy, children/adolescents) (49)
Glucose metric Older/High-risk individuals Comments Time In Range (TIR) % of values between 3.9-10.0 mmol/L >50% 50% TIR equates to an A1C of about 8.0%. Each 10% TIR equates to about 0.5-0.8% change in A1C Time Below Range (TBR) Level 1 and 2: % of values <3.9 mmol/L <1.0%
In older/high-risk individuals using insulin or sulfonylureas, avoidance of hypoglycemia is a priority * Time Above Range (TAR) Level 1: % of values 10.1-13.9 mmol/L n/a Some glucose values between 10.1-13.9 mmol/L are acceptable. Minimizing time higher than this is preferred Level 2: % of values >13.9 mmol/L <10% A1C, glycated hemoglobin; CGM, continuous glucose monitoring.
* In individuals NOT using insulin or sulfonylureas, CGM values <3.9 mmol/L may not indicate true or clinically significant hypoglycemia.
of a structured educational program conducted in 216 people on basal-bolus injection therapy for type 1 or type 2 diabetes who were using or starting isCGM demonstrated that structured education resulted in greater A1C reduction, TIR and reduced diabetes-related distress, compared to usual care (50). The structured program was designed to increase understanding and use of the available glucose information by the individual to optimize diabetes treatment. It emphasized principles of isCGM, analysis of glucose values and trends, recognition of glucose patterns, therapy adjustments based on those glucose patterns, and psychosocial impact of isCGM.
In the high-risk setting of impaired awareness of hypoglycemia or history of severe hypoglycemia, structured education per se was effective to restore hypoglycemia awareness and to reduce frequency of severe hypoglycemia whether CBG testing or rtCGM were used (51). The trial may have underestimated the value of rtCGM which was used only 57% of the time, and greater use of rtCGM was associated with less time in hypoglycemia (TBR) (51 see Supp Table 6). In the Hypo-DE study, where sensors were used 90% of the time, rtCGM reduced incidence and duration of hypoglycemia events (11).
More guidance around self-management education and selfmanagement support is provided in the 2018 CPG (52).
Table 4 Recommended CGM targets for pregnancy (48). Note limited evidence.
# Author Disclosures
A.C. reports consulting and/or speaking honoraria from Abbott, Astra Zeneca, Bausch, Bayer, Boehringer Ingelheim, Dexcom, Eisai, Eli Lilly, HLS Therapeutics, Insulet, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Sanofi, and Takeda, as well as clinical trials with Applied Therapeutics, Boehringer Ingelheim, and Sanofi. D.F. reports funds from Novo Nordisk as part of an expert panel for a randomized trial, outside of the submitted work. R.S. reports consulting and/or speaking honoraria from CCRN, ICEBM, Ensemble-IQ, PPME, MdBriefcase, Pear Healthcare, Antibody, Lifescan, Abbott, Novo Nordisk, Sanofi, HLS Therapeutics, Merck, Dexcom, Astra Zeneca, Lilly, Janssen, and Amgen. J.H. has no conflicts to disclose. For more information, visit www.prisma-statement.org. | None | None |
8f49bac88c3e2f9dc2465a1daa9bef39e52477cf | cma | None | On March 11, 2020, the World Health Organization declared COVID-19, caused by a novel coronavirus, a pandemic, citing concern over alarming levels of spread and severity across the globe. The novel coronavirus has caused a global outbreak of respiratory infections since its discovery in December 2019. Although the scientific understanding of the effects of COVID-19 continues to grow, it is known that symptoms can range from mild (e.g., cough. fever) to severe (e.g., pneumonia, requiring hospitalization).
The situation regarding COVID-19 continues to evolve in BC, Canada, and other jurisdictions around the world. Federal and provincial health officials have urged individuals on chronic medications to acquire an adequate supply of prescription drugs. Ensuring uninterrupted access to essential medications, including opioid agonist treatment (OAT) medications for patients with opioid use disorder, is of critical importance to reduce the risk of harms and death that can be associated with medication destabilization. This bulletin presents guidance and considerations for OAT prescribers and pharmacists in BC to ensure patients can access needed medications while reducing COVID-19 related risks, during this extraordinary period of dual public health emergencies. COVID-19 response planning should include plans for how to return to normal practices following the resolution of the COVID-19 emergency.
This bulletin contains the following information:
- Preparedness planning for patients on (oral and injectable) OAT 2. Guidance for OAT Prescribers 3. Guidance for Pharmacists 4. Guidance for current injectable OAT programs 5. General COVID-19 Preparedness Practices 6. Development of this bulletin 7. Additional Resources
# PreParedness Planning for Patients on (oral and injectable) oat
Clinic and program administrators should review their space and patient flow, patient protocols, and cleaning procedures to determine if current procedures are sufficient to reduce risk of viral transmission. some clinics and programs may be able to safely continue operations and provide oat to all patients, as per normal practices, during the coVid-19 pandemic.
Many patients prescribed OAT currently receive daily witnessed medications, but those who are immunocompromised and those who exhibit symptoms or who are in self-isolation may not be able to attend medical appointments or present to the pharmacy for their witnessed dose or to pick up take-home doses. To facilitate continued access to OAT medications, all health care providers should:
- Talk with all patients about COVID-19, including ways to reduce risk of infection and any specific concerns related to an individual's health (e.g., existing chronic health conditions, immunosuppression). See General COVID-19 Preparedness Practices, below - Develop a contingency plan with patients, in the event they are unable to come in for appointments or access all of their medications through regular means, including OAT - Develop contingency plans for potential staff shortages - Consider alternative avenues to get essential medications to patients that both reduce the number of patient visits (e.g., extending prescription durations) and promote physical distancing (e.g., telemedicine). This may also include pharmacy delivery of OAT (see Guidance for Pharmacists, below), where services exist. If delivery is not an option, prescribers and pharmacists should work closely together to ensure patients can pick up medications with proper safety precautions in place - Support patients who may continue to use alcohol and illicit drugs during this pandemic. Interim clinical guidance is available on the BCCSU's website to support prescribers to prevent clients from experiencing unsupported withdrawal while adhering to physical distancing and self-isolation measures
In order to support continuity of care and medication access, detailed information is provided below for prescribers and pharmacists.
1 See Klaire, 2019 for a rapid micro-induction protocol and guidance from the BC Pharmacy Association for more information and a slower micro-dosing protocol (the Bernese method); consider consulting the RACE line if additional guidance necessary
# guidance for oat Prescribers
- Carefully document in the patient's medical record the rationale for any treatment plan augmentations or alterations due to COVID-19. Enter all prescriptions into PharmaNet - Specific guidance for different types of OAT:
buprenorphine/naloxone buprenorphine/naloxone: If possible, and with a discussion of the risks and benefits with the patient, consider transitioning to buprenorphine/naloxone-first-line treatment for opioid use disorder. Given the superior safety profile, patients can receive longer duration carries (a benefit if they are in selfisolation) and there is reduced risk of overdose and diversion - Micro-induction may be considered for individuals transitioning from another OAT medication to buprenorphine/naloxone, to avoid the need for a washout period and moderate withdrawal to be reached prior to induction 1 - Where clinically appropriate, prescribers should prescribe carry doses in blister packages, if available, by indicating this on the prescription for the pharmacy to arrange
# Methadone
Any formulation of methadone (Methadose, Metadol-D, Sandoz Methadone , or compounded methadone): Where clinically appropriate, prescribers should consider temporarily allowing carry doses in adequately stable patients, including longer take-home intervals and fewer in-person appointments, supporting uninterrupted access to these essential medications sustained release oral morphine sustained release oral morphine (SROM; Kadian): prescribers should temporarily prescribe carry doses, whenever clinically appropriate (e.g., a stable patient with a secure place to store up to a week's supply of medication)
- For daily witnessed ingestion (DWI) doses (e.g., patient deemed too unstable or patient unable to safely store a week's supply of medications), consider not recommending 'sprinkling' (i.e., opening capsules and sprinkling medications) in the prescription. Indicate this clearly on the prescription and communicate with the pharmacy if necessary. This will reduce the amount of time patients spend in pharmacy and reduce medication handling and interactions with pharmacy staff - Note: There is a potential Kadian shortage currently. More information available here injectable oat For patients on injectable Oat (hydromorphone and diacetylmorphine), see specific medication guidance below.
- Ensure prescription does not end on a weekend, statutory holiday, or other time in which prescriber would not be available. If prescription is DWI, ensure that carries are included for statutory holidays. The exact date(s) of carries must be specified on the prescription - The duration of carry doses should be individualized o For patients with symptoms or in isolation, consider means by which patients can have medications safely delivered for daily witnessed doses, or increase carries to ensure adequate medication o Note that the duration of carry or delivery can be written as part-fill in the SIG for a longer prescription (e.g., 7-day weekly carry with first dose witnessed) - When prescribing longer duration of carry doses, clinicians must weigh the benefits of larger dispenses with the risk of overdose, diversion, or risk to household members. In any case where carry doses are provided, counselling on safe storage of medication is critical. Also, ensure that patients have naloxone kits and training on their use - Urine drug tests should only be used when clear clinical utility exists. A negative urine drug test is not required in order to prescribe take-home doses - Wherever possible, provide support to patients via telemedicine (telehealth/virtual service billing codes). A reminder that billing codes for OAT may be eligible for telehealth visits and some may be billed when delegated to a nurse (see OUD billing codes for more information) - During the pandemic, it is now acceptable for prescribers to fax prescriptions, or give verbal prescriptions for controlled drugs to pharmacists, and then deliver (by mail courier or other means) a hard copy of the original duplicate prescription at a later date. o Permit pharmacists to extend prescriptions o Permit pharmacists to transfer prescriptions to other pharmacists o Permit prescribers to issue verbal orders (i.e., over the phone) to extend or refill a prescription o Permit pharmacy employees to deliver prescriptions of controlled substances to patient's homes or other locations where they may be staying. o Guidance on operationalizing these exemptions is available on CPBC's website.
The BCCSU will make every effort to stay apprised of potential disruptions in the drug supply chain or other factors that may affect medication availability and will provide updates as they become available.
# guidance for injectable oat PrograMs
The options provided below are meant to support established health authority-operated injectable opioid agonist treatment (iOAT) programs. The guidance provided is aimed at programs that are unable to continue normal operations.
Clinics that provide iOAT should ensure that relevant public health and occupational health and safety protocols are in place, in the context of COVID-19.
Clinics may consider the following medication transitions aimed at reducing the number of patient visits per day and to support patients in isolation:
OPTION 1: Transition one or more injection doses to oral OAT alone Medication selection
- If patient has an existing oral OAT co-prescription, consider increasing dosage to compensate for the reduction in iOAT doses - If replacing some but not all iOAT doses with oral OAT, prescribe slow-release oral morphine (SROM) or methadone.
- Use the conversion table to determine the equivalent dosage for SROM and methadone o SROM may be preferable due to its better safety profile and significantly lower variability in required dosage o Methadone formulations must be titrated slowly (5-10mg every 5+ days) due to the variability in absorption rates, slow bioaccumulation, and long half-life.
- Due to incomplete cross-tolerance between types of opioids, frequent follow-up and monitoring is recommended to ensure correct dosing for each patient - If replacing all doses with oral OAT, based on patient preference and prescriber discretion, transition to buprenorphine/naloxone may be considered o Buprenorphine/naloxone is not an appropriate co-prescription; due to its high affinity for the opioid receptor, it preferentially binds to the receptor and displaces other opioids if they are present, which can cause precipitated withdrawal o If transitioning fully to buprenorphine/naloxone, induction is possible in 1-3 days, but can take longer - See above guidance and refer to the CRISM National iOAT Clinical Guideline for more information on transitions from iOAT to oral OAT
# Features of this option
- This may be a useful approach for clinics with limited capacity, physical space, and resources - Benefits: Oral OAT medications have a significant body of evidence showing safety and efficacy. They are relatively safe to be provided as take-home doses, and witnessing of doses is on a case-by-case basis. If a patient is treated solely with oral OAT, longer prescriptions and take-home doses would more easily facilitate patients to remain in isolation if needed. - Disadvantages: Transitioning to oral OAT can result in de-stabilization and a return to illicit opioid use to avoid withdrawal symptoms and cravings.
OPTION 2: Provide take-home oral hydromorphone, to replace one or more iOAT doses Prescribing considerations - Patients on diacetylmorphine would need to be converted to hydromorphone o Use the conversion table to determine the equivalent dosage o Ensure that pharmacy has adequate supply - Oral hydromorphone is available in 8mg tablets. Using a simple dosage conversion from IV to oral may result in a in a dose that is inappropriately high. Thus, use clinical judgment to determine a starting dose of oral HDM (e.g., 1-3 tablets q1h as needed up to 14 tablets) and adjust dose as needed - Daily dispensing is preferred o If continuing with one injected dose in clinic, oral hydromorphone can be provided for the remaining hours of the day o Pre-dose assessment in clinic should include asking the patient when the previous day's take-home doses were taken o Instruct patient to wait at least 3 hours after the injected dose in clinic before starting the take-home doses o Use clinical discretion to determine whether witnessing is required o Arrange for regular check-ins and monitoring, including remotely where available o Given that some patients may inject this medication rather than using the intended oral route, prescribers should advise patients on safer injection practices and safe disposal of syringes, as well as provide necessary supplies, if available o Recommended only if the patient is on a stable dose of iOAT, has had no recent post-dose complications, and has adequate housing - For patients in isolation due to COVID-19, daily delivery and witnessing may be possible by a pharmacist
# Features of this option
- Appropriate if Option 1 is deemed to be less optimal for meeting client's treatment needs, based on clinical judgment, and Option 3 is not available. - Benefits: When replacing one dose of iOAT, oral HDM may be less likely to de-stabilize a patient than oral OAT alone. Injectable opioid agonist treatment patients have trialed oral OAT alone and continued to experience cravings and symptoms of withdrawal. - Disadvantages:Oral HDM is not an evidence-based treatment for opioid use disorder and thus, clinicians must rely on their professional judgment, weigh the risks and benefits, and make a care plan that is in the best interest of the patient. There is a risk of destabilization, over-sedation, or undertreatment due to the challenge of converting dosage from IV to oral OPTION 3: Provide pre-filled syringe(s) of hydromorphone as a take-home dose, once per day This option should be considered on a case-by-case basis by the prescriber and the iOAT care team for one or more of the doses prescribed on any given day. It should only be considered in situations where self-isolation has been recommended by a health care provider, when all options to support the patient to attend the iOAT clinic have been explored, and a transition to oral OAT is unlikely to be or has been unsuccessful.
Prescribing considerations - Patient should be on a stable dose of iOAT, have no active concurrent substance use disorder, and have had no recent post-dose complications. - Doses must be dispensed on a daily basis, there should be a reasonable plan for dose transportation, and patient education regarding home administration provided. - Consideration should be given to alternative procedures for pre and post injection assessments, supervision of injection and appropriate spacing of doses.
Features of this option - Benefits: Maintaining injectable hydromorphone is likely to support clinical stability compared to switching to an oral medication, as seen in the SALOME trial. - Disadvantages: There are safety risks both during transport home and for the patient, and potential for diversion with take-home doses.
# GENERAL COVID-19 PREPAREDNESS PRACTICES
- Clinicians should follow hand hygiene, respiratory etiquette, and social distancing measures and advise patients to do the same. Have hand sanitizer available and consider face masks for those who present with respiratory symptoms. More information can be found on the Government of Canada website. - Clinicians should ensure patients have an adequate supply of other required medications (e.g., for HIV, hepatitis C, other chronic conditions) that may be necessary during a period of quarantine, providing extra refills as appropriate. - Clinicians should provide information about COVID-19 to patients, including about social distancing measures when visiting the pharmacy or clinic, and refer patients to the BC Centre for Disease Control for more information. - The BC Centre for Disease Control has created guidance for responding to an overdose in the context of the COVID-19 pandemic, including when rescue breaths and ventilation are required. - The Harm Reduction Coalition has published a fact sheet on COVID-19 operational practices for harm reduction providers, which provides additional relevant guidance.
# DEVELOPMENT OF THIS BULLETIN
This bulletin was developed following consultation with oral and injectable OAT providers in Canada and international jurisdictions. The suggestions and considerations included in this bulletin were synthesized from those providers and were revised through multiple rounds of review by a group of addiction medicine experts in BC. To collate guidance for iOAT specifically, BCCSU staff consulted with health professionals from Germany, the Netherlands, and Canada (including Alberta and BC).
In order to provide brief and practical guidance in the context of the COVID-19 pandemic, this document does not include a review of the scientific evidence and intends for prescribers to rely on their clinical judgment when utilizing this guidance. A comprehensive evidence review on the efficacy of oral and injectable OAT can be found in the provincial Guideline for the Clinical Management of Opioid Use Disorder and the National Injectable Opioid Agonist Treatment for Opioid Use Disorder Clinical Guideline. | #
On March 11, 2020, the World Health Organization declared COVID-19, caused by a novel coronavirus, a pandemic, citing concern over alarming levels of spread and severity across the globe. The novel coronavirus has caused a global outbreak of respiratory infections since its discovery in December 2019. Although the scientific understanding of the effects of COVID-19 continues to grow, it is known that symptoms can range from mild (e.g., cough. fever) to severe (e.g., pneumonia, requiring hospitalization).
The situation regarding COVID-19 continues to evolve in BC, Canada, and other jurisdictions around the world. Federal and provincial health officials have urged individuals on chronic medications to acquire an adequate supply of prescription drugs. Ensuring uninterrupted access to essential medications, including opioid agonist treatment (OAT) medications for patients with opioid use disorder, is of critical importance to reduce the risk of harms and death that can be associated with medication destabilization. This bulletin presents guidance and considerations for OAT prescribers and pharmacists in BC to ensure patients can access needed medications while reducing COVID-19 related risks, during this extraordinary period of dual public health emergencies. COVID-19 response planning should include plans for how to return to normal practices following the resolution of the COVID-19 emergency.
This bulletin contains the following information:
1. Preparedness planning for patients on (oral and injectable) OAT 2. Guidance for OAT Prescribers 3. Guidance for Pharmacists 4. Guidance for current injectable OAT programs 5. General COVID-19 Preparedness Practices 6. Development of this bulletin 7. Additional Resources
# PreParedness Planning for Patients on (oral and injectable) oat
Clinic and program administrators should review their space and patient flow, patient protocols, and cleaning procedures to determine if current procedures are sufficient to reduce risk of viral transmission. some clinics and programs may be able to safely continue operations and provide oat to all patients, as per normal practices, during the coVid-19 pandemic.
Many patients prescribed OAT currently receive daily witnessed medications, but those who are immunocompromised and those who exhibit symptoms or who are in self-isolation may not be able to attend medical appointments or present to the pharmacy for their witnessed dose or to pick up take-home doses. To facilitate continued access to OAT medications, all health care providers should:
• Talk with all patients about COVID-19, including ways to reduce risk of infection and any specific concerns related to an individual's health (e.g., existing chronic health conditions, immunosuppression). See General COVID-19 Preparedness Practices, below • Develop a contingency plan with patients, in the event they are unable to come in for appointments or access all of their medications through regular means, including OAT • Develop contingency plans for potential staff shortages • Consider alternative avenues to get essential medications to patients that both reduce the number of patient visits (e.g., extending prescription durations) and promote physical distancing (e.g., telemedicine). This may also include pharmacy delivery of OAT (see Guidance for Pharmacists, below), where services exist. If delivery is not an option, prescribers and pharmacists should work closely together to ensure patients can pick up medications with proper safety precautions in place • Support patients who may continue to use alcohol and illicit drugs during this pandemic. Interim clinical guidance is available on the BCCSU's website to support prescribers to prevent clients from experiencing unsupported withdrawal while adhering to physical distancing and self-isolation measures
In order to support continuity of care and medication access, detailed information is provided below for prescribers and pharmacists.
1 See Klaire, 2019 for a rapid micro-induction protocol and guidance from the BC Pharmacy Association for more information and a slower micro-dosing protocol (the Bernese method); consider consulting the RACE line if additional guidance necessary
# guidance for oat Prescribers
• Carefully document in the patient's medical record the rationale for any treatment plan augmentations or alterations due to COVID-19. Enter all prescriptions into PharmaNet • Specific guidance for different types of OAT:
buprenorphine/naloxone buprenorphine/naloxone: If possible, and with a discussion of the risks and benefits with the patient, consider transitioning to buprenorphine/naloxone-first-line treatment for opioid use disorder. Given the superior safety profile, patients can receive longer duration carries (a benefit if they are in selfisolation) and there is reduced risk of overdose and diversion • Micro-induction may be considered for individuals transitioning from another OAT medication to buprenorphine/naloxone, to avoid the need for a washout period and moderate withdrawal to be reached prior to induction 1 • Where clinically appropriate, prescribers should prescribe carry doses in blister packages, if available, by indicating this on the prescription for the pharmacy to arrange
# Methadone
Any formulation of methadone (Methadose, Metadol-D, Sandoz Methadone [Sterinova], or compounded methadone): Where clinically appropriate, prescribers should consider temporarily allowing carry doses in adequately stable patients, including longer take-home intervals and fewer in-person appointments, supporting uninterrupted access to these essential medications sustained release oral morphine sustained release oral morphine (SROM; Kadian): prescribers should temporarily prescribe carry doses, whenever clinically appropriate (e.g., a stable patient with a secure place to store up to a week's supply of medication)
• For daily witnessed ingestion (DWI) doses (e.g., patient deemed too unstable or patient unable to safely store a week's supply of medications), consider not recommending 'sprinkling' (i.e., opening capsules and sprinkling medications) in the prescription. Indicate this clearly on the prescription and communicate with the pharmacy if necessary. This will reduce the amount of time patients spend in pharmacy and reduce medication handling and interactions with pharmacy staff • Note: There is a potential Kadian shortage currently. More information available here injectable oat For patients on injectable Oat (hydromorphone and diacetylmorphine), see specific medication guidance below.
• Ensure prescription does not end on a weekend, statutory holiday, or other time in which prescriber would not be available. If prescription is DWI, ensure that carries are included for statutory holidays. The exact date(s) of carries must be specified on the prescription • The duration of carry doses should be individualized o For patients with symptoms or in isolation, consider means by which patients can have medications safely delivered for daily witnessed doses, or increase carries to ensure adequate medication o Note that the duration of carry or delivery can be written as part-fill in the SIG for a longer prescription (e.g., 7-day weekly carry with first dose witnessed) • When prescribing longer duration of carry doses, clinicians must weigh the benefits of larger dispenses with the risk of overdose, diversion, or risk to household members. In any case where carry doses are provided, counselling on safe storage of medication is critical. Also, ensure that patients have naloxone kits and training on their use • Urine drug tests should only be used when clear clinical utility exists. A negative urine drug test is not required in order to prescribe take-home doses • Wherever possible, provide support to patients via telemedicine (telehealth/virtual service billing codes). A reminder that billing codes for OAT may be eligible for telehealth visits and some may be billed when delegated to a nurse (see OUD billing codes for more information) • During the pandemic, it is now acceptable for prescribers to fax prescriptions, or give verbal prescriptions for controlled drugs to pharmacists, and then deliver (by mail courier or other means) a hard copy of the original duplicate prescription at a later date. o Permit pharmacists to extend prescriptions o Permit pharmacists to transfer prescriptions to other pharmacists o Permit prescribers to issue verbal orders (i.e., over the phone) to extend or refill a prescription o Permit pharmacy employees to deliver prescriptions of controlled substances to patient's homes or other locations where they may be staying. o Guidance on operationalizing these exemptions is available on CPBC's website.
The BCCSU will make every effort to stay apprised of potential disruptions in the drug supply chain or other factors that may affect medication availability and will provide updates as they become available.
# guidance for injectable oat PrograMs
The options provided below are meant to support established health authority-operated injectable opioid agonist treatment (iOAT) programs. The guidance provided is aimed at programs that are unable to continue normal operations.
Clinics that provide iOAT should ensure that relevant public health and occupational health and safety protocols are in place, in the context of COVID-19.
Clinics may consider the following medication transitions aimed at reducing the number of patient visits per day and to support patients in isolation:
OPTION 1: Transition one or more injection doses to oral OAT alone Medication selection
• If patient has an existing oral OAT co-prescription, consider increasing dosage to compensate for the reduction in iOAT doses • If replacing some but not all iOAT doses with oral OAT, prescribe slow-release oral morphine (SROM) or methadone.
o Use the conversion table to determine the equivalent dosage for SROM and methadone o SROM may be preferable due to its better safety profile and significantly lower variability in required dosage o Methadone formulations must be titrated slowly (5-10mg every 5+ days) due to the variability in absorption rates, slow bioaccumulation, and long half-life.
• Due to incomplete cross-tolerance between types of opioids, frequent follow-up and monitoring is recommended to ensure correct dosing for each patient • If replacing all doses with oral OAT, based on patient preference and prescriber discretion, transition to buprenorphine/naloxone may be considered o Buprenorphine/naloxone is not an appropriate co-prescription; due to its high affinity for the opioid receptor, it preferentially binds to the receptor and displaces other opioids if they are present, which can cause precipitated withdrawal o If transitioning fully to buprenorphine/naloxone, induction is possible in 1-3 days, but can take longer • See above guidance and refer to the CRISM National iOAT Clinical Guideline for more information on transitions from iOAT to oral OAT
# Features of this option
• This may be a useful approach for clinics with limited capacity, physical space, and resources • Benefits: Oral OAT medications have a significant body of evidence showing safety and efficacy. They are relatively safe to be provided as take-home doses, and witnessing of doses is on a case-by-case basis. If a patient is treated solely with oral OAT, longer prescriptions and take-home doses would more easily facilitate patients to remain in isolation if needed. • Disadvantages: Transitioning to oral OAT can result in de-stabilization and a return to illicit opioid use to avoid withdrawal symptoms and cravings.
OPTION 2: Provide take-home oral hydromorphone, to replace one or more iOAT doses Prescribing considerations • Patients on diacetylmorphine would need to be converted to hydromorphone o Use the conversion table to determine the equivalent dosage o Ensure that pharmacy has adequate supply • Oral hydromorphone is available in 8mg tablets. Using a simple dosage conversion from IV to oral may result in a in a dose that is inappropriately high. Thus, use clinical judgment to determine a starting dose of oral HDM (e.g., 1-3 tablets q1h as needed up to 14 tablets) and adjust dose as needed • Daily dispensing is preferred o If continuing with one injected dose in clinic, oral hydromorphone can be provided for the remaining hours of the day o Pre-dose assessment in clinic should include asking the patient when the previous day's take-home doses were taken o Instruct patient to wait at least 3 hours after the injected dose in clinic before starting the take-home doses o Use clinical discretion to determine whether witnessing is required o Arrange for regular check-ins and monitoring, including remotely where available o Given that some patients may inject this medication rather than using the intended oral route, prescribers should advise patients on safer injection practices and safe disposal of syringes, as well as provide necessary supplies, if available o Recommended only if the patient is on a stable dose of iOAT, has had no recent post-dose complications, and has adequate housing • For patients in isolation due to COVID-19, daily delivery and witnessing may be possible by a pharmacist
# Features of this option
• Appropriate if Option 1 is deemed to be less optimal for meeting client's treatment needs, based on clinical judgment, and Option 3 is not available. • Benefits: When replacing one dose of iOAT, oral HDM may be less likely to de-stabilize a patient than oral OAT alone. Injectable opioid agonist treatment patients have trialed oral OAT alone and continued to experience cravings and symptoms of withdrawal. • Disadvantages:Oral HDM is not an evidence-based treatment for opioid use disorder and thus, clinicians must rely on their professional judgment, weigh the risks and benefits, and make a care plan that is in the best interest of the patient. There is a risk of destabilization, over-sedation, or undertreatment due to the challenge of converting dosage from IV to oral OPTION 3: Provide pre-filled syringe(s) of hydromorphone as a take-home dose, once per day This option should be considered on a case-by-case basis by the prescriber and the iOAT care team for one or more of the doses prescribed on any given day. It should only be considered in situations where self-isolation has been recommended by a health care provider, when all options to support the patient to attend the iOAT clinic have been explored, and a transition to oral OAT is unlikely to be or has been unsuccessful.
Prescribing considerations • Patient should be on a stable dose of iOAT, have no active concurrent substance use disorder, and have had no recent post-dose complications. • Doses must be dispensed on a daily basis, there should be a reasonable plan for dose transportation, and patient education regarding home administration provided. • Consideration should be given to alternative procedures for pre and post injection assessments, supervision of injection and appropriate spacing of doses.
Features of this option • Benefits: Maintaining injectable hydromorphone is likely to support clinical stability compared to switching to an oral medication, as seen in the SALOME trial. • Disadvantages: There are safety risks both during transport home and for the patient, and potential for diversion with take-home doses.
# GENERAL COVID-19 PREPAREDNESS PRACTICES
• Clinicians should follow hand hygiene, respiratory etiquette, and social distancing measures and advise patients to do the same. Have hand sanitizer available and consider face masks for those who present with respiratory symptoms. More information can be found on the Government of Canada website. • Clinicians should ensure patients have an adequate supply of other required medications (e.g., for HIV, hepatitis C, other chronic conditions) that may be necessary during a period of quarantine, providing extra refills as appropriate. • Clinicians should provide information about COVID-19 to patients, including about social distancing measures when visiting the pharmacy or clinic, and refer patients to the BC Centre for Disease Control for more information. • The BC Centre for Disease Control has created guidance for responding to an overdose in the context of the COVID-19 pandemic, including when rescue breaths and ventilation are required. • The Harm Reduction Coalition has published a fact sheet on COVID-19 operational practices for harm reduction providers, which provides additional relevant guidance.
# DEVELOPMENT OF THIS BULLETIN
This bulletin was developed following consultation with oral and injectable OAT providers in Canada and international jurisdictions. The suggestions and considerations included in this bulletin were synthesized from those providers and were revised through multiple rounds of review by a group of addiction medicine experts in BC. To collate guidance for iOAT specifically, BCCSU staff consulted with health professionals from Germany, the Netherlands, and Canada (including Alberta and BC).
In order to provide brief and practical guidance in the context of the COVID-19 pandemic, this document does not include a review of the scientific evidence and intends for prescribers to rely on their clinical judgment when utilizing this guidance. A comprehensive evidence review on the efficacy of oral and injectable OAT can be found in the provincial Guideline for the Clinical Management of Opioid Use Disorder and the National Injectable Opioid Agonist Treatment for Opioid Use Disorder Clinical Guideline. | None | None |
5b7f87ed5b4539ca3f6226b37c778554e2b93fe7 | cma | None | To provide guidance on the diagnosis, treatment and prevention of central venous catheter-related deep vein thrombosis (DVT).Central venous catheters are widely used for resuscitation; administration of chemotherapy, antibiotics and other medications; transfusion therapy; apheresis procedures; parenteral nutrition; blood sample acquisition; and supportive care, especially in patients with malignancy. The incidence rates for central venous catheter-related DVT vary widely among studies (ranging from approximately 2 to 70%), due in part to variable criteria for investigation (e.g. symptomatic patients versus routine screening of all patients with central venous catheters), as well as differences in patient populations (e.g. cancer, surgical, pediatrics) and duration of follow-up. Risk factors for catheter-related DVT include use of larger diameter catheters with multiple lumens, catheter tip malposition, left-sided placement, concomitant infection, history of DVT, and, in cancer patients, the type and stage of cancer, and administration of chemotherapy. Peripherally inserted central catheters (PICCs) are associated with a higher risk of DVT than other centrally inserted catheters, including implanted ports. Heritable thrombophilias likely increase the risk, however the magnitude of risk increase is unclear and screening for them is not currently indicated.# DIAGNOSIS OF CATHETER-RELATED DVT:
Patients with central venous catheter-related DVT may develop unilateral hand or arm swelling, pain or swelling in the neck or shoulder, visible collateral veins on the chest, or symptoms of superior vena cava obstruction, such as facial swelling, dyspnea, and headache. Patients with central venous catheter-related DVT may also be asymptomatic. Symptoms of embolization (e.g. pulmonary embolism, paradoxical stroke) should also prompt an evaluation for DVT in patients with central venous catheters. While a combination of clinical decision rules with D-dimer can be effective ruling out DVT in certain populations, its efficiency is limited in those with central venous catheters and is not recommended. The best initial test for diagnosing catheter-related DVT is duplex ultrasonography. Isolated subclavian vein or more central venous thrombosis may not be well seen with ultrasonography due to anatomical hindrance by the clavicle and chest wall. In difficult cases, magnetic resonance imaging (MRI) or computed tomography (CT) may be required. Direct contrast venography is an invasive procedure and may be difficult to obtain.
# TREATMENT OF CATHETER-RELATED DVT:
The goals of treatment for catheter-associated DVT are to improve acute symptoms, decrease longterm morbidity, prolong patency and survival of the catheter, and prevent embolization and recurrent thrombosis. Acute treatment recommendations are based primarily on trials in patients with lower extremity DVT. Removal of the central venous catheter is not required if it is still needed, functioning properly, and not associated with infection; however, if symptoms persist or worsen despite anticoagulation, the central venous catheter may need to be removed.
Use of low molecular weight heparin (LMWH) has been shown to be effective and safe in upper extremity DVT. Longer-term anticoagulation may involve continuation of LMWH alone, or conversion to warfarin. If LMWH is transitioned to warfarin, there should be an overlap for a minimum of 5 days and until the international normalized ratio (INR) is therapeutic. Direct oral anticoagulants (DOACs) have limited data to support use in catheter-related DVT, but they are known to be equivalent to warfarin in non-cancer patients, and LMWH in cancer patients for treatment of lower extremity DVT and pulmonary embolism. In a recent single arm study of rivaroxaban 15 mg orally twice daily for 21 days followed by 20 mg once daily in 70 cancer patients with central venous catheter-related upper extremity DVT, preservation of line function at 12 weeks was 100% and the risk of recurrent venous thromboembolism was 1.43% during the same period. There was, however, one episode of fatal pulmonary embolism, and the risk of clinically relevant bleeding (12.9%) was higher than anticipated. However, the findings from this study are limited by its small size and the lack of a control arm. The use of DOACs in this demographic continue to be studied. Given the limited data, Canadian expert consensus currently favours LMWH over DOACs or warfarin in the treatment of catheter-related DVT.
Although treatment duration for catheter-related DVT is controversial, it is reasonable to treat patients with a DVT in the axillary or a more proximal upper extremity deep vein for a minimum of 3 months or longer if the catheter remains in place. In those with a DVT involving only the brachial vein or thrombosis confined to the superficial veins, such as the cephalic or basilic vein, treatment with anticoagulation has not been studied. In this situation, anticoagulation with either full dose anticoagulation or less than therapeutic doses of LMWH (e.g. approximately 50% of a treatment dose) to prevent progression of the thrombus while the catheter remains in place is reasonable. There are few data to guide the use of catheter-directed thrombolysis in patients with extensive central catheter-related DVT and so the use of this intervention remains a case-by-case decision, best guided by consultation with a thrombosis expert and/or interventional radiologist.
# PREVENTION OF CATHETER-RELATED DVT:
The most important aspects of prevention of catheter-related DVT include use of central venous catheters only when necessary, insertion of the smallest catheters that satisfy their purpose and prompt removal when no longer needed. The process of PICC exchange has recently been identified as a risk factor for developing DVT, so should be done only when absolutely necessary.
Routine use of thromboprophylaxis in patients with central venous catheters with anticoagulation is not recommended by most guidelines. A systematic review and meta-analysis evaluating anticoagulation thromboprophylaxis (LMWH, warfarin) in cancer patients with central venous catheters, found that LMWH compared to no prophylaxis probably decreases the risk of symptomatic catheter-related VTE by approximately 50%, with no difference in major bleeding or mortality. Low dose warfarin compared to no warfarin did not decrease the incidence of symptomatic catheterrelated VTE and had no beneficial effect on mortality. Low dose apixaban and rivaroxaban have been shown to be effective as thromboprophylaxis in ambulatory cancer patients at high risk for VTE (Khorana score >=2), but these studies did not specifically assess those with central venous catheters. A study is currently underway to compare low dose rivaroxaban to placebo as thromboprophylaxis in cancer patients with central venous catheters. Thromboprophylaxis may be considered in higher-risk cancer patients when the perceived risk of thrombosis outweighs the risk of bleeding and the burden of anticoagulation (e.g. in those with prior venous thrombosis).
# PEDIATRICS:
Central venous catheters are a frequent necessity in children who require supportive care to manage their illness (e.g. chemotherapy, parenteral nutrition, antibiotics, transfusions). The incidence of thrombosis related to catheter use in children is estimated at 3% to 34% of children with central venous catheters, varying between patient populations and with different diagnostic modalities. Without a previous history of thrombosis, thromboprophylaxis in children with central venous catheters is not routinely recommended, but could be considered in children with long-term VTE risk including those on home total parenteral nutrition, or undergoing hemodialysis. In children with cancer without previous VTE, central venous catheters alone are not an indication for thromboprophylaxis, but if other VTE risk factors are present (including asparaginase chemotherapy, obesity, hormonal contraceptives, adolescence, or hospitalization for surgery), thromboprophylaxis with LMWH could be considered.
LMWH and VKA remain the mainstay of the treatment for catheter-related DVT in pediatrics. Both dabigatran and rivaroxaban have been compared to standard of care as treatment of VTE in randomized controlled trials in the pediatric population, which included catheter-related DVT, demonstrating similar efficacy and bleeding risk. Widespread adoption of rivaroxaban and dabigatran is expected once pediatric oral formulations are available. Studies assessing apixaban and edoxaban in the pediatric population are still ongoing.
Pediatricians with expertise in thromboembolism should be involved in decisions about thrombosis prophylaxis and management of thromboembolism in pediatric patients where possible. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Cancer and Thrombosis
# Date of version: 14Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide guidance on the diagnosis, treatment and prevention of central venous catheter-related deep vein thrombosis (DVT).Central venous catheters are widely used for resuscitation; administration of chemotherapy, antibiotics and other medications; transfusion therapy; apheresis procedures; parenteral nutrition; blood sample acquisition; and supportive care, especially in patients with malignancy. The incidence rates for central venous catheter-related DVT vary widely among studies (ranging from approximately 2 to 70%), due in part to variable criteria for investigation (e.g. symptomatic patients versus routine screening of all patients with central venous catheters), as well as differences in patient populations (e.g. cancer, surgical, pediatrics) and duration of follow-up. Risk factors for catheter-related DVT include use of larger diameter catheters with multiple lumens, catheter tip malposition, left-sided placement, concomitant infection, history of DVT, and, in cancer patients, the type and stage of cancer, and administration of chemotherapy. Peripherally inserted central catheters (PICCs) are associated with a higher risk of DVT than other centrally inserted catheters, including implanted ports. Heritable thrombophilias likely increase the risk, however the magnitude of risk increase is unclear and screening for them is not currently indicated.# DIAGNOSIS OF CATHETER-RELATED DVT:
Patients with central venous catheter-related DVT may develop unilateral hand or arm swelling, pain or swelling in the neck or shoulder, visible collateral veins on the chest, or symptoms of superior vena cava obstruction, such as facial swelling, dyspnea, and headache. Patients with central venous catheter-related DVT may also be asymptomatic. Symptoms of embolization (e.g. pulmonary embolism, paradoxical stroke) should also prompt an evaluation for DVT in patients with central venous catheters. While a combination of clinical decision rules with D-dimer can be effective ruling out DVT in certain populations, its efficiency is limited in those with central venous catheters and is not recommended. The best initial test for diagnosing catheter-related DVT is duplex ultrasonography. Isolated subclavian vein or more central venous thrombosis may not be well seen with ultrasonography due to anatomical hindrance by the clavicle and chest wall. In difficult cases, magnetic resonance imaging (MRI) or computed tomography (CT) may be required. Direct contrast venography is an invasive procedure and may be difficult to obtain.
# TREATMENT OF CATHETER-RELATED DVT:
The goals of treatment for catheter-associated DVT are to improve acute symptoms, decrease longterm morbidity, prolong patency and survival of the catheter, and prevent embolization and recurrent thrombosis. Acute treatment recommendations are based primarily on trials in patients with lower extremity DVT. Removal of the central venous catheter is not required if it is still needed, functioning properly, and not associated with infection; however, if symptoms persist or worsen despite anticoagulation, the central venous catheter may need to be removed.
Use of low molecular weight heparin (LMWH) has been shown to be effective and safe in upper extremity DVT. Longer-term anticoagulation may involve continuation of LMWH alone, or conversion to warfarin. If LMWH is transitioned to warfarin, there should be an overlap for a minimum of 5 days and until the international normalized ratio (INR) is therapeutic. Direct oral anticoagulants (DOACs) have limited data to support use in catheter-related DVT, but they are known to be equivalent to warfarin in non-cancer patients, and LMWH in cancer patients for treatment of lower extremity DVT and pulmonary embolism. In a recent single arm study of rivaroxaban 15 mg orally twice daily for 21 days followed by 20 mg once daily in 70 cancer patients with central venous catheter-related upper extremity DVT, preservation of line function at 12 weeks was 100% and the risk of recurrent venous thromboembolism was 1.43% during the same period. There was, however, one episode of fatal pulmonary embolism, and the risk of clinically relevant bleeding (12.9%) was higher than anticipated. However, the findings from this study are limited by its small size and the lack of a control arm. The use of DOACs in this demographic continue to be studied. Given the limited data, Canadian expert consensus currently favours LMWH over DOACs or warfarin in the treatment of catheter-related DVT.
Although treatment duration for catheter-related DVT is controversial, it is reasonable to treat patients with a DVT in the axillary or a more proximal upper extremity deep vein for a minimum of 3 months or longer if the catheter remains in place. In those with a DVT involving only the brachial vein or thrombosis confined to the superficial veins, such as the cephalic or basilic vein, treatment with anticoagulation has not been studied. In this situation, anticoagulation with either full dose anticoagulation or less than therapeutic doses of LMWH (e.g. approximately 50% of a treatment dose) to prevent progression of the thrombus while the catheter remains in place is reasonable. There are few data to guide the use of catheter-directed thrombolysis in patients with extensive central catheter-related DVT and so the use of this intervention remains a case-by-case decision, best guided by consultation with a thrombosis expert and/or interventional radiologist.
# PREVENTION OF CATHETER-RELATED DVT:
The most important aspects of prevention of catheter-related DVT include use of central venous catheters only when necessary, insertion of the smallest catheters that satisfy their purpose and prompt removal when no longer needed. The process of PICC exchange has recently been identified as a risk factor for developing DVT, so should be done only when absolutely necessary.
Routine use of thromboprophylaxis in patients with central venous catheters with anticoagulation is not recommended by most guidelines. A systematic review and meta-analysis evaluating anticoagulation thromboprophylaxis (LMWH, warfarin) in cancer patients with central venous catheters, found that LMWH compared to no prophylaxis probably decreases the risk of symptomatic catheter-related VTE by approximately 50%, with no difference in major bleeding or mortality. Low dose warfarin compared to no warfarin did not decrease the incidence of symptomatic catheterrelated VTE and had no beneficial effect on mortality. Low dose apixaban and rivaroxaban have been shown to be effective as thromboprophylaxis in ambulatory cancer patients at high risk for VTE (Khorana score >=2), but these studies did not specifically assess those with central venous catheters. A study is currently underway to compare low dose rivaroxaban to placebo as thromboprophylaxis in cancer patients with central venous catheters. Thromboprophylaxis may be considered in higher-risk cancer patients when the perceived risk of thrombosis outweighs the risk of bleeding and the burden of anticoagulation (e.g. in those with prior venous thrombosis).
# PEDIATRICS:
Central venous catheters are a frequent necessity in children who require supportive care to manage their illness (e.g. chemotherapy, parenteral nutrition, antibiotics, transfusions). The incidence of thrombosis related to catheter use in children is estimated at 3% to 34% of children with central venous catheters, varying between patient populations and with different diagnostic modalities. Without a previous history of thrombosis, thromboprophylaxis in children with central venous catheters is not routinely recommended, but could be considered in children with long-term VTE risk including those on home total parenteral nutrition, or undergoing hemodialysis. In children with cancer without previous VTE, central venous catheters alone are not an indication for thromboprophylaxis, but if other VTE risk factors are present (including asparaginase chemotherapy, obesity, hormonal contraceptives, adolescence, or hospitalization for surgery), thromboprophylaxis with LMWH could be considered.
LMWH and VKA remain the mainstay of the treatment for catheter-related DVT in pediatrics. Both dabigatran and rivaroxaban have been compared to standard of care as treatment of VTE in randomized controlled trials in the pediatric population, which included catheter-related DVT, demonstrating similar efficacy and bleeding risk. Widespread adoption of rivaroxaban and dabigatran is expected once pediatric oral formulations are available. Studies assessing apixaban and edoxaban in the pediatric population are still ongoing.
Pediatricians with expertise in thromboembolism should be involved in decisions about thrombosis prophylaxis and management of thromboembolism in pediatric patients where possible. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Cancer and Thrombosis
# Date of version: 14Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
04bad10d639279f89cd51b546675babb9ce0bad4 | cma | None | # Background
Prostate cancer is the most commonly diagnosed cancer among Canadian men, and is the third leading cause of cancer-related death. In Canada, there will be an estimated 24,600 new cases of prostate cancer diagnosed, representing 20% of all new cancers in men. On average 67 Canadian men will be diagnosed with, and 13 Canadian men will die from prostate cancer every day. This represents 10% of all cancer deaths in men in 2022. 1 Guideline Questions 1. How should patients with localized prostate cancer be risk stratified? 2. How should patients with localized prostate cancer be managed? 3. How should patients with localized prostate cancer be followed after they have completed treatment?
# Search Strategy
For the most recent version of the guideline, the PubMed database was searched using the following criteria: (local[
All
# Target Population
Adult men (18 years of age or older) with a suspicion or recent diagnosis of localized prostate cancer.
# Recommendations
For a complete list of early detection and screening recommendations please refer to the 2022 Canadian Urological Association recommendations (link 7 o Patients with pubic arch interference may not be eligible for brachytherapy. o Patients with borderline pubic arch interference may be considered for a short course of ADT to reduce gland size. o Patients with a prior transurethral resection (TURP) should be assessed on an individual basis. o Patients with significant baseline obstructive symptoms may not be eligible for brachytherapy (i.e. American Urological Association symptom score >20). External beam radiotherapy: 8 o Intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) should be used for delivery o Hypofractionated radiation may be considered. 9 o Daily image guidance is the standard of care. o The clinical target volume (CTV) is defined as the prostate alone. Whole gland cryosurgery is an alternative therapeutic option for patients who may not be good candidates for surgery or radiation. There is less long-term data regarding efficacy and toxicity compared to the other treatment modalities. 10 Whole gland high intensity focused ultrasound (HIFU) is not a recommended treatment option for low-risk disease. 11 7. Follow-up for Low-Risk Disease: PSA every 6 to 12 months for 5 years, then yearly. Evaluation of treatment morbidity and/or complications.
# Management of Intermediate-Risk Disease
- Treatment Options for Intermediate Risk Disease: 12 Radical prostatectomy plus bilateral pelvic lymph node dissection. 13 External beam radiotherapy 3,14,15 o Intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) should be used for delivery o Hypofractionated radiation and SBRT may be considered. 9, o Short term (neoadjuvant + concurrent, 4-6 months total) ADT may be considered for select patients undergoing radiotherapy. 19, 20 o The CTV is defined as the prostate +/-seminal vesicles. Low-dose rate (LDR) Brachytherapy EBRT with a brachytherapy boost (+/-ADT) is an option for patients with high-tier intermediate risk disease. 8,21,22 o Brachytherapy may be delivered as either LDR or high dose rate (HDR). 8,21,22 o Short term (neoadjuvant + concurrent, 4-6 months total) ADT may be considered for select patients undergoing brachytherapy. 18,19 Active surveillance may be considered for selected patients with low-tier intermediate risk prostate cancer. Whole gland cryosurgery is an alternative therapeutic option for patients who may not be good candidates for surgery or radiation. There is less long-term data regarding efficacy and toxicity compared to the other treatment modalities. 23 Whole gland high intensity focused ultrasound (HIFU) is not a recommended treatment option for intermediate-risk disease. 11 Focal therapy may be considered for selected patients in the context of a clinical trial 9. Follow-up for Intermediate-Risk Disease:
- PSA every 6 to 12 months for the first 5 years, then yearly. Evaluation of treatment morbidity and/or complications.
# Management of High-Risk Disease
All high-risk disease patients should be encouraged to discuss treatment options with both a Urologist and Radiation Oncologist before starting treatment.
- Treatment Options for High-Risk Disease: 12 EBRT + ADT. o There is growing evidence for hypofractionation in this patient group. 28 o The CTV is defined as the prostate + seminal vesicles +/-regional lymph nodes. o EBRT with a brachytherapy boost (+/-ADT for 12 months) is an option for patients with high risk disease. 8,21,22 o ADT should be administered for an 18 -36 month duration and may be initiated prior to radiotherapy or concurrently with EBRT. 27 o An anti-androgen could be co-administered with a LHRH agonist and be continued for at least 7 days (for possible flare in testosterone with initial LHRH agonist alone). o Patients may be considered for the addition of abiraterone plus prednisolone to LHRH agonist o Refer to the clinical practice guideline on Bone Health for Prostate Cancer for recommendations regarding bone health for patients on ADT . Radical Prostatectomy and Pelvic Lymphadenectomy should be considered only for patients with resectable disease where the intent is to achieve negative margins. Patients should be counselled that there is a significant likelihood of requiring multimodality therapy with post-operative radiotherapy and ADT. Whole gland cryosurgery is an alternative therapeutic option for patients who may not be good candidates for surgery or radiation. There is less long-term data regarding efficacy and toxicity compared to the other treatment modalities. 23,29 11. Follow-up for High-Risk Disease First post-operative PSA should be done 4-12 weeks after surgery. Routine PSA should be done every 6 months, unless otherwise specified.
- Post-prostatectomy Treatment Options Early salvage radiation therapy is the preferred strategy over adjuvant radiation therapy (i.e., positive margins, pT3), and should be considered at the time of biochemical failure (PSA ≥0.2 ng/mL on at least 2 readings). 30-33 ADT can be considered with post-operative radiation therapy in select high-risk patients; the optimal type and duration of ADT has not been established. 34,35 The CTV is the prostate bed; addition of pelvic lymph node regions may be considered in select high-risk patients. The total dose to the prostate bed should be at least 66Gy in standard fractionation. 13. ADT alone is an alternative therapeutic option for patients who decline or are not eligible for curative local treatment. 24 Refer to the clinical practice guideline on Bone Health for Prostate Cancer for recommendations regarding bone health for patients on ADT .
# Biochemical Recurrence Following Local Radical Radiation Therapy
- The definition of a biochemical recurrence is PSA nadir +2 ng/mL after primary radiation therapy, or any rise in PSA after salvage RT.
- Investigations to rule out metastatic disease include a bone scan and a CT scan. For postradiotherapy patients, a repeat prostate biopsy is recommended to confirm local recurrence if local salvage therapy is being considered.
- Recommended options for salvage local therapy include salvage cryosurgery or salvage brachytherapy. If salvage local therapy is not offered, or if the patient fails salvage local therapy, initiation of ADT is indicated. Intermittent therapy is not inferior to continuous therapy. 39 There is no absolute PSA threshold for initiating ADT, but a range of 5-10 is reasonable 40 ; and consideration should also be given to PSA doubling time.
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including urologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in theGuideline Resource Unit Handbook.
This guideline was originally developed in January 2017, and was updated in January 2018, March 2020, November 2020, and December 2022.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
ADT, androgen deprivation therapy; CT, computed tomography scan; CTV, clinical target volume; DRE, digital rectal exam; EBRT, eternal beam radiotherapy; HDR, high dose rate; HIFU, high intensity focused ultrasound; ICRU, international commission on radiation units; IMRT, intensity modulated radiotherapy; LDR, low dose rate; LHRH, luteinizing hormonereleasing hormone; MRI, magnetic resonance imaging; PSA, prostate specific antigen; TURP, transurethral resection | # Background
Prostate cancer is the most commonly diagnosed cancer among Canadian men, and is the third leading cause of cancer-related death. In Canada, there will be an estimated 24,600 new cases of prostate cancer diagnosed, representing 20% of all new cancers in men. On average 67 Canadian men will be diagnosed with, and 13 Canadian men will die from prostate cancer every day. This represents 10% of all cancer deaths in men in 2022. 1 Guideline Questions 1. How should patients with localized prostate cancer be risk stratified? 2. How should patients with localized prostate cancer be managed? 3. How should patients with localized prostate cancer be followed after they have completed treatment?
# Search Strategy
For the most recent version of the guideline, the PubMed database was searched using the following criteria: (local[
All
# Target Population
Adult men (18 years of age or older) with a suspicion or recent diagnosis of localized prostate cancer.
# Recommendations
For a complete list of early detection and screening recommendations please refer to the 2022 Canadian Urological Association recommendations (link 7 o Patients with pubic arch interference may not be eligible for brachytherapy. o Patients with borderline pubic arch interference may be considered for a short course of ADT to reduce gland size. o Patients with a prior transurethral resection (TURP) should be assessed on an individual basis. o Patients with significant baseline obstructive symptoms may not be eligible for brachytherapy (i.e. American Urological Association symptom score >20). External beam radiotherapy: 8 o Intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) should be used for delivery o Hypofractionated radiation may be considered. 9 o Daily image guidance is the standard of care. o The clinical target volume (CTV) is defined as the prostate alone. Whole gland cryosurgery is an alternative therapeutic option for patients who may not be good candidates for surgery or radiation. There is less long-term data regarding efficacy and toxicity compared to the other treatment modalities. 10 Whole gland high intensity focused ultrasound (HIFU) is not a recommended treatment option for low-risk disease. 11 7. Follow-up for Low-Risk Disease: PSA every 6 to 12 months for 5 years, then yearly. Evaluation of treatment morbidity and/or complications.
# Management of Intermediate-Risk Disease
8. Treatment Options for Intermediate Risk Disease: 12 Radical prostatectomy plus bilateral pelvic lymph node dissection. 13 External beam radiotherapy 3,14,15 o Intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) should be used for delivery o Hypofractionated radiation and SBRT may be considered. 9,[16][17][18] o Short term (neoadjuvant + concurrent, 4-6 months total) ADT may be considered for select patients undergoing radiotherapy. 19, 20 o The CTV is defined as the prostate +/-seminal vesicles. Low-dose rate (LDR) Brachytherapy EBRT with a brachytherapy boost (+/-ADT) is an option for patients with high-tier intermediate risk disease. 8,21,22 o Brachytherapy may be delivered as either LDR or high dose rate (HDR). 8,21,22 o Short term (neoadjuvant + concurrent, 4-6 months total) ADT may be considered for select patients undergoing brachytherapy. 18,19 Active surveillance may be considered for selected patients with low-tier intermediate risk prostate cancer. Whole gland cryosurgery is an alternative therapeutic option for patients who may not be good candidates for surgery or radiation. There is less long-term data regarding efficacy and toxicity compared to the other treatment modalities. 23 Whole gland high intensity focused ultrasound (HIFU) is not a recommended treatment option for intermediate-risk disease. 11 Focal therapy may be considered for selected patients in the context of a clinical trial 9. Follow-up for Intermediate-Risk Disease:
PSA every 6 to 12 months for the first 5 years, then yearly. Evaluation of treatment morbidity and/or complications.
# Management of High-Risk Disease
All high-risk disease patients should be encouraged to discuss treatment options with both a Urologist and Radiation Oncologist before starting treatment.
10. Treatment Options for High-Risk Disease: 12 EBRT + ADT. [24][25][26][27] o There is growing evidence for hypofractionation in this patient group. 28 o The CTV is defined as the prostate + seminal vesicles +/-regional lymph nodes. o EBRT with a brachytherapy boost (+/-ADT for 12 months) is an option for patients with high risk disease. 8,21,22 o ADT should be administered for an 18 -36 month duration and may be initiated prior to radiotherapy or concurrently with EBRT. 27 o An anti-androgen could be co-administered with a LHRH agonist and be continued for at least 7 days (for possible flare in testosterone with initial LHRH agonist alone). o Patients may be considered for the addition of abiraterone plus prednisolone to LHRH agonist o Refer to the clinical practice guideline on Bone Health for Prostate Cancer for recommendations regarding bone health for patients on ADT [link]. Radical Prostatectomy and Pelvic Lymphadenectomy should be considered only for patients with resectable disease where the intent is to achieve negative margins. Patients should be counselled that there is a significant likelihood of requiring multimodality therapy with post-operative radiotherapy and ADT. Whole gland cryosurgery is an alternative therapeutic option for patients who may not be good candidates for surgery or radiation. There is less long-term data regarding efficacy and toxicity compared to the other treatment modalities. 23,29 11. Follow-up for High-Risk Disease First post-operative PSA should be done 4-12 weeks after surgery. Routine PSA should be done every 6 months, unless otherwise specified.
12. Post-prostatectomy Treatment Options Early salvage radiation therapy is the preferred strategy over adjuvant radiation therapy (i.e., positive margins, pT3), and should be considered at the time of biochemical failure (PSA ≥0.2 ng/mL on at least 2 readings). 30-33 ADT can be considered with post-operative radiation therapy in select high-risk patients; the optimal type and duration of ADT has not been established. 34,35 The CTV is the prostate bed; addition of pelvic lymph node regions may be considered in select high-risk patients. [36][37][38] The total dose to the prostate bed should be at least 66Gy in standard fractionation. 13. ADT alone is an alternative therapeutic option for patients who decline or are not eligible for curative local treatment. 24 Refer to the clinical practice guideline on Bone Health for Prostate Cancer for recommendations regarding bone health for patients on ADT [Cancer Guidelines | Alberta Health Services].
# Biochemical Recurrence Following Local Radical Radiation Therapy
14. The definition of a biochemical recurrence is PSA nadir +2 ng/mL after primary radiation therapy, or any rise in PSA after salvage RT.
15. Investigations to rule out metastatic disease include a bone scan and a CT scan. For postradiotherapy patients, a repeat prostate biopsy is recommended to confirm local recurrence if local salvage therapy is being considered.
16. Recommended options for salvage local therapy include salvage cryosurgery or salvage brachytherapy. If salvage local therapy is not offered, or if the patient fails salvage local therapy, initiation of ADT is indicated. Intermittent therapy is not inferior to continuous therapy. 39 There is no absolute PSA threshold for initiating ADT, but a range of 5-10 is reasonable 40 ; and consideration should also be given to PSA doubling time.
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including urologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in theGuideline Resource Unit Handbook.
This guideline was originally developed in January 2017, and was updated in January 2018, March 2020, November 2020, and December 2022.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
ADT, androgen deprivation therapy; CT, computed tomography scan; CTV, clinical target volume; DRE, digital rectal exam; EBRT, eternal beam radiotherapy; HDR, high dose rate; HIFU, high intensity focused ultrasound; ICRU, international commission on radiation units; IMRT, intensity modulated radiotherapy; LDR, low dose rate; LHRH, luteinizing hormonereleasing hormone; MRI, magnetic resonance imaging; PSA, prostate specific antigen; TURP, transurethral resection
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial Genitourinary Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2022) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of CancerCare Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerCare Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Brita Danielson reports receiving honoraria from Janssen, Amgen, BMS, Bayer, and Ferring. | None | None |
8bf9193f3b8d8b741b35f4c567704c3cd68c6ad9 | cma | None | This publication is intended for information purposes only, and is not intended to be interpreted or used as a standard of medical practice. Best efforts were used to ensure that the information in this publication is accurate; however, the publisher and every person involved in the creation of this publication disclaim any warranty as to the accuracy, completeness, or currency of the contents of this publication. This publication is distributed with the understanding that neither the publisher nor any person involved in the creation of this publication is rendering professional advice. Physicians and other readers must determine the appropriate clinical care for each individual patient on the basis of all the clinical data available for the individual case. The publisher and every person involved in the creation of this publication disclaim any liability arising from contract, negligence, or any other cause of action, to any party, for the publication contents or any consequences arising from its use. The CCSMH gratefully acknowledges support from AIRD & BERLIS LLP for their guidance on Copyright issues and for the review and creation of the disclaimer statement. Funding for the CCSMH Guideline Initiative was originally provided by the Public Health Agency of Canada, Population Health Fund. Guideline updates were made possible through a CIHR-Institute of Aging Betty Havens Award for Knowledge Translation in Aging. The CCSMH gratefully acknowledges the financial contribution of both funders for their ongoing support and continued commitment to the area of seniors' mental health. In addition, special thanks to the original and update Guideline Group members who dedicated countless number of hours and engaged in the creation of the original and updated guidelines and recommendations.# Introduction
T he proportion of Canadians who are seniors is expected to increase dramatically. Currently older adults (i.e., those aged ≥ 65) account for 18% of our country's population (Statistics Canada, 2020). Approximately 20% of those aged 65 and older are living with a mental illness. Although this figure is consistent with the prevalence of mental illness in other age groups, it does not capture the high prevalence rates seen within health and social institutions. For example, it has been reported that 80-90% of nursing home residents live with some form of mental illness and/or cognitive impairment (Seitz et al., 2010;Rovner et al., 1990). Late-life depression is common but often under-diagnosed and undertreated contributing to significant functional impairment and reduced quality of life. The Canadian Coalition for Seniors' Mental Health (CCSMH) National Guideline Project was originally created to support the development of evidence-based recommendations in 4 key areas of seniors' mental health, including depression.
The CCSMH first published national interdisciplinary best practice guidelines on the assessment and treatment of depression in older adults in 2006. Since then a number of clinical trials have been conducted that called for reinforcement or modification of the recommendations made in the initial guidelines. In 2018, CCSMH initiated an update of the guidelines. A team of interdisciplinary health care professionals from across Canada examined the latest peer-reviewed journal articles published since 2006.
In Section 3 (page 6), all new recommendations and recommendations with major modifications are described, with explanations. Some additional recommendation updates with relatively minor changes are only described in Section 4, which compares the original 2006 recommendations to the 2021 recommendations. New or modified recommendations are listed in the right-hand column. Readers are encouraged to review Sections 3 and 4.
# Methods
A systematic search for peer-reviewed scholarly articles was performed in 5 databases including Medline, Embase, HealthStar, Cochrane, and PsychINFO from the beginning of the end date of the literature review from the previous version of the guideline-July 2006-through December 2018. The searches included and were restricted to English papers only and search terms used were the same as for the 2006 Guidelines.
Multiple phases of title and abstract review were conducted by one of the authors to identify 344 full-text articles from an initial yield of 1560 articles from database searches; those were further categorized based on types of study such as controlled trials (especially randomized), meta-analyses, reviews (especially systematic), and practice guidelines or expert committee reports potentially relevant to the subject area. Subsequently, additional relevant articles of which the members were aware were included.
A working group was assembled (listed on page 2) and participated in the evidence review followed by development of updated recommendations. Individual working group members focused on specific areas and wrote summaries with proposed recommendation updates. The working group met several times to discuss proposed changes, any gaps or controversies with proposed updated recommendations, and consensus was obtained. The proposed updates were presented at the Canadian Academy of Geriatric Psychiatry (CAGP)-CCSMH virtual conference in October 2020, providing an opportunity for feedback from our peers.
The overall grouping of the 2006 recommendations is retained with the addition of a few new categories. The strength of each recommendation was assessed using the same system utilized in the 2006 Guidelines (i.e., Shekelle et al., 1999) Categories of Evidence and Strength of Recommendations) summarized on the next page. (Shekelle et al., 1999) (Shekelle et al., 1999) Evidence from meta-analysis of randomized controlled trials Ia Evidence from at least 1 randomized controlled trial Ib Evidence from at least 1 controlled study without randomization IIa
# CATEGORIES OF EVIDENCE FOR CAUSAL RELATIONSHIPS AND TREATMENT
# STRENGTH OF RECOMMENDATION
Evidence from at least 1 other type of quasi-experimental study IIb
Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies
# III
Evidence from expert committees reports or opinions and/or clinical experience of respected authorities IV
# Directly based on category I evidence A
Directly based on category II evidence or extrapolated recommendation from category I evidence B
Directly based on category III evidence or extrapolated recommendation from category I or II evidence C Directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence D
The strength of the recommendations, ranging from A to D (see below), is based on the entire body of evidence (i.e., all studies relevant to the issue) and the expert opinion of the Guideline Development Group regarding the available evidence. For example, a strength level of D has been given to evidence extrapolated from literature on younger population groups or considered a good practice point by the Guideline Development Group.
It is important to interpret the rating for the strength of recommendation (A to D) as a synthesis of all the underlying evidence and not as a strict indication of the relevant importance of the recommendation for clinical practice or quality of care. Some recommendations with little empirical support, resulting in a lower rating for strength on this scale, are in fact critical components of the assessment and treatment of depression.
T he updated Guidelines include a greater emphasis on depression prevention. Historically, healthcare systems have under-funded prevention approaches, especially in the mental health arena. Although research on prevention is in its infancy, prevention may be an alternative strategy to further reduce the disease burden of depression, which has been described as a global public health priority (Reynolds et al., 2012). Universal prevention focuses on the general public or a whole population group regardless of risk status. Selective prevention targets individuals or subgroups that are at higher risk of developing mental disorders than average individuals or subgroups. Indicated prevention focuses on individuals who are identified as having prodromal symptoms or biological markers of mental disorders, but who do not yet meet the diagnostic criteria for a full-blown diagnosis. The recommendations below primarily focus on universal and selective prevention. Of note, there is not enough evidence to recommend the use of antidepressants for people at high risk, although 1 small study suggested a reduced risk in individuals who had suffered a stroke (Robinson et al., 2008 Studies of interventions for social isolation, loneliness, and depression among older adults have been conducted globally. For example, Chiang et al. (2010) investigated the effects of weekly reminiscence therapy sessions on older adults living in long-term care homes. This intervention significantly decreased feelings of loneliness and depressive symptoms among participants. Similarly, a randomized controlled trial (RCT) conducted by Westerhof et al. (2017) aimed to understand the effectiveness of an autobiographical memory discussion intervention among older adults living in residential care. Participants with clinically relevant depressive symptoms had a significant reduction in symptoms during and post-intervention. In addition, loneliness significantly decreased among intervention participants. Tse et al. (2014) investigated the effectiveness of a weekly physical exercise program on nursing home residents. The findings showed significant improvements in both loneliness and depression.
There are several published systematic reviews of social isolation and/or loneliness and/or depression interventions. Quan et al. (2019) The definition of social prescribing comes from Friedli and Watson (2004). Ways to Wellness, an organization located in the United Kingdom, examined the effects of social prescribing in an urban setting amongst middle-aged and older adults with chronic and multiple long-term conditions (Moffatt et al., 2017). Individuals were referred to a 'Link Worker' who identified meaningful health and wellness community and voluntary services and resources. Service users reported positive changes including reduced social isolation and improved mental health after 6 months. Age United Kingdom (UK) conducted a Social Prescribing Pilot Project that investigated the effectiveness of general practitioners referring older adults aged 55 years and older who had mild to moderate depression or who experienced loneliness or social isolation to the social prescribing service. Older adults who participated in this study demonstrated a significant improvement in their emotional well-being. The Alliance for Healthier Communities in Ontario, Canada (2020) conducted an 18-month mixed methods pilot study on the effectiveness of social prescribing across 11 community health centres. In the Rx: Community -Social Prescribing in Ontario study, approximately half of participants were between the ages of 61-80 years. The most frequent reasons for referral were: (a) anxiety, (b) depression, (c) social isolation, and (d) mental health symptoms. Clients reported a significant improvement in mental well-being, reduced loneliness, and increased sense of belonging and connectedness. It should be noted that Bickerdike et al. (2017) suggested that more research was required in order to support the widespread use of this approach.
# NEW: PREVENTION
A stepped-care approach (e.g., watchful waiting, cognitive behavioural therapy bibliotherapy, problem-solving therapy, and referral to primary care for antidepressant medication) can reduce the incidence of depressive and anxiety disorders in community-dwelling older adults with subthreshold depression or anxiety.
A stepped-care approach has been shown to reduce the incidence of depressive and anxiety disorders in communitydwelling older adults with subthreshold depression or anxiety. Van't Veer-Tazelaar et al. (2009) studied the following steps: a watchful waiting approach, CBT-based bibliotherapy, CBTbased problem-solving treatment, and referral to primary care for medication, if required. The intervention group had a 50% reduction in incidence of major depressive disorder or anxiety disorder over a 12-month period compared to usual care.
Other promising approaches to preventing depression in older adults with subthreshold depression include the use of lay counsellors in middle and low-income countries (Dias et al., 2019) and the use of problem-solving therapy (Reynolds et al., 2014).
# NEW: PREVENTION
Higher levels of physical activity are consistently associated with lower odds of developing future depression. This finding is consistent across all age groups including older adults. Clinicians should encourage patients with low levels of physical activity to become more active. Tools are available for clinicians to assist patients in setting health-related goals (e.g., Fountain of Health).
Schuch et al. carried out a meta-analysis of 49 studies of physical activity (2018). Compared with people with low levels of physical activity, those with high levels had significantly lower odds of developing depression. Furthermore, physical activity had a protective effect against the emergence of depression across all age groups including older adults.
Protective effects against depression (major depression or symptoms) were found across geographical regions, with adjusted odds ratios ranging from 0.65 to 0.84 in Asia, Europe, North America, and Oceania.
The Canadian Program entitled Fountain of Health provides clinicians and the public with tools to support behaviour change, aimed at improving lifestyle behaviours including exercise (Gough et al., 2019;Cassidy et al., 2020;www.fountainofhealth.ca).
# NEW: PREVENTION
Clinicians should utilize the instilling of hope and positive thinking as important therapeutic tools in the prevention of depression and in helping individuals with depressive symptoms or disorders.
The therapeutic value of hope to health, healing, wellbeing, and quality of life has been well described (Moore 2005;Wilson et al., 2010). There is increasing interest in understanding the role of hope in healing, goal-setting, coping with illness, and as an approach to combat hopelessness. When confronted with illness or loss people are highly vulnerable. Clinicians should consider the important role of instilling authentic hope and positive thinking in their interactions with patients and families in all healthcare settings. There have been a limited number of studies focused on assessing the impact of interventions specifically designed to increase hope with variable results (Kwon et al., 2015;Cheavens at al., 2006;Wilson et al., 2010). A review of 9 studies, utilizing such interventions by nurses in patients coping with cancer, concluded that it is possible to increase hope in this group (Li et al., 2018). Moore (2005) suggests that nurses are in key positions to have conversations with their clients/patients about hope and about strategies to find renewed hope in any situation. She notes that others have stressed the importance of honouring hope as a complex and multidimensional component of people's experiences through illness and suffering (Bland & Darlington, 2002). Although more research is necessary to understand optimal interventions, we would encourage all healthcare staff to reflect on how best to incorporate the instilling of hope into their practices. In 2006 it was recommended that ECT should be considered if adequate trials of antidepressants combined with psychotherapy have been ineffective or if the health of the patient is deteriorating rapidly due to depression. The modification above underlines the need to consider ECT in a number of different circumstances, including its potential use as a first-line treatment in some patients who are at risk of poor outcomes. Its use for continuation/maintenance treatment for some patients is also noted.
We have added repetitive transcranial magnetic stimulation (rTMS) as an additional option for patients with major depressive disorder (MDD) who have failed to respond to at least 1 adequate trial of antidepressant (see page 11). In the 2006 Guidelines it was recommended that if there is no specific contraindication to its use, patients with psychotic depression should be offered treatment with ECT when available. Alternatively, a combination of antidepressant plus antipsychotic medication was recommended. We now recommend that combined pharmacotherapy can also be considered first line. The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) trial investigated the effectiveness of combined antipsychotic medications with antidepressants (Meyers et al., 2009). The trial found higher remission rates after 12 weeks of treatment with olanzapine combined with sertraline (41.9%) as compared to olanzapine with placebo (23.9%). This was the case for patients both less than 60 and greater than 60 years of age. A 2016 meta-analysis identified 8 RCTs of exercise interventions in adults aged 60 and older with depression. Adjusting for publication bias resulted in a large effect size of exercise on depressive symptoms with aerobic exercise combined with strength training, but not either alone. Benefit was also found with group-based interventions, which were of moderate but not vigorous intensity (Schuch et al., 2016). A review of previous meta-analyses examined the effects of exercise on late-life depression (symptoms or disorder) in adults older than 60 years. Three meta-analyses met eligibility criteria. A total of 1487 participants from diverse settings with ages ranging from 63.5-77.5 years were included. Depressive symptoms were significantly reduced by exercise, and the authors conclude it is a safe and effective treatment that should be incorporated into the standard care of older adults with depression (Catalan-Matamoros et al., 2016).
# NEW: PSYCHOTHERAPIES AND PSYCHOSOCIAL INTERVENTIONS
# MODIFIED: PSYCHOTHERAPIES AND PSYCHOSOCIAL INTERVENTIONS
# Psychotherapies with the most evidence for effectiveness in older adults include: cognitive behaviour therapies (CBT; individual and group) and problem-solving therapy (PST). PST can be provided to older adults with cognitive impairment and executive dysfunction; CBT and PST have also shown benefit for older adults with depression and medical comorbidity.
Psychotherapies and psychosocial treatments should be made available to older adults with depression (symptoms and disorder) in diverse settings (community, hospital, long-term care) across all regions of Canada.
# There is also evidence to support behaviour therapy, behavioural activation, reminiscence, and other psychotherapies including psychodynamic psychotherapy and interpersonal psychotherapy (IPT).
Internet-delivered therapies may be comparable to face-to-face treatment, and may improve access to services for individuals in under-serviced areas and those with mobility issues.
We emphasize the vital need for psychotherapies and psychosocial treatments to be made available for older adults with depression in diverse settings in all regions of the country.
Although many forms of psychotherapy have demonstrated benefits for older adults with depression, we note that the most evidence for effectiveness is for CBT (individual and group) and PST. Numerous meta-analyses support CBT as an effective treatment for late-life depression (Cuijpers et al., 2006;Pinquart et al., 2007;Peng et al., 2009) when provided in both individual and group formats. Some of these meta-analyses also found evidence in support of other psychotherapies such as reminiscence therapy. Emerging studies also suggest CBT is an effective intervention for depressed older adults with medical comorbidities such as chronic pain (Ehde et al., 2014) and heart failure (Jeyanantham et al., 2017). Meta-analyses of psychotherapeutic interventions also support the effectiveness of PST for late-life depression showing moderate to high effect sizes (Cuipjers et al., 2016Kirkham et al., 2016, including among frail older adults (Jonsson et al., 2016).
Internet-delivered cognitive behavioural therapy (iCBT) has been piloted with depressed older adults with favourable results (Titov et al., 2015). Such interventions can improve access to psychotherapy, especially for older adults in underserviced areas, and/or those who face mobility challenges. One RCT comparing online or iCBT to usual care among depressed older adults with knee osteoarthritis showed benefit compared to usual care (O' Moore et al., 2018). This approach is highly relevant during the expansion of virtual care related to the COVID-19 pandemic.
# MODIFIED: SELECTING AN ANTIDEPRESSANT/MONITORING FOR SIDE EFFECTS AND DRUG INTERACTIONS
# It is recommended that clinicians consider sertraline or duloxetine as first-line medications for an acute episode of major depression in older adults. Alternatives include escitalopram and citalopram based on the low possibility of drug interactions but concern about QTc interval may limit dosage to sub-therapeutic levels.
In addition, we suggest clinicians should choose an antidepressant with lowest risk of anticholinergic side effects and drug-drug interactions, as well as being relatively safe in the case of cardiovascular comorbidity. Patients need to be closely monitored for medication compliance, substance use, suicidal ideation, and development of drug toxicity.
Because of concerns about QTc prolongation with citalopram and escitalopram, and incorporating level of evidence, we are recommending sertraline or duloxetine as first-line medications for an acute episode of major depression in older adults. Citalopram and escitalopram remain useful options.
There are a variety of other appropriate antidepressants for older adults such as venlafaxine, bupropion, and mirtazapine.
In addition vortioxetine is a relatively new antidepressant, which has shown benefit for older adults, including some evidence of improvement in depression-related cognitive dysfunction (McIntyre et al., 2014;Nomikos et al., 2017;McIntyre et al., 2016). In most cases, fluoxetine is not recommended due to its long biological half-life, paroxetine is not recommended due to higher anticholinergic effects, and first generation monoamine oxidase inhibitors are not recommended due to higher risk of serious drug-drug and drug-food interactions. Tricyclic antidepressants should only be considered as third-line agents with due consideration of their potentially serious side effects.
A number of systematic reviews and meta-analyses have been conducted since the last iteration of these guidelines. Overall, the meta-analyses have found that antidepressants are efficacious for geriatric depression. A systematic review and meta-analysis of non-tricyclic "second generation" antidepressants found that these antidepressants were superior to placebo for MDD in adults over 60 years of age. The mean pooled response rates for antidepressant and placebo were 44.4% and 34.7%, respectively. The therapeutic effects were found to be modest and vary according to study and medication (Nelson et al., 2008). Of interest, it was found that longer trials of 10-12 weeks were needed for older adult to achieve a response. A meta-analysis of 51 double-blind RCTs of anti depressants in older patients found that all classes of antidepressant (tricyclic antidepressants , selective serotonin reuptake inhibitors , and other antidepressants) were superior to placebo to achieve response, with less robust findings for remission. There were no differences in remission or response rates between classes of antidepressants. The numbers needed to treat (NNT) were 14.4 and 6.7 for response and remission, respectively (Kok et al., 2012). The efficacy of duloxetine was supported by a systematic review and metaanalysis of 12 trials of antidepressants for geriatric major depression, with less convincing outcomes for SSRIs . The 2006 Guidelines recommended weekly visits after starting an antidepressant. Although ideal, this has been deemed often unrealistic (e.g., in primary care and in many mental health ambulatory settings). A brief check-in by phone may be helpful for some patients who are experiencing side effects and may encourage patients to continue taking the medication as the initial side effects frequently diminish.
# MODIFIED: TITRATION AND DURATION OF THERAPY (INADEQUATE RESPONSE)
When significant improvement has occurred but recovery is not complete after an adequate trial, the clinician should consider:
- a further 4 weeks of monotherapy or consider augmentation with another antidepressant or lithium or an antipsychotic (e.g., aripiprazole) or specific psychotherapy (e.g., IPT, CBT, PST).
- a switch to another antidepressant (same or another class) after discussing with the patient the potential risk of losing any significant improvements made with the first treatment.
- augmentation with lithium remains a viable option but needs to be used carefully due to the risk of lithium toxicity; the clinician must be aware of how to monitor the patient on lithium over time through investigations.
# NOTE: 2006 recommendation did not include augmentation with an antipsychotic.
The atypical antipsychotic aripiprazole has been investigated for treatment-refractory depression with promising results. A post hoc examination of 3 RCTs for patients 18-67 years of age demonstrated that augmentation with aripiprazole was superior to placebo in reducing depression and achieving remission in the 61-67 year-old subgroup (Steffens et al., 2011).
A subsequent randomized, placebo-controlled trial of aripiprazole for older adults (average age 66) who did not respond to venlafaxine found that augmentation with aripiprazole (average daily dose 7 mg) resulted in remission significantly more often than placebo (44% vs 29%) (Lenze et al., 2015). The NNT to achieve remission with aripiprazole augmentation was 6. Extended-release quetiapine has demonstrated efficacy as monotherapy for geriatric depression (Katila et al., 2013). It must be noted that atypical antipsychotic medications have significant potential side effects such as tardive dyskinesia, akathisia, extrapyramidal side effects, and prolongation of QTc, and there may be an increased risk of death and stroke, based on the dementia literature.
In attempting to achieve optimal outcomes, some experts favour an approach that utilizes a treatment algorithm. One Canadian example of this approach was described by Mulsant et al. (2014). In this algorithm, the first-line antidepressant was escitalopram, with sertraline and duloxetine as alternatives.
For non-responders, duloxetine is the preferred second-line antidepressant, with venlafaxine and desvenlafaxine as alternatives. Duloxetine was favoured partly due to the impact on the management of several pain syndromes that are quite common in older adults. If the patient fails an SSRI and a serotonin and norepinephrine reuptake inhibitor (SNRI); i.e., no response despite an adequate trial at a therapeutic dose) the next step is the use of the TCA nortriptyline, with bupropion as an alternative. For those patients who achieve a partial response to a first-or second-line antidepressant (SSRI or SNRI), the algorithm recommends augmentation with either lithium or an atypical antipsychotic. An alternative is combining the SSRI or SNRI with mirtazapine or bupropion.
# MODIFIED: MONITORING FOR SIDE EFFECTS AND DRUG INTERACTIONS (SODIUM)
When prescribing SSRI or SNRI antidepressants to older adults, the prescriber should screen for a history of hyponatremia before prescribing, as part of the consent process and then consider getting a sodium level prior to starting the antidepressant if there is a history of hyponatremia. The 2006 Guidelines recommended that a sodium level be done after 1 month, especially if the patient was taking a medication known to cause hyponatremia. Reports suggest that hyponatremia often occurs with the first 2 weeks of treatment (Leth-Møller et al., 2016;Lien, 2018).
A review of 21 studies and over 100 case reports revealed a relatively higher risk of hyponatremia with SSRIs and venlafaxine, particularly when combined with patient risk factors for hyponatremia (De Picker et al., 2014). The risks associated with mirtazapine were lower. A recent commentary compared 4 population-based studies, revealing that SSRIs and SNRIs are most likely to cause hyponatremia in older adults, with TCAs and mirtazapine having lower risk. There are case reports for bupropion possibly causing hyponatremia as well (Lien, 2018). rTMS is a brain stimulation method that uses magnetic field pulses, rather than an electrical current, and does not induce a seizure. The procedure requires a stimulator and coil to produce an electromagnetic field. A typical treatment course is 5 days per week for between 4-6 weeks. In general, the treatment has a favourable adverse effect profile with common side effects including scalp discomfort and transient headache.
There are no cognitive adverse effects reported with rTMS. In 2008, the FDA approved rTMS as a treatment for depression for patients not responding to at least 1 antidepressant medication with a maximum age of 69 (Manepalli et al., 2014).
Despite the relatively large number of rTMS studies completed to date, there is a paucity of studies evaluating the efficacy of rTMS in treatment-resistant late-life depression specifically. A number of older reports have suggested that older age is a negative predictor of response to rTMS (Figiel et al., 1998;Fregni et al., 2006;Manes et al., 2001;Mosimann et al., 2002). However, these studies were limited in several important ways: short treatment courses and suboptimal stimulation parameters, particularly with respect to the stimulation intensity needed to overcome the prefrontal atrophy that occurs with advancing age. The proposed mechanism for these negative findings is likely related to the increased scalp-tocortex distance in the elderly (Figiel et al. 1998). Imaging studies (Mosimann et al., 2004;Kozel et al., 2000) and a small uncontrolled clinical pilot study (Nahas et al., 2004) have suggested a correlation between antidepressant effect of rTMS and scalp-to-cortex distance. Nahas et al. (2004) used an open design in which they adjusted stimulus intensity based on the distance of the scalp to the cortex and used magnetic resonance imaging (MRI) co-registration to target the dorsolateral prefrontal cortex (DLPFC), in 18 older subjects. The average intensity required was 114%; significantly higher than the intensity used in other treatment trials at the time. Interestingly, a more recent RCT in an elderly sample with depression and cerebrovascular damage found unilateral rTMS at 110% stimulation intensity resulted in a significant, but modest 27.3% remission rate (Jorge et al., 2008).
The rTMS field has moved to using 120% of the motor threshold intensity across the age range of subjects and as a result, meta-analyses of more recent DLPFC rTMS have not found that older age is a negative predictor of response (Berlim et al., 2014;Gross et al., 2007). Some preliminary data suggest that older adults may respond better to a sequential bilateral form of rTMS where low frequency (i.e., 1 Hz) right-sided stimulation is immediately followed by high frequency (i.e., 10 Hz) left-sided stimulation, using 120% stimulation intensity (Blumberger et al., 2012;Blumberger et al., 2016;Trevizol et al.,2019). Other data suggest that older adults may respond better with a coil that generates a larger induced electrical field than the standard figure of 8 coils (Levkovitz et al., 2009). A controlled trial in older adults aged 60-80 demonstrated that deep rTMS led to a statistically significant higher remission rate compared to sham (Kaster et al., 2018).
Further study of rTMS in older adults is warranted given that optimal treatment parameters have demonstrated more promising results than earlier studies. Controlled studies across the age spectrum of older adults (i.e., over age 70) are needed to confirm efficacy and tolerability in this subgroup of older adults. Older adults may be particularly able to benefit from rTMS as daily schedules may be more conducive to the 5 days weekly treatment schedule. rTMS has good patient acceptability due to the favourable adverse effect profile, in particular the lack of cognitive side effects. There is some recent evidence that pharmacogenetic testing might improve outcomes among older adults with MDD who had failed a trial of at least 1 antidepressant.
In a controlled trial of 206 adults (aged 65 or older) participants receiving care guided by pharmacogenetic testing showed significantly improved response and rates of remission compared to usual care (Forester et al., 2020). However, this testing is not widely available and is expensive. We do not recommend its use in routine practice, although some patients who are intolerant of several antidepressants may benefit from a pharmacogenetic test. A number of meta-analyses and systematic reviews have investigated the efficacy of antidepressants for depression associated with dementia. The initial Cochrane review in 2002 was negative (Bains et al., 2002). This was followed by a positive meta-analysis of 5 studies, which showed a NNT of 5 to achieve remission (Thompson et al., 2007). Subsequently, 4 more meta-analyses, including another Cochrane review in 2018, were negative (Nelson et al., 2011, Sepehry et al., 2012, Orgeta et al., 2017, Dudas et al., 2018. We would still suggest that antidepressant medication could be offered if symptoms are severe and persistent.
# NEW: SPECIAL POPULATIONS: PARKINSON'S DISEASE
We recommend SSRIs as first line for the treatment of depression in patients with Parkinson's disease with SNRIs as an alternative.
# CBT can also be considered.
The 2006 Guidelines did not make a recommendation for patients with depression associated with Parkinson's disease. A meta-analysis of 20 RCTs compared pharmacologic, behavioural, or rTMS with a placebo/other drugs or methods. There were 13 medication trials, 9 of 13 were placebo-controlled and most were studies involving antidepressants. Two studies examined dopamine agonists and 1 study examined memantine. Antidepressant medications were found to be efficacious, specifically SSRIs and SNRIs. Non-antidepressant medications (e.g., dopamine agonists) did not have positive results. CBT was also beneficial (Bomasang-Layno et al., 2015). Another metaanalysis assessed the efficacy of antidepressants for depression in Parkinson's disease compared to placebo or a control group. This involved 20 studies and of those, 12 were randomized, placebo-controlled trials, while the others were either comparative studies or antidepressant versus no treatment. The results demonstrated efficacy for SSRIs, MAOIs, and TCAs when compared with placebo. The antidepressants were well-tolerated overall (Mills et al., 2018). Given equal efficacy among antidepressants, we recommend SSRIs or SNRIs, as they are generally better tolerated than older antidepressants such as TCAs. Several meta-analyses have demonstrated that a variety of antidepressants are superior to placebo in PSD (Xu et al., 2016;Deng et al. 2017;Qin et al., 2018). We favour SSRIs as first line based on overall risk of side effects, although they are associated with an increased risk of bleeding when combined with non-steroidal anti-inflammatory medication (Shin 2015).
Methylphenidate may be efficacious based on 1 placebocontrolled RCT (Grade et al., 1998).
# NEW: MODELS OF CARE (COLLABORATIVE, INTERPROFESSIONAL MODELS)
Core elements of evidence-based models for treating late-life depression in primary care include improved patient education, and incorporating interprofessional staff as depression care managers who routinely assess and follow patients clinically, utilizing a stepped-care approach. Treatment prescriptions are provided by a primary care physician or nurse practitioner, with as needed psychiatric consultation. An individualized plan of care should be developed using a collaborative approach.
Interventions that integrate mental health services into primary care have increased the number of patients who are treated for depression and the quality of that treatment. The most effective models involve systematic depression screening and monitoring, interprofessional teams that include primary care providers and mental health specialists, a depression care manager to work directly with patients over time, and the use of guideline-based depression treatment (Bruce & Sirey, 2018). Three major studies have demonstrated the effectiveness of integrated approaches (PRISM-E, IMPACT, and PROSPECT) in the care of older adults. Thota et al., (2012) carried out an extensive review and meta-analysis of collaborative care to improve the management of depressive disorders across multiple patient populations. The results from their metaanalyses suggest robust evidence of effectiveness of collaborative care in improving depression symptoms, adherence to treatment; response to treatment, remission of symptoms, recovery from symptoms, quality of life/functional status, and satisfaction with care for patients diagnosed with depression.
# NEW: MODELS OF CARE (VIRTUAL CARE)
To optimize access to clinical services, " The use of telepsychiatry for care of older adults has been shown to be feasible and effective (Conn et al., 2013;Ramos-Ríos et al., 2012). A systematic review of studies demonstrated that telehealth care is feasible and well-accepted in the areas of inpatient and nursing home consultation, cognitive testing, dementia diagnosis and treatment of depression in integrated and collaborative care models and psychotherapy (Gentry et al., 2019). However, the use of telepsychiatry in Canada has been quite limited prior to the COVID-19 pandemic. Since then the use of virtual care approaches has dramatically increased across multiple areas of healthcare. Older adults are often at a disadvantage with many having limited capacity to utilize newer technologies.
As such we strongly advocate for senior-friendly virtual care options with appropriate equipment and support. Health care providers should be familiar with the physical, psychological, and social risk factors for depressive disorders in older adults and include a screening for depression for their clients/ patients who present with some of these risk factors.
# Unchanged
We recommend targeted screening of those elderly at higher risk for depression due to the following situations:
- Recently bereaved with unusual symptoms (e.g., active suicidal ideation, guilt not related to the deceased, psychomotor retardation, mood congruent delusions, marked functional impairment after 2 months of the loss, reaction that seems out of proportion with the loss) Essentially unchanged, but note that the exclusion of major depression in the first 2 months after the loss and in bereavement was removed in Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition (DSM-V). We recommend initial treatment with supportive psychosocial interventions or psychotherapy. If symptoms become severe enough to meet DSM-IV diagnostic criteria for a depressive disorder or persist after resolution of the stressor, more specific therapies in keeping with the revised diagnosis should be considered (e.g., medication, more intensive/ specific psychotherapy).
# Recommendations: Screening and Assessment -Screening and Screening Tools
No change except for new version of DSM (DSM-5).
# TREATMENT OPTIONS FOR TYPE AND SEVERITY OF DEPRESSION (CONT'D)
Recommendations Patients with severe unipolar depression should be offered a combination of antidepressants and concurrent psychotherapy when appropriate services are available and there is no contra-indication to either treatment.
# Unchanged
ECT should be considered if adequate trials of antidepressants combined with psychotherapy have been ineffective or if the health of the patient is deteriorating rapidly due to depression.
Electroconvulsive therapy (ECT) should be considered in the treatment of older patients with severe unipolar depression who have previously had a good response to a course of ECT and/or failed to respond to 1 or more adequate antidepressant trials plus psychotherapy, especially if their health is deteriorating rapidly due to depression. ECT is a firstline treatment in older, depressed patients who are at high risk of poor outcomes-those with suicidal ideation or intent, severe physical illness, or with psychotic features.
ECT can also be useful for continuation/maintenance therapy of older patients who are partially responsive, treatment resistant, or treatment intolerant with pharmacotherapy during the acute phase of treatment.
Recommendation: Treatment: Major Depressive Disorder, Single or Recurrent Episodes -Severe with Psychotic Features
# RECOMMENDATIONS 2021 NEW OR UPDATED RECOMMENDATIONS
If there is no specific contraindication to its use, patients with psychotic depression should be offered treatment with ECT when available. Alternatively, a combination of antidepressant plus antipsychotic medication should be used. If this combination is not effective (e.g., poorly tolerated, no improvement in at least some of the symptoms within 4-8 weeks of treatment, or lack of remission despite optimisation of dose and duration of treatment over more than 8-12 weeks), ECT needs to be offered. ECT should also be considered if severe health consequences (e.g., suicide, metabolic derangement) are imminent because pharmacological treatment has been poorly tolerated or would be too slow to provide needed improvements.
Recently, more placebo-controlled clinical trials reported safe and effective use of combined antidepressant and antipsychotic drugs in MDD with psychotic features, so we recommend that clinicians use their judgement based on severity and patient's physical conditions to try combination pharmacotherapy first. ECT should be considered after 4-8 weeks if combination therapy fails, is poorly tolerated, or if patient develops severe health consequences. Change of terminology from depression with co-morbid substance abuse to depression with co-morbid substance use disorder.
# TREATMENT OPTIONS FOR TYPE AND SEVERITY OF DEPRESSION (CONT'D)
Recommendation Change of terminology from depression with co-morbid substance abuse to depression with co-morbid substance use disorder. Psychotherapies and/or psychosocial treatments should be made available to older adults with depression (symptoms or disorder) in all settings (community, hospital, long-term care).
# Recommendations: Pharmacogenetic Testing
Evidence-based psychotherapies recommended for geriatric depressions include: behaviour therapy; cognitive-behaviour therapy; problem-solving therapy; brief dynamic therapy; interpersonal therapy; and reminiscence therapy.
Psychotherapies with the most evidence for effectiveness in older adults include: cognitive behavioural therapy (CBT)individual and group, and problem-solving therapy (PST). PST can be provided to older adults with cognitive impairment and executive dysfunction; CBT and PST have also been studied in older adults with medical comorbidity.
There is also evidence to support behaviour therapy, behavioural activation, reminiscence, and other psychotherapies including psychodynamic psychotherapy and interpersonal therapy.
Internet-delivered therapies may be comparable to face-toface treatment, and may improve access to services for individuals in under-serviced areas and those with mobility issues. When choosing agents from a specific class, clinicians should select those found to be safer with the elderly (e.g., selecting drugs with the lowest anti-cholinergic properties amongst available antidepressants).
We suggest clinicians choose an antidepressant with the lowest risk of anticholinergic side effects and drug-drug interactions as well as being relatively safe in the case of cardiovascular comorbidity. Patients need to be closely monitored for medication compliance, substance use, suicidal ideation, and development of drug toxicity.
We recommend that physicians and pharmacists consult up-to-date drug interaction data bases when a new antidepressant is prescribed to patients taking multiple medications. We recommend checking sodium blood levels after one month of treatment with SSRIs, especially with patients taking other medications that can cause hyponatremia (e.g., diuretics).
We recommend checking sodium levels before switching to another agent due to poor response or tolerance or when patients display symptoms of hyponatremia (e.g., fatigue, malaise, delirium).
When prescribing SSRI or SNRI antidepressants to older adults, the prescriber should screen for a history of hyponatremia before prescribing, as part of the consent process and then consider getting a sodium level prior to starting the antidepressant if there is a history of hyponatremia. Before considering a change in medication, it is important to ensure an adequate trial. Change should be made if: there is no improvement in symptoms after at least 4 weeks at the maximum tolerated or recommended dose; there is insufficient improvement after 8 weeks at the maximum tolerated or recommended dose.
# Unchanged
When significant improvement has occurred but recovery is not complete after an adequate trial, the clinician should consider:
- a further 4 weeks of treatment with or without augmentation with another antidepressant or lithium or specific psychotherapy (e.g., IPT, CBT, PST); - a switch to another antidepressant (same or another class) after discussing with the patient the potential risk of losing any significant improvements made with the first treatment.
When significant improvement has occurred but recovery is not complete after an adequate trial, the clinician should consider:
- a further 4 weeks of monotherapy or consider augmentation with another antidepressant or lithium or an antipsychotic (e.g., aripiprazole) or specific psychotherapy (e.g., IPT, CBT, PST). - a switch to another antidepressant (same or another class) after discussing with the patient the potential risk of losing any significant improvements made with the first treatment. - augmentation with lithium remains a viable option, but needs to be used carefully due to the risk of lithium toxicity. The clinician must be aware of how to monitor the patient on lithium over time through investigations.
When switching agents, it is generally safe to reduce the current medication while starting low doses of the alternate agent. Specific drug interaction profiles need to be checked for both drugs involved during this overlap since antidepressants commonly interact with each other.
# Unchanged
Augmentation strategies require supervision by experienced physicians.
# Unchanged
Given its long half-life and risk of interaction with many of the drugs prescribed for the elderly, we do not recommend the use of fluoxetine as first-line treatment despite its documented efficacy.
Fluoxetine is not recommended due to long biological halflife, paroxetine is not recommended due to higher anticholinergic effects, and first generation MAOIs are not recommended due to higher risk of serious drug-drug or drug-food interactions.
Antidepressants, especially SSRIs, should not be abruptly discontinued but should be tapered off over a 7 to10 day period when possible. In LTC homes, the response to antidepressant therapy should be evaluated monthly after initial improvement and at quarterly care conferences, as well as at the annual assessment after remission of symptoms.
A decision to continue or discontinue the antidepressant therapy should be based on:
- whether the depression has been treated long enough to allow sustained remission of symptoms (e.g., now one year of full remission); or - whether the treatment is still tolerated well in the context of their health problems; and - the risks of discontinuation (i.e., return of original depressive symptoms) are less than those associated with continuation of medication.
# Unchanged
Health care professionals should provide older depressed adults with education regarding the nature of depression, its biological, psychological and social aspects, effective coping strategies, and lifestyle changes that will assist their recovery, while being mindful of the individual's stresses and strengths.
# Unchanged
Families of depressed older adults should be provided with information regarding the signs and symptoms of depression, attitudes and behaviours of the depressed person and their own reaction to them, and depression coping strategies, as well as available treatment options and the benefits of treatment.
# Unchanged
The choice of mood stabilizer should be based on prior response to treatment, type of illness (e.g., rapid-cycling or not), medical contraindications to the use of specific mood stabilizers (i.e., side effects that could worsen pre-existing medical problems), and potential interactions with other drugs required by the patient.
# Unchanged
All mood stabilizers require monitoring over time for possible short-term and longer-term adverse events.
All mood stabilizers require monitoring over time for possible short-term and longer-term adverse events. Using lithium requires the patient, family, and healthcare team to understand the factors that may increase lithium levels leading to potential toxicity. Lithium can cause hypothyroidism, hypercalcemia through hyperparathyroidism, and renal dysfunction. The clinician must regularly monitor the patient on lithium, including laboratory investigations. There is limited evidence to recommend antidepressant therapy for mild or moderate depression associated with dementia. Behavioural interventions may be utilized as a firstline intervention and antidepressant medication could be offered if symptoms are severe and persistent, understanding that efficacy is not well established and that side effects could occur.
In selecting pharmacological treatment for depression with dementia, clinicians should select drugs that have low anticholinergic properties, such as citalopram and escitalopram, sertraline, moclobemide, venlafaxine, or bupropion.
As noted above, we recommend duloxetine and sertraline as first-line antidepressants, while recognizing that other antidepressants are also appropriate. Limiting exposure to anticholinergic properties remains an important consideration in patients with both dementia and depression.
# SPECIAL POPULATIONS (CONT'D)
Recommendations: Special Populations: Dementia
# RECOMMENDATIONS 2021 NEW OR UPDATED RECOMMENDATIONS
Psychosocial treatment should be part of the treatment of depression co-existing with dementia. This treatment should be flexible to account for the decline in functioning as well as multifaceted to provide help with the diversity of problems facing the patient and caregiver. It should be delivered by clinicians sensitized to the vulnerabilities and frailties of older adults with dementia. This treatment should include helping caregivers deal with the disease in a skill-oriented manner.
# Unchanged
For patients who have psychotic depression and dementia, a combination of antidepressant and antipsychotic medication is usually the first choice, although ECT may be used if medications are ineffective or rapid response is required to maintain safety.
# MODELS OF CARE
Recommendations: Models of Care
# RECOMMENDATIONS 2021 NEW OR UPDATED RECOMMENDATIONS
Health care professionals and organizations should implement a model of care that addresses the physical/ functional as well as the psychosocial needs of older depressed adults.
Given the complex care needs of older adults, these are most likely to require interdisciplinary involvement in care, whether in primary care or specialized mental health settings.
# Unchanged
Health care professionals and organizations should implement a model of care that promotes continuity of care as older adults appear to respond better to consistent primary care providers.
# Unchanged
New:
Core elements of evidence-based models for treating late-life depression in primary care include: improved patient education, incorporating interprofessional staff as depression care managers who routinely assess and follow patients clinically, utilizing a stepped-care approach. Treatment prescriptions are provided by a primary care physician or nurse practitioner, with as needed psychiatric consultation.
An individualized plan of care should be developed using a collaborative approach. | This publication is intended for information purposes only, and is not intended to be interpreted or used as a standard of medical practice. Best efforts were used to ensure that the information in this publication is accurate; however, the publisher and every person involved in the creation of this publication disclaim any warranty as to the accuracy, completeness, or currency of the contents of this publication. This publication is distributed with the understanding that neither the publisher nor any person involved in the creation of this publication is rendering professional advice. Physicians and other readers must determine the appropriate clinical care for each individual patient on the basis of all the clinical data available for the individual case. The publisher and every person involved in the creation of this publication disclaim any liability arising from contract, negligence, or any other cause of action, to any party, for the publication contents or any consequences arising from its use. The CCSMH gratefully acknowledges support from AIRD & BERLIS LLP for their guidance on Copyright issues and for the review and creation of the disclaimer statement. Funding for the CCSMH Guideline Initiative was originally provided by the Public Health Agency of Canada, Population Health Fund. Guideline updates were made possible through a CIHR-Institute of Aging Betty Havens Award for Knowledge Translation in Aging. The CCSMH gratefully acknowledges the financial contribution of both funders for their ongoing support and continued commitment to the area of seniors' mental health. In addition, special thanks to the original and update Guideline Group members who dedicated countless number of hours and engaged in the creation of the original and updated guidelines and recommendations.# Introduction
T he proportion of Canadians who are seniors is expected to increase dramatically. Currently older adults (i.e., those aged ≥ 65) account for 18% of our country's population (Statistics Canada, 2020). Approximately 20% of those aged 65 and older are living with a mental illness. Although this figure is consistent with the prevalence of mental illness in other age groups, it does not capture the high prevalence rates seen within health and social institutions. For example, it has been reported that 80-90% of nursing home residents live with some form of mental illness and/or cognitive impairment (Seitz et al., 2010;Rovner et al., 1990). Late-life depression is common but often under-diagnosed and undertreated contributing to significant functional impairment and reduced quality of life. The Canadian Coalition for Seniors' Mental Health (CCSMH) National Guideline Project was originally created to support the development of evidence-based recommendations in 4 key areas of seniors' mental health, including depression.
The CCSMH first published national interdisciplinary best practice guidelines on the assessment and treatment of depression in older adults in 2006. Since then a number of clinical trials have been conducted that called for reinforcement or modification of the recommendations made in the initial guidelines. In 2018, CCSMH initiated an update of the guidelines. A team of interdisciplinary health care professionals from across Canada examined the latest peer-reviewed journal articles published since 2006.
In Section 3 (page 6), all new recommendations and recommendations with major modifications are described, with explanations. Some additional recommendation updates with relatively minor changes are only described in Section 4, which compares the original 2006 recommendations to the 2021 recommendations. New or modified recommendations are listed in the right-hand column. Readers are encouraged to review Sections 3 and 4.
# Methods
A systematic search for peer-reviewed scholarly articles was performed in 5 databases including Medline, Embase, HealthStar, Cochrane, and PsychINFO from the beginning of the end date of the literature review from the previous version of the guideline-July 2006-through December 2018. The searches included and were restricted to English papers only and search terms used were the same as for the 2006 Guidelines.
Multiple phases of title and abstract review were conducted by one of the authors to identify 344 full-text articles from an initial yield of 1560 articles from database searches; those were further categorized based on types of study such as controlled trials (especially randomized), meta-analyses, reviews (especially systematic), and practice guidelines or expert committee reports potentially relevant to the subject area. Subsequently, additional relevant articles of which the members were aware were included.
A working group was assembled (listed on page 2) and participated in the evidence review followed by development of updated recommendations. Individual working group members focused on specific areas and wrote summaries with proposed recommendation updates. The working group met several times to discuss proposed changes, any gaps or controversies with proposed updated recommendations, and consensus was obtained. The proposed updates were presented at the Canadian Academy of Geriatric Psychiatry (CAGP)-CCSMH virtual conference in October 2020, providing an opportunity for feedback from our peers.
The overall grouping of the 2006 recommendations is retained with the addition of a few new categories. The strength of each recommendation was assessed using the same system utilized in the 2006 Guidelines (i.e., Shekelle et al., 1999) Categories of Evidence and Strength of Recommendations) summarized on the next page. (Shekelle et al., 1999) (Shekelle et al., 1999) Evidence from meta-analysis of randomized controlled trials Ia Evidence from at least 1 randomized controlled trial Ib Evidence from at least 1 controlled study without randomization IIa
# CATEGORIES OF EVIDENCE FOR CAUSAL RELATIONSHIPS AND TREATMENT
# STRENGTH OF RECOMMENDATION
Evidence from at least 1 other type of quasi-experimental study IIb
Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies
# III
Evidence from expert committees reports or opinions and/or clinical experience of respected authorities IV
# Directly based on category I evidence A
Directly based on category II evidence or extrapolated recommendation from category I evidence B
Directly based on category III evidence or extrapolated recommendation from category I or II evidence C Directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence D
The strength of the recommendations, ranging from A to D (see below), is based on the entire body of evidence (i.e., all studies relevant to the issue) and the expert opinion of the Guideline Development Group regarding the available evidence. For example, a strength level of D has been given to evidence extrapolated from literature on younger population groups or considered a good practice point by the Guideline Development Group.
It is important to interpret the rating for the strength of recommendation (A to D) as a synthesis of all the underlying evidence and not as a strict indication of the relevant importance of the recommendation for clinical practice or quality of care. Some recommendations with little empirical support, resulting in a lower rating for strength on this scale, are in fact critical components of the assessment and treatment of depression.
T he updated Guidelines include a greater emphasis on depression prevention. Historically, healthcare systems have under-funded prevention approaches, especially in the mental health arena. Although research on prevention is in its infancy, prevention may be an alternative strategy to further reduce the disease burden of depression, which has been described as a global public health priority (Reynolds et al., 2012). Universal prevention focuses on the general public or a whole population group regardless of risk status. Selective prevention targets individuals or subgroups that are at higher risk of developing mental disorders than average individuals or subgroups. Indicated prevention focuses on individuals who are identified as having prodromal symptoms or biological markers of mental disorders, but who do not yet meet the diagnostic criteria for a full-blown diagnosis. The recommendations below primarily focus on universal and selective prevention. Of note, there is not enough evidence to recommend the use of antidepressants for people at high risk, although 1 small study suggested a reduced risk in individuals who had suffered a stroke (Robinson et al., 2008 Studies of interventions for social isolation, loneliness, and depression among older adults have been conducted globally. For example, Chiang et al. (2010) investigated the effects of weekly reminiscence therapy sessions on older adults living in long-term care homes. This intervention significantly decreased feelings of loneliness and depressive symptoms among participants. Similarly, a randomized controlled trial (RCT) conducted by Westerhof et al. (2017) aimed to understand the effectiveness of an autobiographical memory discussion intervention among older adults living in residential care. Participants with clinically relevant depressive symptoms had a significant reduction in symptoms during and post-intervention. In addition, loneliness significantly decreased among intervention participants. Tse et al. (2014) investigated the effectiveness of a weekly physical exercise program on nursing home residents. The findings showed significant improvements in both loneliness and depression.
There are several published systematic reviews of social isolation and/or loneliness and/or depression interventions. Quan et al. (2019) The definition of social prescribing comes from Friedli and Watson (2004). Ways to Wellness, an organization located in the United Kingdom, examined the effects of social prescribing in an urban setting amongst middle-aged and older adults with chronic and multiple long-term conditions (Moffatt et al., 2017). Individuals were referred to a 'Link Worker' who identified meaningful health and wellness community and voluntary services and resources. Service users reported positive changes including reduced social isolation and improved mental health after 6 months. Age United Kingdom (UK) conducted a Social Prescribing Pilot Project that investigated the effectiveness of general practitioners referring older adults aged 55 years and older who had mild to moderate depression or who experienced loneliness or social isolation to the social prescribing service. Older adults who participated in this study demonstrated a significant improvement in their emotional well-being. The Alliance for Healthier Communities in Ontario, Canada (2020) conducted an 18-month mixed methods pilot study on the effectiveness of social prescribing across 11 community health centres. In the Rx: Community -Social Prescribing in Ontario study, approximately half of participants were between the ages of 61-80 years. The most frequent reasons for referral were: (a) anxiety, (b) depression, (c) social isolation, and (d) mental health symptoms. Clients reported a significant improvement in mental well-being, reduced loneliness, and increased sense of belonging and connectedness. It should be noted that Bickerdike et al. (2017) suggested that more research was required in order to support the widespread use of this approach.
# NEW: PREVENTION
A stepped-care approach (e.g., watchful waiting, cognitive behavioural therapy [CBT-based] bibliotherapy, problem-solving therapy, and referral to primary care for antidepressant medication) can reduce the incidence of depressive and anxiety disorders in community-dwelling older adults with subthreshold depression or anxiety. [B]
A stepped-care approach has been shown to reduce the incidence of depressive and anxiety disorders in communitydwelling older adults with subthreshold depression or anxiety. Van't Veer-Tazelaar et al. (2009) studied the following steps: a watchful waiting approach, CBT-based bibliotherapy, CBTbased problem-solving treatment, and referral to primary care for medication, if required. The intervention group had a 50% reduction in incidence of major depressive disorder or anxiety disorder over a 12-month period compared to usual care.
Other promising approaches to preventing depression in older adults with subthreshold depression include the use of lay counsellors in middle and low-income countries (Dias et al., 2019) and the use of problem-solving therapy (Reynolds et al., 2014).
# NEW: PREVENTION
Higher levels of physical activity are consistently associated with lower odds of developing future depression. This finding is consistent across all age groups including older adults. Clinicians should encourage patients with low levels of physical activity to become more active. Tools are available for clinicians to assist patients in setting health-related goals (e.g., Fountain of Health).
[B]
Schuch et al. carried out a meta-analysis of 49 studies of physical activity (2018). Compared with people with low levels of physical activity, those with high levels had significantly lower odds of developing depression. Furthermore, physical activity had a protective effect against the emergence of depression across all age groups including older adults.
Protective effects against depression (major depression or symptoms) were found across geographical regions, with adjusted odds ratios ranging from 0.65 to 0.84 in Asia, Europe, North America, and Oceania.
The Canadian Program entitled Fountain of Health provides clinicians and the public with tools to support behaviour change, aimed at improving lifestyle behaviours including exercise (Gough et al., 2019;Cassidy et al., 2020;www.fountainofhealth.ca).
# NEW: PREVENTION
Clinicians should utilize the instilling of hope and positive thinking as important therapeutic tools in the prevention of depression and in helping individuals with depressive symptoms or disorders.
[D]
The therapeutic value of hope to health, healing, wellbeing, and quality of life has been well described (Moore 2005;Wilson et al., 2010). There is increasing interest in understanding the role of hope in healing, goal-setting, coping with illness, and as an approach to combat hopelessness. When confronted with illness or loss people are highly vulnerable. Clinicians should consider the important role of instilling authentic hope and positive thinking in their interactions with patients and families in all healthcare settings. There have been a limited number of studies focused on assessing the impact of interventions specifically designed to increase hope with variable results (Kwon et al., 2015;Cheavens at al., 2006;Wilson et al., 2010). A review of 9 studies, utilizing such interventions by nurses in patients coping with cancer, concluded that it is possible to increase hope in this group (Li et al., 2018). Moore (2005) suggests that nurses are in key positions to have conversations with their clients/patients about hope and about strategies to find renewed hope in any situation. She notes that others have stressed the importance of honouring hope as a complex and multidimensional component of people's experiences through illness and suffering (Bland & Darlington, 2002). Although more research is necessary to understand optimal interventions, we would encourage all healthcare staff to reflect on how best to incorporate the instilling of hope into their practices. In 2006 it was recommended that ECT should be considered if adequate trials of antidepressants combined with psychotherapy have been ineffective or if the health of the patient is deteriorating rapidly due to depression. The modification above underlines the need to consider ECT in a number of different circumstances, including its potential use as a first-line treatment in some patients who are at risk of poor outcomes. Its use for continuation/maintenance treatment for some patients is also noted.
We have added repetitive transcranial magnetic stimulation (rTMS) as an additional option for patients with major depressive disorder (MDD) who have failed to respond to at least 1 adequate trial of antidepressant (see page 11). In the 2006 Guidelines it was recommended that if there is no specific contraindication to its use, patients with psychotic depression should be offered treatment with ECT when available. Alternatively, a combination of antidepressant plus antipsychotic medication was recommended. We now recommend that combined pharmacotherapy can also be considered first line. The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) trial investigated the effectiveness of combined antipsychotic medications with antidepressants (Meyers et al., 2009). The trial found higher remission rates after 12 weeks of treatment with olanzapine combined with sertraline (41.9%) as compared to olanzapine with placebo (23.9%). This was the case for patients both less than 60 and greater than 60 years of age. A 2016 meta-analysis identified 8 RCTs of exercise interventions in adults aged 60 and older with depression. Adjusting for publication bias resulted in a large effect size of exercise on depressive symptoms with aerobic exercise combined with strength training, but not either alone. Benefit was also found with group-based interventions, which were of moderate but not vigorous intensity (Schuch et al., 2016). A review of previous meta-analyses examined the effects of exercise on late-life depression (symptoms or disorder) in adults older than 60 years. Three meta-analyses met eligibility criteria. A total of 1487 participants from diverse settings with ages ranging from 63.5-77.5 years were included. Depressive symptoms were significantly reduced by exercise, and the authors conclude it is a safe and effective treatment that should be incorporated into the standard care of older adults with depression (Catalan-Matamoros et al., 2016).
# NEW: PSYCHOTHERAPIES AND PSYCHOSOCIAL INTERVENTIONS
# MODIFIED: PSYCHOTHERAPIES AND PSYCHOSOCIAL INTERVENTIONS
# Psychotherapies with the most evidence for effectiveness in older adults include: cognitive behaviour therapies (CBT; individual and group) and problem-solving therapy (PST). PST can be provided to older adults with cognitive impairment and executive dysfunction; CBT and PST have also shown benefit for older adults with depression and medical comorbidity. [B]
Psychotherapies and psychosocial treatments should be made available to older adults with depression (symptoms and disorder) in diverse settings (community, hospital, long-term care) across all regions of Canada.
[A]
# There is also evidence to support behaviour therapy, behavioural activation, reminiscence, and other psychotherapies including psychodynamic psychotherapy and interpersonal psychotherapy (IPT). [B]
Internet-delivered therapies may be comparable to face-to-face treatment, and may improve access to services for individuals in under-serviced areas and those with mobility issues.
[C]
We emphasize the vital need for psychotherapies and psychosocial treatments to be made available for older adults with depression in diverse settings in all regions of the country.
Although many forms of psychotherapy have demonstrated benefits for older adults with depression, we note that the most evidence for effectiveness is for CBT (individual and group) and PST. Numerous meta-analyses support CBT as an effective treatment for late-life depression (Cuijpers et al., 2006;Pinquart et al., 2007;Peng et al., 2009) when provided in both individual and group formats. Some of these meta-analyses also found evidence in support of other psychotherapies such as reminiscence therapy. Emerging studies also suggest CBT is an effective intervention for depressed older adults with medical comorbidities such as chronic pain (Ehde et al., 2014) and heart failure (Jeyanantham et al., 2017). Meta-analyses of psychotherapeutic interventions also support the effectiveness of PST for late-life depression showing moderate to high effect sizes (Cuipjers et al., 2016Kirkham et al., 2016, including among frail older adults (Jonsson et al., 2016).
Internet-delivered cognitive behavioural therapy (iCBT) has been piloted with depressed older adults with favourable results (Titov et al., 2015). Such interventions can improve access to psychotherapy, especially for older adults in underserviced areas, and/or those who face mobility challenges. One RCT comparing online or iCBT to usual care among depressed older adults with knee osteoarthritis showed benefit compared to usual care (O' Moore et al., 2018). This approach is highly relevant during the expansion of virtual care related to the COVID-19 pandemic.
# MODIFIED: SELECTING AN ANTIDEPRESSANT/MONITORING FOR SIDE EFFECTS AND DRUG INTERACTIONS
# It is recommended that clinicians consider sertraline or duloxetine as first-line medications for an acute episode of major depression in older adults. Alternatives include escitalopram and citalopram based on the low possibility of drug interactions but concern about QTc interval may limit dosage to sub-therapeutic levels. [A]
In addition, we suggest clinicians should choose an antidepressant with lowest risk of anticholinergic side effects and drug-drug interactions, as well as being relatively safe in the case of cardiovascular comorbidity. Patients need to be closely monitored for medication compliance, substance use, suicidal ideation, and development of drug toxicity.
[D]
Because of concerns about QTc prolongation with citalopram and escitalopram, and incorporating level of evidence, we are recommending sertraline or duloxetine as first-line medications for an acute episode of major depression in older adults. Citalopram and escitalopram remain useful options.
There are a variety of other appropriate antidepressants for older adults such as venlafaxine, bupropion, and mirtazapine.
In addition vortioxetine is a relatively new antidepressant, which has shown benefit for older adults, including some evidence of improvement in depression-related cognitive dysfunction (McIntyre et al., 2014;Nomikos et al., 2017;McIntyre et al., 2016). In most cases, fluoxetine is not recommended due to its long biological half-life, paroxetine is not recommended due to higher anticholinergic effects, and first generation monoamine oxidase inhibitors are not recommended due to higher risk of serious drug-drug and drug-food interactions. Tricyclic antidepressants should only be considered as third-line agents with due consideration of their potentially serious side effects.
A number of systematic reviews and meta-analyses have been conducted since the last iteration of these guidelines. Overall, the meta-analyses have found that antidepressants are efficacious for geriatric depression. A systematic review and meta-analysis of non-tricyclic "second generation" antidepressants found that these antidepressants were superior to placebo for MDD in adults over 60 years of age. The mean pooled response rates for antidepressant and placebo were 44.4% and 34.7%, respectively. The therapeutic effects were found to be modest and vary according to study and medication (Nelson et al., 2008). Of interest, it was found that longer trials of 10-12 weeks were needed for older adult to achieve a response. A meta-analysis of 51 double-blind RCTs of anti depressants in older patients found that all classes of antidepressant (tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs], and other antidepressants) were superior to placebo to achieve response, with less robust findings for remission. There were no differences in remission or response rates between classes of antidepressants. The numbers needed to treat (NNT) were 14.4 and 6.7 for response and remission, respectively (Kok et al., 2012). The efficacy of duloxetine was supported by a systematic review and metaanalysis of 12 trials of antidepressants for geriatric major depression, with less convincing outcomes for SSRIs . The 2006 Guidelines recommended weekly visits after starting an antidepressant. Although ideal, this has been deemed often unrealistic (e.g., in primary care and in many mental health ambulatory settings). A brief check-in by phone may be helpful for some patients who are experiencing side effects and may encourage patients to continue taking the medication as the initial side effects frequently diminish.
# MODIFIED: TITRATION AND DURATION OF THERAPY (INADEQUATE RESPONSE)
When significant improvement has occurred but recovery is not complete after an adequate trial, the clinician should consider:
• a further 4 weeks of monotherapy or consider augmentation with another antidepressant or lithium or an antipsychotic (e.g., aripiprazole) or specific psychotherapy (e.g., IPT, CBT, PST).
• a switch to another antidepressant (same or another class) after discussing with the patient the potential risk of losing any significant improvements made with the first treatment.
[C]
• augmentation with lithium remains a viable option but needs to be used carefully due to the risk of lithium toxicity; the clinician must be aware of how to monitor the patient on lithium over time through investigations.
# NOTE: 2006 recommendation did not include augmentation with an antipsychotic.
The atypical antipsychotic aripiprazole has been investigated for treatment-refractory depression with promising results. A post hoc examination of 3 RCTs for patients 18-67 years of age demonstrated that augmentation with aripiprazole was superior to placebo in reducing depression and achieving remission in the 61-67 year-old subgroup (Steffens et al., 2011).
A subsequent randomized, placebo-controlled trial of aripiprazole for older adults (average age 66) who did not respond to venlafaxine found that augmentation with aripiprazole (average daily dose 7 mg) resulted in remission significantly more often than placebo (44% vs 29%) (Lenze et al., 2015). The NNT to achieve remission with aripiprazole augmentation was 6. Extended-release quetiapine has demonstrated efficacy as monotherapy for geriatric depression (Katila et al., 2013). It must be noted that atypical antipsychotic medications have significant potential side effects such as tardive dyskinesia, akathisia, extrapyramidal side effects, and prolongation of QTc, and there may be an increased risk of death and stroke, based on the dementia literature.
In attempting to achieve optimal outcomes, some experts favour an approach that utilizes a treatment algorithm. One Canadian example of this approach was described by Mulsant et al. (2014). In this algorithm, the first-line antidepressant was escitalopram, with sertraline and duloxetine as alternatives.
For non-responders, duloxetine is the preferred second-line antidepressant, with venlafaxine and desvenlafaxine as alternatives. Duloxetine was favoured partly due to the impact on the management of several pain syndromes that are quite common in older adults. If the patient fails an SSRI and a serotonin and norepinephrine reuptake inhibitor (SNRI); i.e., no response despite an adequate trial at a therapeutic dose) the next step is the use of the TCA nortriptyline, with bupropion as an alternative. For those patients who achieve a partial response to a first-or second-line antidepressant (SSRI or SNRI), the algorithm recommends augmentation with either lithium or an atypical antipsychotic. An alternative is combining the SSRI or SNRI with mirtazapine or bupropion.
# MODIFIED: MONITORING FOR SIDE EFFECTS AND DRUG INTERACTIONS (SODIUM)
When prescribing SSRI or SNRI antidepressants to older adults, the prescriber should screen for a history of hyponatremia before prescribing, as part of the consent process and then consider getting a sodium level prior to starting the antidepressant if there is a history of hyponatremia. The 2006 Guidelines recommended that a sodium level be done after 1 month, especially if the patient was taking a medication known to cause hyponatremia. Reports suggest that hyponatremia often occurs with the first 2 weeks of treatment (Leth-Møller et al., 2016;Lien, 2018).
A review of 21 studies and over 100 case reports revealed a relatively higher risk of hyponatremia with SSRIs and venlafaxine, particularly when combined with patient risk factors for hyponatremia (De Picker et al., 2014). The risks associated with mirtazapine were lower. A recent commentary compared 4 population-based studies, revealing that SSRIs and SNRIs are most likely to cause hyponatremia in older adults, with TCAs and mirtazapine having lower risk. There are case reports for bupropion possibly causing hyponatremia as well (Lien, 2018). rTMS is a brain stimulation method that uses magnetic field pulses, rather than an electrical current, and does not induce a seizure. The procedure requires a stimulator and coil to produce an electromagnetic field. A typical treatment course is 5 days per week for between 4-6 weeks. In general, the treatment has a favourable adverse effect profile with common side effects including scalp discomfort and transient headache.
There are no cognitive adverse effects reported with rTMS. In 2008, the FDA approved rTMS as a treatment for depression for patients not responding to at least 1 antidepressant medication with a maximum age of 69 (Manepalli et al., 2014).
Despite the relatively large number of rTMS studies completed to date, there is a paucity of studies evaluating the efficacy of rTMS in treatment-resistant late-life depression specifically. A number of older reports have suggested that older age is a negative predictor of response to rTMS (Figiel et al., 1998;Fregni et al., 2006;Manes et al., 2001;Mosimann et al., 2002). However, these studies were limited in several important ways: short treatment courses and suboptimal stimulation parameters, particularly with respect to the stimulation intensity needed to overcome the prefrontal atrophy that occurs with advancing age. The proposed mechanism for these negative findings is likely related to the increased scalp-tocortex distance in the elderly (Figiel et al. 1998). Imaging studies (Mosimann et al., 2004;Kozel et al., 2000) and a small uncontrolled clinical pilot study (Nahas et al., 2004) have suggested a correlation between antidepressant effect of rTMS and scalp-to-cortex distance. Nahas et al. (2004) used an open design in which they adjusted stimulus intensity based on the distance of the scalp to the cortex and used magnetic resonance imaging (MRI) co-registration to target the dorsolateral prefrontal cortex (DLPFC), in 18 older subjects. The average intensity required was 114%; significantly higher than the intensity used in other treatment trials at the time. Interestingly, a more recent RCT in an elderly sample with depression and cerebrovascular damage found unilateral rTMS at 110% stimulation intensity resulted in a significant, but modest 27.3% remission rate (Jorge et al., 2008).
The rTMS field has moved to using 120% of the motor threshold intensity across the age range of subjects and as a result, meta-analyses of more recent DLPFC rTMS have not found that older age is a negative predictor of response (Berlim et al., 2014;Gross et al., 2007). Some preliminary data suggest that older adults may respond better to a sequential bilateral form of rTMS where low frequency (i.e., 1 Hz) right-sided stimulation is immediately followed by high frequency (i.e., 10 Hz) left-sided stimulation, using 120% stimulation intensity (Blumberger et al., 2012;Blumberger et al., 2016;Trevizol et al.,2019). Other data suggest that older adults may respond better with a coil that generates a larger induced electrical field than the standard figure of 8 coils (Levkovitz et al., 2009). A controlled trial in older adults aged 60-80 demonstrated that deep rTMS led to a statistically significant higher remission rate compared to sham (Kaster et al., 2018).
Further study of rTMS in older adults is warranted given that optimal treatment parameters have demonstrated more promising results than earlier studies. Controlled studies across the age spectrum of older adults (i.e., over age 70) are needed to confirm efficacy and tolerability in this subgroup of older adults. Older adults may be particularly able to benefit from rTMS as daily schedules may be more conducive to the 5 days weekly treatment schedule. rTMS has good patient acceptability due to the favourable adverse effect profile, in particular the lack of cognitive side effects. There is some recent evidence that pharmacogenetic testing might improve outcomes among older adults with MDD who had failed a trial of at least 1 antidepressant.
In a controlled trial of 206 adults (aged 65 or older) participants receiving care guided by pharmacogenetic testing showed significantly improved response and rates of remission compared to usual care (Forester et al., 2020). However, this testing is not widely available and is expensive. We do not recommend its use in routine practice, although some patients who are intolerant of several antidepressants may benefit from a pharmacogenetic test. A number of meta-analyses and systematic reviews have investigated the efficacy of antidepressants for depression associated with dementia. The initial Cochrane review in 2002 was negative (Bains et al., 2002). This was followed by a positive meta-analysis of 5 studies, which showed a NNT of 5 to achieve remission (Thompson et al., 2007). Subsequently, 4 more meta-analyses, including another Cochrane review in 2018, were negative (Nelson et al., 2011, Sepehry et al., 2012, Orgeta et al., 2017, Dudas et al., 2018. We would still suggest that antidepressant medication could be offered if symptoms are severe and persistent.
# NEW: SPECIAL POPULATIONS: PARKINSON'S DISEASE
We recommend SSRIs as first line for the treatment of depression in patients with Parkinson's disease with SNRIs as an alternative.
# CBT can also be considered. [B]
The 2006 Guidelines did not make a recommendation for patients with depression associated with Parkinson's disease. A meta-analysis of 20 RCTs compared pharmacologic, behavioural, or rTMS with a placebo/other drugs or methods. There were 13 medication trials, 9 of 13 were placebo-controlled and most were studies involving antidepressants. Two studies examined dopamine agonists and 1 study examined memantine. Antidepressant medications were found to be efficacious, specifically SSRIs and SNRIs. Non-antidepressant medications (e.g., dopamine agonists) did not have positive results. CBT was also beneficial (Bomasang-Layno et al., 2015). Another metaanalysis assessed the efficacy of antidepressants for depression in Parkinson's disease compared to placebo or a control group. This involved 20 studies and of those, 12 were randomized, placebo-controlled trials, while the others were either comparative studies or antidepressant versus no treatment. The results demonstrated efficacy for SSRIs, MAOIs, and TCAs when compared with placebo. The antidepressants were well-tolerated overall (Mills et al., 2018). Given equal efficacy among antidepressants, we recommend SSRIs or SNRIs, as they are generally better tolerated than older antidepressants such as TCAs. Several meta-analyses have demonstrated that a variety of antidepressants are superior to placebo in PSD (Xu et al., 2016;Deng et al. 2017;Qin et al., 2018). We favour SSRIs as first line based on overall risk of side effects, although they are associated with an increased risk of bleeding when combined with non-steroidal anti-inflammatory medication (Shin 2015).
Methylphenidate may be efficacious based on 1 placebocontrolled RCT (Grade et al., 1998).
# NEW: MODELS OF CARE (COLLABORATIVE, INTERPROFESSIONAL MODELS)
Core elements of evidence-based models for treating late-life depression in primary care include improved patient education, and incorporating interprofessional staff as depression care managers who routinely assess and follow patients clinically, utilizing a stepped-care approach. Treatment prescriptions are provided by a primary care physician or nurse practitioner, with as needed psychiatric consultation. An individualized plan of care should be developed using a collaborative approach.
[A]
Interventions that integrate mental health services into primary care have increased the number of patients who are treated for depression and the quality of that treatment. The most effective models involve systematic depression screening and monitoring, interprofessional teams that include primary care providers and mental health specialists, a depression care manager to work directly with patients over time, and the use of guideline-based depression treatment (Bruce & Sirey, 2018). Three major studies have demonstrated the effectiveness of integrated approaches (PRISM-E, IMPACT, and PROSPECT) in the care of older adults. Thota et al., (2012) carried out an extensive review and meta-analysis of collaborative care to improve the management of depressive disorders across multiple patient populations. The results from their metaanalyses suggest robust evidence of effectiveness of collaborative care in improving depression symptoms, adherence to treatment; response to treatment, remission of symptoms, recovery from symptoms, quality of life/functional status, and satisfaction with care for patients diagnosed with depression.
# NEW: MODELS OF CARE (VIRTUAL CARE)
To optimize access to clinical services, " The use of telepsychiatry for care of older adults has been shown to be feasible and effective (Conn et al., 2013;Ramos-Ríos et al., 2012). A systematic review of studies demonstrated that telehealth care is feasible and well-accepted in the areas of inpatient and nursing home consultation, cognitive testing, dementia diagnosis and treatment of depression in integrated and collaborative care models and psychotherapy (Gentry et al., 2019). However, the use of telepsychiatry in Canada has been quite limited prior to the COVID-19 pandemic. Since then the use of virtual care approaches has dramatically increased across multiple areas of healthcare. Older adults are often at a disadvantage with many having limited capacity to utilize newer technologies.
As such we strongly advocate for senior-friendly virtual care options with appropriate equipment and support. Health care providers should be familiar with the physical, psychological, and social risk factors for depressive disorders in older adults and include a screening for depression for their clients/ patients who present with some of these risk factors.
[D]
# Unchanged
We recommend targeted screening of those elderly at higher risk for depression due to the following situations:
• Recently bereaved with unusual symptoms (e.g., active suicidal ideation, guilt not related to the deceased, psychomotor retardation, mood congruent delusions, marked functional impairment after 2 months of the loss, reaction that seems out of proportion with the loss) Essentially unchanged, but note that the exclusion of major depression in the first 2 months after the loss and in bereavement was removed in Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition (DSM-V). We recommend initial treatment with supportive psychosocial interventions or psychotherapy. If symptoms become severe enough to meet DSM-IV diagnostic criteria for a depressive disorder or persist after resolution of the stressor, more specific therapies in keeping with the revised diagnosis should be considered (e.g., medication, more intensive/ specific psychotherapy).
# Recommendations: Screening and Assessment -Screening and Screening Tools
[D]
No change except for new version of DSM (DSM-5).
# TREATMENT OPTIONS FOR TYPE AND SEVERITY OF DEPRESSION (CONT'D)
Recommendations Patients with severe unipolar depression should be offered a combination of antidepressants and concurrent psychotherapy when appropriate services are available and there is no contra-indication to either treatment.
[D]
# Unchanged
ECT should be considered if adequate trials of antidepressants combined with psychotherapy have been ineffective or if the health of the patient is deteriorating rapidly due to depression.
[D]
Electroconvulsive therapy (ECT) should be considered in the treatment of older patients with severe unipolar depression who have previously had a good response to a course of ECT and/or failed to respond to 1 or more adequate antidepressant trials plus psychotherapy, especially if their health is deteriorating rapidly due to depression. ECT is a firstline treatment in older, depressed patients who are at high risk of poor outcomes-those with suicidal ideation or intent, severe physical illness, or with psychotic features.
[A]
ECT can also be useful for continuation/maintenance therapy of older patients who are partially responsive, treatment resistant, or treatment intolerant with pharmacotherapy during the acute phase of treatment.
[B]
Recommendation: Treatment: Major Depressive Disorder, Single or Recurrent Episodes -Severe with Psychotic Features
# RECOMMENDATIONS 2021 NEW OR UPDATED RECOMMENDATIONS
If there is no specific contraindication to its use, patients with psychotic depression should be offered treatment with ECT when available. Alternatively, a combination of antidepressant plus antipsychotic medication should be used. If this combination is not effective (e.g., poorly tolerated, no improvement in at least some of the symptoms within 4-8 weeks of treatment, or lack of remission despite optimisation of dose and duration of treatment over more than 8-12 weeks), ECT needs to be offered. ECT should also be considered if severe health consequences (e.g., suicide, metabolic derangement) are imminent because pharmacological treatment has been poorly tolerated or would be too slow to provide needed improvements.
[D]
Recently, more placebo-controlled clinical trials reported safe and effective use of combined antidepressant and antipsychotic drugs in MDD with psychotic features, so we recommend that clinicians use their judgement based on severity and patient's physical conditions to try combination pharmacotherapy first. ECT should be considered after 4-8 weeks if combination therapy fails, is poorly tolerated, or if patient develops severe health consequences. Change of terminology from depression with co-morbid substance abuse to depression with co-morbid substance use disorder.
# TREATMENT OPTIONS FOR TYPE AND SEVERITY OF DEPRESSION (CONT'D)
Recommendation Change of terminology from depression with co-morbid substance abuse to depression with co-morbid substance use disorder. Psychotherapies and/or psychosocial treatments should be made available to older adults with depression (symptoms or disorder) in all settings (community, hospital, long-term care).
# Recommendations: Pharmacogenetic Testing
[A]
Evidence-based psychotherapies recommended for geriatric depressions include: behaviour therapy; cognitive-behaviour therapy; problem-solving therapy; brief dynamic therapy; interpersonal therapy; and reminiscence therapy.
[A]
Psychotherapies with the most evidence for effectiveness in older adults include: cognitive behavioural therapy (CBT)individual and group, and problem-solving therapy (PST). PST can be provided to older adults with cognitive impairment and executive dysfunction; CBT and PST have also been studied in older adults with medical comorbidity.
[B]
There is also evidence to support behaviour therapy, behavioural activation, reminiscence, and other psychotherapies including psychodynamic psychotherapy and interpersonal therapy.
[B]
Internet-delivered therapies may be comparable to face-toface treatment, and may improve access to services for individuals in under-serviced areas and those with mobility issues. When choosing agents from a specific class, clinicians should select those found to be safer with the elderly (e.g., selecting drugs with the lowest anti-cholinergic properties amongst available antidepressants).
[D]
We suggest clinicians choose an antidepressant with the lowest risk of anticholinergic side effects and drug-drug interactions as well as being relatively safe in the case of cardiovascular comorbidity. Patients need to be closely monitored for medication compliance, substance use, suicidal ideation, and development of drug toxicity.
[D]
We recommend that physicians and pharmacists consult up-to-date drug interaction data bases when a new antidepressant is prescribed to patients taking multiple medications. We recommend checking sodium blood levels after one month of treatment with SSRIs, especially with patients taking other medications that can cause hyponatremia (e.g., diuretics).
[C]
We recommend checking sodium levels before switching to another agent due to poor response or tolerance or when patients display symptoms of hyponatremia (e.g., fatigue, malaise, delirium).
[C]
When prescribing SSRI or SNRI antidepressants to older adults, the prescriber should screen for a history of hyponatremia before prescribing, as part of the consent process and then consider getting a sodium level prior to starting the antidepressant if there is a history of hyponatremia. Before considering a change in medication, it is important to ensure an adequate trial. Change should be made if: there is no improvement in symptoms after at least 4 weeks at the maximum tolerated or recommended dose; there is insufficient improvement after 8 weeks at the maximum tolerated or recommended dose.
[C]
# Unchanged
When significant improvement has occurred but recovery is not complete after an adequate trial, the clinician should consider:
• a further 4 weeks of treatment with or without augmentation with another antidepressant or lithium or specific psychotherapy (e.g., IPT, CBT, PST); • a switch to another antidepressant (same or another class) after discussing with the patient the potential risk of losing any significant improvements made with the first treatment.
[C]
When significant improvement has occurred but recovery is not complete after an adequate trial, the clinician should consider:
• a further 4 weeks of monotherapy or consider augmentation with another antidepressant or lithium or an antipsychotic (e.g., aripiprazole) or specific psychotherapy (e.g., IPT, CBT, PST). • a switch to another antidepressant (same or another class) after discussing with the patient the potential risk of losing any significant improvements made with the first treatment. • augmentation with lithium remains a viable option, but needs to be used carefully due to the risk of lithium toxicity. The clinician must be aware of how to monitor the patient on lithium over time through investigations.
[C]
When switching agents, it is generally safe to reduce the current medication while starting low doses of the alternate agent. Specific drug interaction profiles need to be checked for both drugs involved during this overlap since antidepressants commonly interact with each other.
[C]
# Unchanged
Augmentation strategies require supervision by experienced physicians.
[D]
# Unchanged
Given its long half-life and risk of interaction with many of the drugs prescribed for the elderly, we do not recommend the use of fluoxetine as first-line treatment despite its documented efficacy.
[C]
Fluoxetine is not recommended due to long biological halflife, paroxetine is not recommended due to higher anticholinergic effects, and first generation MAOIs are not recommended due to higher risk of serious drug-drug or drug-food interactions.
[D]
Antidepressants, especially SSRIs, should not be abruptly discontinued but should be tapered off over a 7 to10 day period when possible. In LTC homes, the response to antidepressant therapy should be evaluated monthly after initial improvement and at quarterly care conferences, as well as at the annual assessment after remission of symptoms.
A decision to continue or discontinue the antidepressant therapy should be based on:
• whether the depression has been treated long enough to allow sustained remission of symptoms (e.g., now one year of full remission); or • whether the treatment is still tolerated well in the context of their health problems; and • the risks of discontinuation (i.e., return of original depressive symptoms) are less than those associated with continuation of medication.
# Unchanged
Health care professionals should provide older depressed adults with education regarding the nature of depression, its biological, psychological and social aspects, effective coping strategies, and lifestyle changes that will assist their recovery, while being mindful of the individual's stresses and strengths.
[B]
# Unchanged
Families of depressed older adults should be provided with information regarding the signs and symptoms of depression, attitudes and behaviours of the depressed person and their own reaction to them, and depression coping strategies, as well as available treatment options and the benefits of treatment.
# Unchanged
The choice of mood stabilizer should be based on prior response to treatment, type of illness (e.g., rapid-cycling or not), medical contraindications to the use of specific mood stabilizers (i.e., side effects that could worsen pre-existing medical problems), and potential interactions with other drugs required by the patient.
[C]
# Unchanged
All mood stabilizers require monitoring over time for possible short-term and longer-term adverse events.
[B]
All mood stabilizers require monitoring over time for possible short-term and longer-term adverse events. Using lithium requires the patient, family, and healthcare team to understand the factors that may increase lithium levels leading to potential toxicity. Lithium can cause hypothyroidism, hypercalcemia through hyperparathyroidism, and renal dysfunction. The clinician must regularly monitor the patient on lithium, including laboratory investigations. There is limited evidence to recommend antidepressant therapy for mild or moderate depression associated with dementia. Behavioural interventions may be utilized as a firstline intervention and antidepressant medication could be offered if symptoms are severe and persistent, understanding that efficacy is not well established and that side effects could occur.
[D]
In selecting pharmacological treatment for depression with dementia, clinicians should select drugs that have low anticholinergic properties, such as citalopram and escitalopram, sertraline, moclobemide, venlafaxine, or bupropion.
[C]
As noted above, we recommend duloxetine and sertraline as first-line antidepressants, while recognizing that other antidepressants are also appropriate. Limiting exposure to anticholinergic properties remains an important consideration in patients with both dementia and depression.
# SPECIAL POPULATIONS (CONT'D)
Recommendations: Special Populations: Dementia
# RECOMMENDATIONS 2021 NEW OR UPDATED RECOMMENDATIONS
Psychosocial treatment should be part of the treatment of depression co-existing with dementia. This treatment should be flexible to account for the decline in functioning as well as multifaceted to provide help with the diversity of problems facing the patient and caregiver. It should be delivered by clinicians sensitized to the vulnerabilities and frailties of older adults with dementia. This treatment should include helping caregivers deal with the disease in a skill-oriented manner.
[A]
# Unchanged
For patients who have psychotic depression and dementia, a combination of antidepressant and antipsychotic medication is usually the first choice, although ECT may be used if medications are ineffective or rapid response is required to maintain safety.
# MODELS OF CARE
Recommendations: Models of Care
# RECOMMENDATIONS 2021 NEW OR UPDATED RECOMMENDATIONS
Health care professionals and organizations should implement a model of care that addresses the physical/ functional as well as the psychosocial needs of older depressed adults.
Given the complex care needs of older adults, these are most likely to require interdisciplinary involvement in care, whether in primary care or specialized mental health settings.
[B]
# Unchanged
Health care professionals and organizations should implement a model of care that promotes continuity of care as older adults appear to respond better to consistent primary care providers.
[B]
# Unchanged
New:
Core elements of evidence-based models for treating late-life depression in primary care include: improved patient education, incorporating interprofessional staff as depression care managers who routinely assess and follow patients clinically, utilizing a stepped-care approach. Treatment prescriptions are provided by a primary care physician or nurse practitioner, with as needed psychiatric consultation.
An individualized plan of care should be developed using a collaborative approach. | None | None |
f2a7d5319c2e2027ee5e72f28aa57a08c1f4e987 | cma | None | Low-density lipoprotein LTBI Latent tuberculosis (TB) infection MAC Mycobacterium avium complex MCV Mean corpuscular volume MHT Menopausal hormone therapy MI Myocardial infarction MMR Mumps, measles and rubella MRI Magnetic resonance imaging MSM Men who have sex with men MSP Medical services plan NAAT Nucleic acid amplification test NACI National Advisory Committee of Immunization (Canada) NASH Non-alcoholic steatohepatitis NNRTI Non-nucleoside reverse transcriptase inhibitor NRTI Nucleoside reverse transcriptase inhibitor NP Nurse practitioner OI Opportunistic infection# INTRODUCTION - 22
Figure 2.
# 1: The HIV Cascade of Care - 22
2.2 MODES OF HIV TRANSMISSION
# - 2.3 NATURAL HISTORY OF HIV/AIDS - Figure 2.2: Natural history of HIV/AIDS.
2.4 HIV TESTING
RECOMMENDATIONS: - 3.
# INITIAL ASSESSMENT - Table 3.1: Initial assessment, medical history. - 3.2 PHYSICAL EXAMINATION
Table 3.
# 2: HIV-related physical examination. - 3.3 BASELINE LABORATORY EVALUATION
Table 3.
# 3: Baseline laboratory assessment - 3.4 COUNSELLING PLWH REGARDING HIV TRANSMISSION RISK - 4 SCREENING AND IMMUNIZATION FOR SELECTED CO-MORBID INFECTIONS
# SCREENING FOR CO-MORBID INFECTIONS - 4.2 IMMUNIZATIONS AND HIV - 4.2.1 Recommended Vaccines - Table 4.1: Recommended vaccines for adults living with HIV - 4.2.2 Additional Vaccines - 4.2.3 Contraindicated Vaccines - 5 SPECIAL CONSIDERATIONS FOR CISGENDER WOMEN LIVING WITH HIV (WLWH)
# INTRODUCTION - 5.2 SPECIAL CONSIDERATIONS RELATED TO ART DURING PREGNANCY AND THE POST-PARTUM PERIOD - 5.3 REPRODUCTIVE ISSUES AND GYNECOLOGIC HEALTH IN THE CONTEXT OF HIV - 5.4 ART AND WEIGHT GAIN IN WOMEN - 5.5 MENOPAUSE - 5.6 BONE HEALTH - 6 SPECIAL CONSIDERATIONS FOR TRANSGENDER INDIVIDUALS LIVING WITH HIV - 7 COMMON NON-INFECTIOUS CO-MORBIDITIES
# INTRODUCTION - 7.2 CARDIOVASCULAR DISEASE - 7.3 INSULIN RESISTANCE (IR) AND DIABETES MELLITUS (DM) - 7.4 BONE - 7.5 RENAL DISEASE - 7.6 HYPOGONADISM - 7.7 NEUROCOGNITIVE IMPAIRMENT - 7.8 LUNG DISEASE
7.9 LIVER DISEASE/CIRRHOSIS - 7.
# CANCER - 89 Table 7.1 Recommendations for cancer screening in PLWH - 7.11 MENTAL HEALTH - 8 SPECIAL CONSIDERATIONS FOR INDIVIDUALS WITH ADVANCED HIV -OPPORTUNISTIC INFECTION & PROPHYLAXIS
-- 9.1 CHRONIC DISEASE MODEL OF CARE - 9.2 ACTIVE REFERRAL FOLLOWING DIAGNOSIS- Figure 9
# .1: The Chronic Care Model - 107 9.3 ADDRESSING SOCIAL DETERMINANTS OF HEALTH - 9.4 PEER-SUPPORT AND PATIENT OR PEER NAVIGATION - 9.5 CASE MANAGEMENT - 9.6 OUTREACH SERVICES - 9.7 OTHER SUPPORTS - APPENDIX 1: SIGNS AND SYMPTOMS ASSOCIATED WITH HIV SEROCONVERSION SYNDROME/ACUTE RETROVIRAL SYNDROME AND THEIR FREQUENCY IN SYMPTOMATIC INDIVIDUALS - APPENDIX 2: AIDS-DEFINING CONDITIONS - APPENDIX 3: SCREENING FOR NON-INFECTIOUS CO-MORBID CONDITIONS IN PEOPLE LIVING WITH HIV (PLWH) - APPENDIX 4: CONTACT LIST - PROVINCIAL AND REGIONAL HIV/AIDS SERVICE ORGANIZATIONS - 117 REGIONAL HEALTH AUTHORITY CONTACTS/ COMMUNICABLE DISEASE NURSING CONTACTS - 117 APPENDIX 5: OTHER GUIDELINES RELATED TO THE CARE OF PEOPLE LIVING WITH HIV (PLWH) - DISCLAIMER
No financial or in-kind commercial support has been received for the development of these guidelines; no commercial organization has supported the development of these guidelines. The content of the guidelines has been developed by the authors and reflect best practices in HIV care in British Columbia. Both positive and negative trials are mentioned where possible. Generic names of medications are used in place of brand names where possible.
These Guidelines represent the view of the Primary Care Guidelines Writing Committee, in consultation with an external group of experts and are based on available scientific evidence current to July 31, 2021. These Guidelines may be superseded by subsequent Guidelines. Please check for the most recent Guidelines. Every health care professional is responsible for exercising their own professional skill and judgment and should consider these Guidelines in the context of the individual patient's circumstances, in consultation with that patient or their guardian(s), and when appropriate, external experts (e.g., specialty consultation). These Guidelines are not medical advice nor are they intended to be the only approach to the management of a clinical problem. These Guidelines should not be relied on by any individual as a substitute for the advice or professional judgment of a health care professional.
# WHAT'S NEW IN THE GUIDELINES
# Updated: November 2022
Toxoplasma Serology Table 3.3, Toxoplasma IgG serology, has been updated for agreement with the existing recommendations provided in the body of the Primary Care Guidelines. Toxoplasma IgG serology is indicated in all persons, regardless of CD4 cell count (Table 3.3). Previous versions stated toxoplasma IgG serology is indicated in persons with CD4 cell count <200 cells/mm3.
# INTRODUC TION
There has been a significant decrease in the morbidity and mortality of people living with HIV (PLWH) in the province of British Columbia since the introduction of potent antiretroviral treatment in 1996. According to the British Columbia Centre for Excellence in HIV/AIDS (BC-CfE) HIV Quarterly Monitoring Report for the fourth quarter of 2019, there were approximately 10,603 people in the province living with HIV.(1) Among them, around 7415 were receiving antiretroviral treatment in 2020. (2) The Primary Care Guidelines for the Management of HIV/AIDS in Adults in British Columbia, along with other therapeutic guidelines, have been developed by the BC-CfE to provide support for care and treatment programs for PLWH. These guidelines also respond to the need to expand HIV treatment to meet the goals of 90-90-90 in British Columbia and respond to requests from primary care providers in the community for HIV-specific guidelines.
# OBJECTIVES
- To provide consensus-based guidelines for the management of primary care for PLWH. 2. To provide practical and easily accessible information and resources for primary care providers of PLWH in the province of British Columbia.
# METHODS
# Process Overview and Committee Composition
An expert committee composed of primary care and infectious disease physicians, a nurse practitioner, a pharmacist, and a person living with HIV prepared the original guidelines in 2011. Since the guidelines were first published, they have been consistently reviewed and revised to ensure that the information is up-to-date. In 2014/15, the original expert committee collectively undertook a review of the 2011 guidelines. The most recent review was finalized in 2021 by a review committee consisting of primary care, public health, and infectious disease physicians (refer to above). Where applicable, the committee updated epidemiology, baseline assessment, immunizations, and co-morbidities data and added new recommendations. The revisions were sent out to subject matter experts for review where necessary.
# Consensus Development on the Basis of Evidence
The review committee met a total of eight times. Committee members developed sections, in consultation with external medical experts where appropriate, and presented their work at committee meetings, where all recommendations were discussed until consensus was reached. The final manuscript was reviewed by all committee members and then presented to and reviewed by members of the Committee for Drug Evaluation and Therapy (CDET) at the BC-CfE and reviewed by external reviewers (listed above).
Each recommendation in the guidelines has been assigned a level of evidence based on the GRADE criteria (refer to Table 1.
Note that this method of grading recommendations is different from previous versions of the BC-CfE Primary Care Guidelines.
# Quality of Evidence Definition
A High
Further research is very unlikely to change our confidence in the estimate of effect.
Several high-quality studies with consistent results
In special cases: one large, high-quality multi-centre trial
# B Moderate
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
One high-quality study Several studies with some limitations
# C Low
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
One or more studies with severe limitations
# D Very Low
Any estimate of effect is very uncertain.
# Expert opinion
No direct research evidence One or more studies with very severe limitations
# WLWH
Women living with HIV
# X-ray
Penetrating form of high-energy electromagnetic radiation
# SUMMARY OF PRIMARY CARE RECOMMENDATIONS FOR THE MANAGEMENT OF HIV/AIDS INITIAL ASSESSMENT OF PEOPLE LIVING WITH HIV (PLWH)
- All PLWH should have timely access to a primary care clinician with knowledge in the management of HIV infection and should receive care in a culturally sensitive environment. Primary care clinicians without expertise in HIV care should consult with a physician with this expertise. (D)
- All patients entering HIV care should have documented evidence of HIV antibody testing. If laboratory confirmation is not available, a repeat HIV antibody test should be performed. (D) 3. Clinicians should obtain a comprehensive present and past medical history, including HIV-related information, assessment of present medications, family history and psycho-social issues, and review of systems and conduct a complete physical examination upon the patient's entry into care. (D) 4. A baseline CD4 cell count (absolute and fraction) and quantitative HIV RNA (plasma viral load) should be done for all patients upon entry into care. (A) 5. All patients should be assessed for transmitted HIV drug resistance using genotypic drug resistance testing. Ideally, the drug resistance testing should be conducted on the first available sample of HIV plasma viral load. (B) 6. HLA-B*5701 testing is recommended once at baseline for all patients. HLA-B*5701-positive patients must not be given abacavir-containing regimens. (A) 7. Hematology (CBC with differential and platelet count) and comprehensive biochemistry (liver and renal function, lipid profile, fasting blood glucose and/or HbA1C) is recommended at baseline to support management of ART toxicities and to evaluate other potential co-morbidities. (D) 8. A chest X-ray should be performed at baseline in all PLWH. (D) 9. All patients should receive baseline screening for a variety of other infectious agents to assess the need for immunization, monitoring, and counselling (see Section 4, Screening and Immunization for Selected Co-Morbid Infections). (D) 10. PLWH should be advised of the risk of onward transmission, the effectiveness of HIV treatment in preventing transmission, other practices to prevent transmission, and the legal implications of HIV non-disclosure with their sexual partners. (D)
# SCREENING AND IMMUNIZATION FOR SELECTED CO-MORBID INFECTIONS
Tuberculosis Screening
- All PLWH should be screened at baseline for Mycobacterium (M.) tuberculosis (TB) infection. (A) Screening involves reviewing history of TB exposure and/or treatment history and previous tuberculin skin test (TST) and/or interferon gamma release assay (IGRA) results. (B) A chest X-ray should be undertaken if there is history of TB exposure or positive screening test. (B) 2. In BC, the TST using 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) is the main test for diagnosing latent TB infection (LTBI), provided there are no contraindications. (B)
- IGRAs are currently recommended as an adjunct test to TST and may be valuable in the following two situations: a) PLWH with CD4 cell count <200 cells/mm 3 who are TST-negative (if possible, the T-SPOT® assay is preferred); and b) PLWH with a history of contact with active TB and who are TST-negative. (C)
# Toxoplasmosis Screening
- All PLWH should be screened at baseline for Toxoplasma IgG antibodies to determine prior exposure to Toxoplasma (T.) gondii. (D)
# Hepatitis Screening
- PLWH should be screened at baseline for hepatitis A virus (HAV) using total anti-HAV antibodies. (B)
- PLWH should be screened at baseline for hepatitis B virus (HBV) using HBsAg (hepatitis B surface antigen), anti-HBs (hepatitis B surface antibody), and anti-HBc (hepatitis B core antibody). (B)
# Screening for Syphilis and Other Sexually Transmitted Infections (STIs)
- All PLWH should be screened for syphilis at baseline with Treponema pallidum-specific enzyme immunoassay (EIA). (B) Syphilis screening should be repeated annually, or every 3-6 months in the presence of ongoing risk behaviours, or in the presence of symptoms. (D)
- A lumbar puncture should always be performed for patients with a reactive syphilis serology who have neurologic or ocular symptoms or signs, irrespective of past syphilis treatment history. (D)
- All PLWH should be screened at baseline for gonorrhea and chlamydia. (B) Screening should occur every 3-6 months in the presence of ongoing risk behaviours or in the presence of symptoms. (D)
# Recommended Vaccines
Hepatitis A
- All PLWH who are susceptible (anti-hepatitis A negative) should be vaccinated against HAV, ideally when CD4 >200 cells/mm 3 . (B)
- The HAV vaccine should be administered intramuscularly at the standard dose, at 0, 1, and 6 months. (B)
# Hepatitis B
- All PLWH who are susceptible to hepatitis B virus (HBV) infection (HBsAg negative and anti-HBs less than 10 IU/mL) should be vaccinated against HBV, ideally when CD4 >200 cells/ mm 3 . (B)
- HBV vaccination should also be offered to PLWH who have positive hepatitis B total core antibody (anti-HBc) with negative HBsAg and anti-HBs results (titre less than 10 IU/mL) and undetectable HBV DNA. (D)
- In the situations described above, HBV vaccine should be administered intramuscularly (IM) to PLWH 20 years of age and older at a higher dose (40 mcg).
- Recombivax HB® (10 mcg/mL): give 4.0 mL IM at 0, 1, and 6 months (B)
- Recombivax HB ® Adult Dialysis formulation (40 mcg/mL) give 1.0 mL IM at 0, 1, and 6 months (B)
- Engerix®-B Adult (20 mcg/mL): give 2.0 mL IM at 0, 1, 2, and 6 months (B)
- Post-serologic testing (using anti-HBs) within 1-6 months of completion of the vaccine series is recommended to monitor success of immune response to vaccine. (B)
# Pneumococcal Disease
- All PLWH should be vaccinated against pneumococcal disease using standard vaccine doses (A), regardless of CD4 cell counts and according to the following schedules: (i) Individuals who have not previously received any pneumococcal vaccine: One dose of conjugate pneumococcal vaccine (Pneu-C-13) is followed at least 8 weeks later by one dose of polysaccharide pneumococcal vaccine (Pneu-P-23). (B) (ii) Individuals who have received a pneumococcal polysaccharide vaccine (Pneu-P-23) previously: The Pneu-C-13 dose should be administered at least one year after any previous dose of Pneu-P-23. (C) (iii) If re-immunization with Pneu-P-23 is needed, it should be given at least 8 weeks after the Pneu-C-13 dose and at least 5 years after the initial Pneu-P-23 dose. (C)
# Influenza
- All PLWH should be vaccinated annually against influenza using standard doses of the inactivated vaccine, regardless of CD4 cell counts or HIV plasma viral load. (B)
# Tetanus and Diphtheria
- All PLWH should be offered a tetanus and diphtheria (Td) toxoid booster every 10 years, ideally when CD4 >200 cells/mm 3 . (D)
# Human Papillomavirus (HPV)
- HPV-9 vaccine is recommended for all PLWH aged 9-27 years (A) and should be strongly considered in women and MSM aged 27 years and older. (B) A three-dose series is recommended in adults.
# Additional Vaccines
Measles, Mumps, and Rubella (MMR)
- All PLWH without evidence of immunity and with CD4 cell counts >200 cells/mm 3 should be considered for measles and/or mumps and/or rubella vaccination (given as a two-dose series of MMR vaccine). (B)
# Varicella
- All PLWH without evidence of immunity and with CD4 cell counts >200 cells/mm 3 may be considered for varicella vaccination (given as a two-dose series of varicella vaccine given >3 months apart). (D)
Herpes Zoster
# Hypogonadism
- Cisgender men living with HIV presenting with symptoms of hypogonadism should be assessed with a morning serum total testosterone level; an abnormal testosterone level should be confirmed with repeat testing. (B) An estimated bioavailable testosterone measurement may be helpful to assess certain individuals, including obese cisgender men with borderline low total testosterone levels. (B)
- Testosterone replacement is indicated only for symptomatic cisgender men with total testosterone levels less than 10 mmol/L (B) and should be prescribed in consultation with a specialist. (D)
- Endocrine therapy for transgender individuals living with HIV should be provided in consultation with an endocrinologist or other clinician who has experience providing endocrine care to transgender individuals. (D)
# Neurocognitive Impairment
- ART to suppress plasma viral load should be started early and administered continuously to prevent or minimize HIV-related neurocognitive impairment. (B)
- In PLWH presenting with cognitive complaints that affect their daily functioning, an investigation should be done to rule out relevant underlying conditions. (B)
# Lung Disease
- Smoking cessation should be strongly encouraged in all PLWH because they are at a higher risk for chronic obstructive pulmonary disease (COPD) and lung cancer than smokers who do not have HIV. (A)
- A chest X-ray should be performed at baseline in all PLWH. (D) Once infection has been treated or ruled out, patients with persistently abnormal chest X-ray findings should be investigated and referred to a respiratory specialist if necessary. (D)
# Mental Health
- Mental health should be proactively assessed during clinic visits, and identified conditions should be managed using a stepped-care approach. (D)
# BACKGROUND
# INTRODUCTION
Today, HIV infection is a chronic manageable medical condition. Early diagnosis and initiation of potent antiretroviral therapy (ART) has dramatically improved the management of HIV infection and has led to substantial reductions in HIV-related morbidity and mortality.(1, 2) A study from 2013 estimated that a 20-year-old living with HIV and receiving ART in the U.S. or Canada could expect to live into their early 70s, a life expectancy approaching that of the general population.(3) In addition, there is now clear evidence that the widespread use of ART prevents HIV transmission at the individual (4-6) and population level. (7)(8)(9) In order for ART to be effective, individuals must be fully engaged in care, from the initial assessment following diagnosis, in order to receive timely initiation of ART and achieve long-term retention in care and virologic suppression. This concept, known as the HIV Cascade (or Continuum) of Care (10) has been adopted as the framework for assessing progress in HIV care and treatment in BC (Figure 2.1) and more generally as the 90-90-90 targets promoted by UNAIDS. (11) As of the end of 2018, an estimated 92% of people living with HIV (PLWH) in BC were diagnosed, 91% of those diagnosed were receiving ART, and of those on ART, 94% had a measured HIV viral load <200 copies/mL. (12) Providing appropriate and accessible primary care services is key to helping PLWH to remain fully engaged in HIV care and treatment.
# MODES OF HIV TRANSMISSION
The key modes of HIV transmission -sexual contact, perinatal transmission, and exposure to infected blood (e.g. through sharing of injection drug paraphernalia or receipt of contaminated blood products) -were clarified early in the AIDS epidemic. In untreated PLWH, HIV is present in significant concentrations in blood, semen, vaginal and rectal fluids, breast milk, and other body fluids contaminated with blood. However, the likelihood of HIV transmission by different routes of exposure varies markedly, as shown in
# NATURAL HISTORY OF HIV/AIDS
The mean time from HIV exposure to onset of acute seroconversion illness is generally 2-4 weeks, with a range of 5-29 days (19), and only an estimated 34% of PLWH will experience symptomatic seroconversion illness (see Appendix 1, page 112: Signs and symptoms associated with HIV Seroconversion Syndrome/ Acute Retroviral Syndrome and their frequency in symptomatic individuals). (20) During seroconversion without ART, there is an initial drop in CD4 cell counts and peak of viremia before CD4 cell counts increase (although to levels typically below pre-infection levels) and viral load decreases and stabilizes at a set point for several years (Figure 2.2). Without ART, there is considerable variability in the time of onset of further symptoms and late-stage disease. People whose CD4 cell counts stabilize above 500 cells/mm 3 may remain healthy for several years before CD4 cell counts begin to decline. In some cases, CD4 cell counts can drop rapidly after infection in the absence of ART; however, the usual scenario is that without treatment, CD4 cell counts decline over approximately 5-8 years until symptoms begin to appear. A small proportion of PLWH (5-10%), called "long-term non-progressors, " will maintain low viral load and stable CD4 cell counts for decades without specific treatment.( 21 However, timely initiation of ART will effectively prevent disease progression. In previous eras, HIV treatment was often deferred until PLWH demonstrated some degree of disease progression; however, there is now clear evidence that treating PLWH immediately after diagnosis provides substantial clinical benefits and this should be emphasized at all clinical encounters. Evidence:
# HIV TESTING
Newly diagnosed individuals should be assessed by a primary care physician or nurse practitioner (NP) within a few days of receiving a positive HIV test result (ideally less than 2 weeks) so that the baseline laboratory workup can be ordered and the individual can receive appropriate counselling and rapid initiation of antiretroviral treatment (ART
# INITIAL ASSESSMENT
Clinicians should obtain a comprehensive present and past medical history, including HIV-related information, assessment of present medications, family history and psychosocial issues and review of systems. A complete physical examination should be performed upon the patient's entry into care or as soon afterwards as possible. In the setting of rapid ART initiation, clinicians may abbreviate the initial assessment and conduct a more targeted exam. A more comprehensive assessment should be done in follow-up.
Important elements of the initial assessment are included in In the course of taking a medical history, health care providers should also assess the individual's understanding of HIV disease (including risk for HIV transmission), explore their understanding of and readiness to initiate ART, note potential barriers to treatment adherence, and identify their psychosocial needs. The baseline evaluation should also include a discussion of risk reduction and disclosure to sexual and/or needle-sharing partners, especially with individuals who are not receiving HIV treatment and are still at high risk of HIV transmission (see Section 3.4).
# PHYSICAL EXAMINATION
Clinicians should perform a comprehensive physical examination at baseline and when appropriate, with particular attention to systems potentially affected by HIV (see Table 3
# BASELINE LABORATORY EVALUATION
Two main surrogate markers are used to monitor the disease progression in PLWH: CD4 cell count to assess immune function and plasma HIV RNA (viral load) to assess level of HIV viremia.
The absolute CD4 cell count is a significant clinical indicator of immunocompetence in PLWH.( 9) It is a calculated value based on the total white blood cell (WBC) count and the percentages of total and CD4 T-lymphocytes. (10) This absolute number may fluctuate in individuals or may be influenced by factors that affect the total WBC count and lymphocyte percentages, such as the use of bone marrow-suppressive medications or the presence of acute infections. Splenectomy or co-infection with human T-lymphotropic virus type 1 (HTLV-I) may cause misleadingly elevated CD4 cell counts. These markers are used to stage HIV disease initially and are subsequently used as predictors of disease progression and survival.(11) CD4 cell counts are also used to determine the risk of opportunistic infections (OIs), the need for prophylaxis for OIs or other AIDS-defining illnesses, and when to stop prophylaxis. (12,13) HIV plasma viral load (HIV pVL) is the most important indicator of infectivity and response to ART and should be measured in all PLWH at initial assessment, at initiation of therapy and on a regular basis thereafter.(12) A patient's baseline viral load level and the magnitude of viral load decline after initiation of ART provide prognostic information about the probability of disease progression.( 14) Commercially available HIV-1 RNA assays do not detect HIV-2 viral load (for more information regarding HIV-2 refer to the HIV-2 infection chapter in the United States Department of Health and Human Services (DHHS) guidelines; . hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf). (15) All patients should be assessed for transmitted HIV drug resistance using genotypic drug resistance testing, regardless of the estimated duration of HIV infection. Ideally, drug resistance testing should be conducted on the first available sample of HIV plasma viral load. A resistance test should be done in individuals who reengage in care and are not currently receiving ART, recognizing that the absence of resistance mutations due to lack of selective pressure may not accurately reflect drug activity.(15) Standard genotypic drug resistance testing in ART-naïve persons involves testing for mutations in the reverse transcriptase and protease genes. Although reports of transmission of virus resistant to integrase strand transfer inhibitors (INSTIs) are rare, clinicians are increasingly prescribing this class of antiretrovirals and there is potential for the transmission of INSTI-resistant virus. (16)(17)(18)(19) In BC, when HIV resistance testing is requested for a patient whose plasma viral load exceeds 250 copies/mL for the first time since diagnosis, the sample automatically undergoes testing for resistance to the INSTI class. (11) In BC, resistance testing can be requested in archived viral load samples. For more information regarding drug resistance testing, refer to the Laboratory Program tab on the BC-CfE website (/ laboratory-test-order-forms).
HLA-B*5701 is not a specific HIV test, but rather a genetic test. Screening for HLA-B*5701 identifies persons at a high risk for hypersensitivity reaction (HSR) to the antiretroviral agent abacavir. Screening should be performed prior to starting any patient on an abacavir-containing regimen (including fixed-dose combinations, e.g. Kivexa, Triumeq®). HSRs, including fatalities, have been documented in individuals re-challenged with abacavir after a suspected HSR. In addition, screening for HLA-B*5701 should be performed, if not done previously, for patients who are re-initiating abacavir following a gap in therapy, even if they had previously tolerated the drug, because there is a potential for HSR in this setting. (20,21) Hematological panel (CBC with differential and platelet count) should be done at baseline since anemia, leukopenia and thrombocytopenia are common in people with untreated HIV infection. A comprehensive chemistry panel (including creatinine, eGFR, serum phosphorus, urinalysis, urine albumin to creatine ratio (UACR), albumin, total bilirubin, aspartate transaminase, and alanine transaminase) is important to assess baseline renal and hepatic function and pre-existing conditions. Screening for diabetes mellitus with fasting glucose and/or hemoglobin A1C is recommended due to the increased incidence of diabetes in this population. A lipid profile should be done upon initial assessment when possible, since many ART drugs, HIV infection itself, and other host factors can increase cholesterol and triglyceride levels.
A chest radiography should be done at baseline to rule out underlying lung disease and for use as a baseline comparison in future evaluations of any respiratory illness, particularly in persons from high TB prevalence populations (see Table 3.
All individuals should receive baseline screening for a variety of other infectious agents, including other sexually transmitted infections and hepatitis A, B, and C virus, to assess the need for treatment, immunization, monitoring, and counselling (see Section 4). Rates of sexually transmitted infections have increased significantly in men who have sex with men, and screening at baseline for gonorrhea and chlamydia in urine and other sites of contact (oral and anal) are recommended. Furthermore, all PLWH should receive a syphilis test at baseline.
# COUNSELLING PLWH REGARDING HIV TRANSMISSION RISK
Recommendation:
- PLWH should be advised of the risk of onward transmission, practices to prevent transmission, especially the effectiveness of HIV treatment in preventing transmission, and the legal implications of HIV non-disclosure with their sexual partners.
# Evidence:
Safer sex and substance use practices to prevent onward transmission of HIV should be discussed with PLWH, and are especially important while the plasma HIV viral load is high (e.g. prior to starting ART and during the first few weeks of therapy or when there is treatment interruption). It has now been clearly demonstrated that even after repeated sexual exposures without using condoms, PLWH who are adherent to ART and have HIV plasma viral load <200 copies/mL do not transmit HIV via sexual contact. This principle of "undetectable = untransmittable" or "U=U" has been shown for both heterosexual couples and men who have sex with men.(24-28) However, the Supreme Court of Canada (2012) ruled that there is an obligation to disclose HIV-positive status in relation to vaginal or anal sex unless both of the following conditions are met: a condom is used and the PLWH has "low" viral load (<1500 copies/mL). Under these circumstances, the Supreme Court of Canada holds that there is no realistic possibility of transmission. If PLWH were to engage in sexual activity that is considered to have a "realistic possibility of HIV transmission" without first disclosing their HIV status, they can be subject to criminal prosecution (most often aggravated sexual assault). (29,30) PLWH should be advised of the legal implications of HIV non-disclosure. Further information for PLWH is available from:
# SCREENING AND IMMUNIZATION FOR SELEC TED CO-MORBID INFEC TIONS 4.1 SCREENING FOR CO-MORBID INFECTIONS
Tuberculosis Screening Recommendations:
- All PLWH should be screened at baseline for Mycobacterium (M.) tuberculosis (TB) infection.
(A) Screening involves reviewing history of TB exposure and/or treatment history and previous tuberculin skin test (TST) and/or interferon gamma release assay (IGRA) results. (B) A chest X-ray should be undertaken if there is history of TB exposure or positive screening test. (B)
- In BC, the TST using 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) is the main test for diagnosing latent TB infection (LTBI), provided there are no contraindications. (B) The tuberculin skin test (TST), consisting of the intradermal injection of a small amount of purified protein derived from M. tuberculosis bacteria, is the standard screening test for TB. In a person who has cell-mediated immunity to these tuberculin antigens, a cell-mediated, delayed hypersensitivity reaction will occur within 48-72 hours. The reaction will cause localized swelling and will manifest as induration of the skin at the injection site. Induration of ≥5 mm is considered significant in PLWH.(1) TST remains the standard method of diagnosing LTBI(1) in Canada, although it is recognized that TST has certain limitations. The sensitivity of the TST decreases in parallel with an individual's CD4 cell count. The TST has particularly low sensitivity in people with CD4 <200 cells/mm 3 Positive TST results should be followed by treatment for LTBI, once active TB disease is ruled out, through referral to provincial TB Services offered by the BCCDC.
# Toxoplasmosis Screening
Recommendation:
- All PLWH should be screened at baseline for Toxoplasma IgG antibodies to determine prior exposure to Toxoplasma (T.) gondii. (D)
# Evidence:
Seroprevalence of T. gondii in North American adults is approximately 10-20%. Toxoplasma encephalitis (TE) is the most frequent clinical manifestation of central nervous system (CNS) disease in PLWH. (15) The serologic test for Toxoplasma cannot be used to diagnose or reliably exclude toxoplasmosis in PLWH. (12) Positive serology identifies individuals at a greater risk of disease. Peripheral blood serology is positive for Toxoplasma IgG (but negative for IgM) in the vast majority of patients with AIDS-related TE. However, in one study from San Francisco, 16% of those presenting with AIDS-related TE had negative serum serology for IgG by immunofluorescence.(15) Among T. gondii-infected (i.e. Toxoplasma IgG antibody positive) adult PLWH not receiving prophylaxis and with CD4 cell counts <100 cells/mm 3 , the probability of developing clinical toxoplasmosis is approximately 38%.( 12)
# Hepatitis Screening
Recommendations:
- PLWH should be screened at baseline for hepatitis A virus (HAV) using total anti-HAV antibodies. (B) HIV and hepatitis B virus (HBV) share routes of transmission, including percutaneous (principally among people who inject drugs ), sexual (anal, vaginal, and oral) and vertical transmission. (16) The reported prevalence of HIV-HBV co-infection is between 6-10%, with higher rates observed in PWID, MSM, and individuals from endemic areas.(20) HIV-HBV co-infection is associated with an eight-fold increase in risk of mortality compared to HBV mono-infection.( 21) Therefore, traditional HBV markers, such as HBsAg (surface antigen), anti-HBs (surface antibodies), and anti-HBc (core antibodies), will assist in distinguishing individuals who are chronically infected from those who have developed a natural or acquired immune response or those susceptible to HBV infection (thus, in need of receiving immunization).
Assessment for liver disease from chronic HBV infection and screening for hepatocellular carcinoma should follow standard Canadian guidelines.( 22) However, all PLWH with chronic HBV infection should be offered ART including tenofovir disoproxil fumarate (DF) or tenofovir alafenamide (AF) in combination with emtricitabine in order to control HBV viral replication.
In Canada, the prevalence of HIV-hepatitis C (HCV) co-infection ranges from 20% to almost 90% in certain subgroups.( 23) HCV is highly prevalent among PWID; a review of international studies suggests that between 50-95% of PWID are infected with HCV. (24) Canadian studies report HCV rates as high as 82% among PWID. (25,26) If left untreated, HCV infection becomes chronic in up to 85% of co-infected individuals, potentially leading to progressive fibrosis and ultimately cirrhosis and death.(24) A metaanalysis of seventeen studies concluded that the rate of progression to hepatic fibrosis among individuals co-infected with HIV-HCV appears constant across all stages of fibrosis, and that chronic HCV outcomes are worse among co-infected individuals. Over the period studied, ART did not appear to fully reverse the adverse effect of HIV infection on HCV disease prognosis. (27) The probability of survival is also reduced among HIV-HCV co-infected individuals compared to those who are HIV mono-infected.( 28
# Screening for Syphilis and other Sexually Transmitted Infections (STIs)
Recommendations:
- All PLWH should be screened for syphilis at baseline with Treponema pallidum-specific enzyme immunoassay (EIA). (B) Syphilis screening should be repeated annually, or every 3-6 months in the presence of ongoing risk behaviours, or in the presence of symptoms. (D)
- A lumbar puncture should always be performed for patients with a reactive syphilis serology who have neurologic or ocular symptoms or signs, irrespective of past syphilis treatment history. (D)
- All PLWH should be screened at baseline for gonorrhea and chlamydia. (B) Screening should occur every 3-6 months in the presence of ongoing risk behaviours or in the presence of symptoms. (D)
# Evidence:
In North America, sexual transmission is the predominant route for acquiring HIV. This has prompted the recommendation to screen all PLWH for asymptomatic sexually transmitted infections (STIs). A cohort study reported a baseline STI prevalence of 14% among PLWH (n=212, 95% confidence interval 9%-19%) and the incidence of new infections was 20.8 cases per 100 person-years (95% CI 14.8-28.4).( 31)
The prevalence of STIs in British Columbia is increasing. The provincial prevalence of infectious syphilis, as elsewhere in North America, has increased over the past fifteen years. With the exception of a short period of decline in 2009-2010, infectious syphilis rates have increased steadily to 14. A lumbar puncture should always be performed for patients with a reactive syphilis serology who have neurologic or ocular symptoms or signs, irrespective of past syphilis treatment history. In asymptomatic patients, a lumbar puncture may be considered for those patients with an RPR titre of > 1:32 or a CD4 of < 350 cell/mm 3 , which are laboratory criteria that improve the ability to identify asymptomatic neurosyphilis.(34) However, studies defining the clinical outcomes associated with a broader versus more narrow utilization of lumbar puncture in asymptomatic PLWH with syphilis have not been conducted.
For gonorrhea and chlamydia, a Nucleic Acid Amplification Test (NAAT) should be conducted at baseline in all PLWH using first-catch urine specimen and site-specific testing as indicated (oropharyngeal and rectal swabs) for MSM and others with potential sexual exposure at these sites. The validated multisite APTIMA swab is recommended for use (as opposed to the urethral/cervical swab). In PLWH who have a cervix, a cervical swab could be taken. Although not validated, vaginal swabs can be used for screening in transfeminine individuals who are post-operative (i.e. after gender-affirming surgery). In cases of possible sexual assault, pharyngeal, anal, and/or vaginal swabs should be taken. (35) Prevalent and incident asymptomatic STIs are common among MSM living with HIV, and thus increasing the frequency of screening to every 3-6 months is warranted for those with ongoing risk for infection (i.e. ongoing sexual activity with casual or multiple partners).
# IMMUNIZATIONS AND HIV
Prevention of intercurrent illness is a crucial aspect of HIV care. (29,36) The use of vaccines provides an opportunity to prevent infectious diseases in PLWH, who are more susceptible to these diseases. (17) Immunosuppression can reduce the effectiveness of vaccines and increase the risks associated with live vaccines. (17,19,37) CD4 cell counts are an important measure that can be used to help optimize the timing of immunizations and predict patient response to vaccines -in general, if a PLWH has a CD4 cell count ≥200 cells/mm 3 they will have a better response to vaccination.
General principles that primary care providers can follow for PLWH are shown below (adapted from the BCCDC Immunization Guide and the Canadian Immunization Guide)(17):
- Immunize at the time when maximum immune response can be anticipated (i.e. early in the course of HIV disease or following CD4 recovery with antiretroviral therapy).
- It is safer, and likely more effective, to immunize when CD4 cell counts are >200 cells/mm 3 .
- Use caution in the use of live vaccines based on CD4 cell counts.
- Use of the measles, mumps, and rubella (MMR) and varicella vaccines in those with CD4 <200 cells/mm 3 is not recommended.
- There is no contraindication to the use of inactivated or component vaccines at any CD4 level.
# RECOMMENDED VACCINES
# Hepatitis A
Recommendations:
- All PLWH who are susceptible (anti-hepatitis A negative) should be vaccinated against HAV, ideally when CD4 >200 cells/mm 3 . (B)
- The HAV vaccine should be administered intramuscularly at the standard dose, at 0, 1, and 6 months. (B)
# Evidence:
Serologic response rates of all HAV vaccines are between 95-100% amongst HIV-negative individuals.(17) Seroconversion rates are lower among PLWH for many vaccines and HAV seroconversion is no exception, with rates ranging from 48-64% (depending on the timing of measurement of serological response). (38,39) A meta-analysis reported an overall response rate of 64% for PLWH.(40) A three-dose regimen (at 0, 1, 6 months) has been shown to have better results than a two-dose regimen (at 0 and 6 months) among PLWH, with one comparative study reporting seroconversion rates of 78% and 61%, respectively.(41) The standard HAV vaccination doses are 1.0 mL intramuscularly (IM).( 37)
# Hepatitis B
Recommendations:
- All PLWH who are susceptible to hepatitis B virus (HBV) infection (HBsAg negative and anti-HBs less than 10 IU/mL) should be vaccinated against HBV, ideally when CD4 >200 cells/ mm 3 . (B)
- HBV vaccination should also be offered to PLWH who have positive hepatitis B total core antibody (anti-HBc) with negative HBsAg and anti-HBs results (titre less than 10 IU/mL) and undetectable HBV DNA. (D)
- In the situations described above, HBV vaccine should be administered intramuscularly (IM) to PLWH 20 years of age and older at a higher dose (40 mcg).
# Evidence:
The overall seroconversion rate (defined as Anti-HBs >10 mIU/mL) to standard HBV vaccine dosing (10 mcg of Recombivax HB® or 20 mcg of Engerix®-B IM ) following a 0, 1, and 6 month dosing regimen appears to be on the order of 26-65%. (17,(42)(43)(44) The etiology of poor seroconversion rates in PLWH is multi-factorial and not completely elucidated. Contributing factors may include age, sex, race, CD4 cell count (both nadir and at time of vaccination), HIV viral load, treatment with antiretrovirals, smoking and alcohol abuse. The benefit of using higher doses of HBV vaccine in immunocompromised individuals is now well-established, both in HIV and in other immunodeficiency states. (42,45,46) In particular, higher HBV seroconversion rates are reported in PLWH on antiretroviral therapy (ART) with low HIV plasma viral load and high CD4 cell counts. The low seroconversion rate is an indication to conduct post-vaccination testing (HBsAg and anti-HBs) on one occasion, between 1 and 6 months after the completion of the initial vaccination series. (47) PLWH with isolated antibody to hepatitis B core antigen (HBsAg negative and surface antibody titre 10 IU/mL has been documented, no further testing or vaccination is required, even if a later measurement is found to be <10 IU/mL.
Vaccine non-responders following the first series should receive a complete second series of three doses.
If they fail to respond to a second series, they should be recorded as susceptible and receive hepatitis B immune globulin (HBIg) following a high risk hepatitis B exposure.( 49)
# Pneumococcal Disease
Recommendations:
- All PLWH should be vaccinated against pneumococcal disease using standard vaccine doses (A), regardless of CD4 cell counts and according to the following schedules: While one study comparing Pneu-C-7 to Pneu-P-23 found that the conjugated vaccine elicited better serologic response,( 66) other studies have looked into possible synergistic effect of a dual vaccination regimen that incorporates both the conjugate and the polysaccharide vaccines, with the conjugate vaccine used first as an immune primer. (67)(68)(69)(70)(71) In addition, the sequence of vaccination is important, as initial receipt of Pneu-P-23 followed by conjugate vaccine results in lower antibody levels than initial vaccination with the conjugate vaccine.( 72) PLWH who receive the polysaccharide vaccine first should have delayed administration of the conjugate vaccine at least 12 months later. The National Advisory Committee on Immunization (NACI) concluded that there is good evidence to recommend the use of Pneu-C-13 for PLWH, given the efficacy and immunogenicity of Pneu-C-7.(73) The Pneu-C-13 vaccination dose is 0.5 mL IM and the Pneu-P-23 vaccination dose is 0.5 mL (subcutaneously or IM), although SC administration is associated with more discomfort at the injection site.(37)
# Influenza
Recommendation:
- All PLWH should be vaccinated annually against influenza using standard doses of the inactivated vaccine, regardless of CD4 cell counts or HIV plasma viral load. (B)
# Evidence:
Caused by influenza A and B viruses, influenza occurs in Canada every year, generally during late fall and the winter months. Influenza A viruses are the most common cause of annual influenza epidemics. (17) The annual incidence of influenza varies widely, depending on the virulence of circulating strains and the susceptibility of the population, which is affected by antigenic changes in the virus, vaccine match, and vaccine coverage.(17) PLWH form part of the group at the greatest risk of serious infections, complications, hospitalizations, and/or death from influenza. (17,74) In PLWH, influenza vaccine reduces the incidence of respiratory illnesses from 49% to 29% and of laboratory-confirmed influenza from 21% to 0%. (75) As is the case with other vaccines, influenza vaccine efficacy is impaired in PLWH. One study estimated that vaccine efficacy decreased from 65% in PLWH with CD4 cell counts >100 cells/mm 3 to 11% in those with lower CD4 cell counts.(76) However, the benefits of the influenza vaccine in preventing severe illness and hospital/intensive care unit admissions prompted the US Centers for Disease Control (CDC) to recommend the use of the vaccine in PLWH, regardless of CD4 cell counts or HIV plasma viral load. (77) A single annual IM dose of 0.5 mL is currently recommended. (17,37) There is no indication for pre-or post-immunization serology testing.(17) Inactivated influenza vaccine is recommended and live attenuated intranasal vaccine should not be used in this population. (19,29,37,78) Influenza vaccines publicly funded in British Columbia vary year to year. For details of which vaccines are being used in any given season, refer to the BCCDC's Immunization Manual ().( 79)
# Tetanus and Diphtheria
Recommendation:
- All PLWH should be offered a tetanus and diphtheria (Td) toxoid booster every 10 years, ideally when CD4 >200 cells/mm 3 . (D)
# Evidence:
The recommendation above is based on the assumption that the diphtheria vaccine is being offered to an adult who has completed a primary series of childhood vaccinations. Routine immunization against diphtheria in infancy and childhood is a common practice throughout the world and has contributed to a significant decline in morbidity and mortality from this disease.(80) Serosurveys of healthy adult populations in Canada indicate that approximately 20% of those surveyed (higher in some age groups) do not have protective levels of antibody to diphtheria. Thus, the potential for re-emergence of this disease exists.( 81)
The immunity conferred by diphtheria vaccine is antitoxic, not antibacterial. Vaccination thus protects against the systemic effects of diphtheria toxin but not directly against local infection.(81) After the primary vaccination series in immunocompetent individuals, over 99% develop antibody levels that are considered protective against disease. (80) The antitoxin is believed to persist at protective levels for 10 years or more. Titres decline slowly with time but are boosted by additional vaccine doses. (80) Tetanus is rare in Canada. However, serosurveys suggest that a substantial proportion of Canadians have non-protective tetanus antitoxin levels. Factors associated with lack of immunity to tetanus include increasing age, birth outside Canada, and absence of immunization records. (81) The antibody response to tetanus boosters given to adults living with HIV or other humoral immune deficiencies is suboptimal.(80)
# Human Papillomavirus (HPV)
Recommendation:
- HPV-9 vaccine is recommended for all PLWH aged 9-27 years (A) and should be strongly considered in women and MSM aged 27 years and older. (B) A three-dose series is recommended in adults.
# Evidence:
Human papillomavirus (HPV) is a sexually transmitted pathogen that causes ano-genital disease in all sexes. HIV-mediated immune suppression appears to facilitate HPV persistence and its oncogenic potential. In part, this appears to be due to direct enhancement of HPV integration in the presence of HIV.( 82)
In an international study, 77% of women living with HIV (WLWH) had HPV detected at least once (incident infection). HPV 16 was the most frequent genotype, with mixed infection seen in 26%.( 83
# ADDITIONAL VACCINES
Note: This guideline does not provide an exhaustive list of vaccines available to PLWH, including travel vaccines or additional vaccines that may be appropriate in specific circumstances. Please see NACI guidelines for further information regarding additional vaccines for PLWH: . canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html#a29
# Measles, Mumps and Rubella (MMR)
Recommendation:
- All PLWH without evidence of immunity and with CD4 cell counts >200 cells/mm 3 should be considered for measles and/or mumps and/or rubella vaccination (given as a two-dose series of MMR vaccine). (B)
# Evidence:
In general, live-virus vaccines should not be used among PLWH. In severely immunocompromised populations, measles can present critically and in a prolonged fashion, with a high risk for severe complications.(92-95) Measles, Mumps, Rubella (MMR) vaccination in PLWH with CD4 cell counts >200 cells/mm 3 appears to be safe with no serious adverse events reported.(96-98) Thus, all PLWH without severe immunosuppression (i.e. with CD4 cell count >200 cells/mm 3 ) and no evidence of immunity to measles, mumps, or rubella should be considered for the MMR vaccine.(29, 99) Evidence of immunity includes being born before 1970 or having previously received two doses of measles-or mumps-containing vaccine. All PLWH born before 1957 or who have previously received one dose of rubella-containing vaccine, have serologic proof of immunity, or have had prior lab confirmed rubella disease, are considered to have immunity against rubella. Thus, serological testing may be indicated to confirm the diagnosis of measles, mumps, or rubella or to determine immune status. Serologic testing is not recommended before or after receiving measles-, mumps-or rubella-containing vaccine. If serology is inadvertently done subsequent to appropriate MMR immunization and does not demonstrate immunity, re-immunization is not necessary.(100)
# Varicella
Recommendation:
- All PLWH without evidence of immunity and with CD4 cell counts >200 cells/mm 3 may be considered for varicella vaccination (given as a two-dose series of varicella vaccine given >3 months apart). (D)
# Evidence:
At the time of publication of these guidelines, there were no published data on varicella vaccination among susceptible PLWH. However, based on expert opinion, varicella vaccine may be safe to offer to susceptible individuals with CD4 counts >200 cells/mm 3 . Live attenuated varicella vaccine remains contraindicated in PLWH with CD4 counts 3 months apart.
A varicella susceptible person is defined as someone who does not have a history of varicella or herpes zoster after 12 months of age and who does not have a history of age-appropriate varicella immunization.
A self-reported history of varicella is adequate for those born before 2004; for those born in 2004 and later, history of a diagnosis by a health care provider is required for reliability. Children who have a history of either physician-diagnosed herpes zoster or lab-confirmed varicella after their first dose of vaccine do not require a second dose. If disease history is uncertain, provide a second dose.( 101)
# Herpes Zoster
Recommendation:
- The use of inactivated herpes zoster vaccine for prevention of shingles in PLWH over age 50 can now be considered. (D) Dosage and schedule: 0.5mL IM at 0 and 2-6 months. No requirement for repeat dosing currently exists. (D)
# Evidence:
Herpes zoster, commonly known as shingles, is a cutaneous manifestation of the reactivation of the varicella zoster virus (VZV), which causes chickenpox. Manifestations increase after age 50 in the general population and include complications such as post-herpetic neuralgia.
# COVID-19
Recommendation:
# Evidence:
PLWH aged 18 years or older should be vaccinated for COVID-19 if they have no contraindications (see below). These vaccines are not expected to be associated with more serious or different adverse events among PLWH or other immunocompromised individuals. While the evidence is mixed, PLWH may be at increased risk of serious illness due to COVID-19, and in the absence of contraindications should receive any of the COVID-19 vaccines currently approved in Canada as appropriate for their age group, regardless of CD4 count (i.e.: Pfizer-BioNTech, Moderna, AstraZeneca, and Janssen vaccines).
PLWH who have CD4 counts <200 cells/mm 3 or are not virologically suppressed should be counselled regarding the unknown efficacy and safety of the vaccines given that such subjects were not included in the vaccine licensing studies. For more information, visit the BC-CfE Committee for Drug Evaluation and Therapy (CDET) statement on the use of COVID-19 mRNA vaccines in PLWH: / therapeutic-guidelines/healthcare-providers/therapeutic-guidelines/bc-centre-excellence-hivaids-cdetcommittee-statement.
# CONTRAINDICATED VACCINES
Recommendation:
- The following live vaccines are contraindicated in PLWH: oral polio, live intranasal influenza vaccine, and BCG (Bacillus Calmette-Guérin). (B)
# Evidence:
For PLWH, additional live vaccines (often used in the context of foreign travel) are either contraindicated or should be used with caution in circumstances where the benefits of a live vaccination are likely to outweigh the risks. Primary care providers may wish to consult with a physician with expertise in HIV or immunization about offering such vaccines to PLWH.(106)
# SPECIAL CONSIDERATIONS FOR CISGENDER WOMEN- LIVING WITH HIV (WLWH)
Note: Guidelines and resources specific to pregnancy and post-partum care, and infant care can be found on the Oak Tree Clinic/BC Women's Hospital and Health Centre website: / health-professionals/professional-resources/hiv-aids-resources.
# INTRODUCTION
In Canada in 2018, 29% of newly diagnosed HIV cases were in women,( 1) and among the estimated 63,110 people living with HIV (PLWH) in Canada in 2016, 23 % were women. (2) The majority of women living with HIV (WLWH) acquired the disease via heterosexual contact (64%). This holds true for women born in Canada or other non-endemic countries, as well as immigrants from HIV-endemic countries. Injection drug use is the second most common means of transmission for women (28%).( 3) In BC, the proportion of women affected by HIV is smaller than for the country as a whole: 8% of British Columbians newly diagnosed with HIV in 2017 were women.(4) Similar to national trends, heterosexual contact is the most common route of HIV transmission for women in BC, followed by injection drug use.
Frequently, women are caretakers for children/partners/parents and extended family members/ friends, and they may not give sufficient priority to their own medical/psychosocial care and wellbeing. Furthermore, women frequently face unequal power and socioeconomic relationships with their partners. These social factors may increase women's isolation and depression and compromise their adherence to medical care and their antiretroviral therapy (ART). Continued gender inequities with regard to the social determinants of health, particularly poverty and unstable housing, are significant factors disproportionately impacting women and their ability to participate in HIV care. Women who are Indigenous or from other racialized groups and sex workers are especially vulnerable due to multiple intersecting barriers. WLWH in Canada have very high rates of trauma and post-traumatic stress.(5) Many women are affected by multiple forms of trauma, including adverse childhood events, intergenerational trauma, historical trauma, institutional trauma, and stigma. Refugee women have commonly experienced severe trauma related to armed conflict in their country of origin and sexual assault. Based on data from the Canadian HIV Women's Sexual & Reproductive Health Cohort Study (CHIWOS) study, which included more than 1440 WLWH from three Canadian provinces, more than 79% of WLWH reported experiencing violence in adulthood -four times higher than the prevalence among the general population of women in Canada.(6, 7)
Since trauma is recognized as a root cause of multiple health challenges and is an important social determinant of health, in order to be successful in the care of WLWH, clinicians should address at each HIV visit the social determinants of health, including the person's current personal safety and food and - In this chapter, the term women refers to any persons whose gender identity or expression (i.e. woman) coincides with their sex assigned at birth (i.e. female), also referred to as cisgender women. For a discussion of terms used to describe persons whose gender identity or expression do not coincide with their sex assigned at birth, see the footnote on page 75.
housing security, using a trauma informed care model (/).( 8)
A useful Canadian resource for women-centred HIV care is available at: /.
It should be noted that not all individuals with a cervix or with pregnancy potential self-identify as women, and not all individuals who self-identify as women have a cervix or have childbearing potential.
For this reason, all recommendations are written using gender inclusive language.
It is important for clinicians to provide trauma-informed care and communicate clearly and respectfully with PLWH, to ensure that they receive care that is appropriate to their needs and life circumstances without judgment, assumptions, or unwanted disclosure with respect to their life, gender, and sexuality. This includes respecting the gender identity and expression of individuals (e.g. using their preferred pronoun and name in conversations and in emails and letters from the clinic addressed to the patient), and creating a safe, non-judgmental space for the person to discuss issues related to their sexual, reproductive, and general health. Cultivating this cultural safety for all, including transgender and non-binary individuals, is also an important part of trauma-informed care.
# SPECIAL CONSIDERATIONS RELATED TO ART DURING PREGNANCY AND THE POST-PARTUM PERIOD
Recommendations:
- All pregnant PLWH should be treated with ART for their HIV infection, regardless of their immunologic or virologic status, to prevent infection of their fetus. (A)
- Clinicians should review the latest recommendations regarding ART for individuals who are pregnant or of childbearing potential, since some drugs may be contraindicated or should be used with the guidance of specialized care providers. (D)
# Evidence:
The indications for and goals of ART are the same for all PLWH. Pregnancy plans and wishes should be discussed with all PLWH in reproductive age potential, in each HIV visit. If pregnancy is desired, preconception counselling should be offered, including education around the importance of attaining maximal and sustained viral suppression before attempting conception and maintaining it throughout pregnancy and delivery, for the health of the pregnant person, to prevent sexual HIV transmission to partners without HIV, and to minimize the risk of HIV transmission to the infant. ART regimen selection preconception and during pregnancy should be made in accordance with current BC Guidelines for the Care of HIV Positive Pregnant Women (), and in consultation with providers who have expertise in this area.
When providing care for individuals planning pregnancy and any individuals of childbearing potential who are not using effective and consistent contraception, providers should carefully review all medications (antiretrovirals and concomitant medications) and avoid drugs with potential reproductive toxicity. The time of greatest developmental risk to the fetus is the first trimester, often before pregnancy is even recognized.
Like many other chronic conditions (e.g. diabetes), HIV can affect the medical management of pregnancy. Nausea and vomiting during early pregnancy can affect ART adherence. Therefore, pregnancy in PLWH is considered high risk and complex. Consultation with an obstetrician specialising in the management of HIV is recommended. In BC, preconception counselling, ARV regimen guidance, and specialized obstetrical services can be obtained from the Oak Tree Clinic in Vancouver: or 604-875-2212; a referral form is available on their website ().
Following delivery, clinical, immunologic, and virologic follow-up should continue as recommended for non-pregnant adults and adolescents. ART should be continued post-partum for the optimal health of the individual. Several studies have demonstrated that adherence to ART may worsen in the post-partum period.(9, 10) Clinicians caring for postpartum individuals should specifically address ART adherence, including an evaluation of specific facilitators and barriers to adherence.
Because use of ART during lactation reduces but does not eliminate the risk of transmission of HIV in breast milk, PLWH in BC should be counselled to avoid breastfeeding, where safe alternatives can be provided. (11) In BC, free formula is provided for all babies born to mothers living with HIV for one year, coordinated by the Oak Tree Clinic. PLWH should avoid pre-mastication of food fed to their infants because the practice has been associated with transmission of HIV from parent to child.(12)
# REPRODUCTIVE ISSUES AND GYNECOLOGIC HEALTH IN THE CONTEXT OF HIV
Recommendations:
- Contraception needs and pregnancy plans should be discussed with all individuals of childbearing potential (aged 15-50 years) upon initiation of HIV care and routinely thereafter, as pregnancy may affect the choice and timing of antiretrovirals. (D)
- Selection of a contraceptive method should take into account the PLWH's desires about family planning and preferred contraceptive method, ART regimen, other medications, and co-morbid conditions. (D) Intrauterine devices (IUDs) can be considered as a safe and effective contraception option for PLWH. (B)
- When prescribing ART, clinicians should take into account that some ARVs have significant pharmacokinetic (PK) interactions with hormonal contraceptives; other effective contraception options should be considered to prevent unplanned pregnancy. (B) Switching to an ARV drug that does not have interactions with hormonal contraceptives may also be considered. (B)
# Evidence:
The incidence and prevalence of gynecological problems are high among WLWH throughout the course of their HIV disease.( 13
# ART AND WEIGHT GAIN IN WOMEN
# Evidence:
Various studies have suggested that sex assigned at birth may influence the frequency, presentation, and severity of some ART-related adverse events, including metabolic complications.(31) Pharmacokinetics of antiretroviral drugs may differ between cisgender men and women, (32) due to factors such as body weight, plasma volume, hormones, gastric emptying time, plasma protein levels, cytochrome P (CYP) 450 activity, drug transporter function, and excretion activity. (33)(34)(35) Several studies indicate that cisgender women experience metabolic complications associated with ART use differently than cisgender men. WLWH are more likely to experience increases in central fat and are at a higher risk of developing particular patterns of lipodystrophy than men living with HIV. Initiation of ART often leads to weight gain. While some of this weight gain may be an appropriate "return-to-health" effect, excessive increases in weight may lead to obesity. Recent data suggest greater weight gain occurs on ART initiation among women than men, especially with the use of integrase strand transfer inhibitors and tenofovir alafenamide (AF). (44)(45)(46)(47) Other factors associated with greater weight gain on ART include black race and lower baseline CD4 cell count. (44,47) The mechanisms by which certain ARV agents differentially contribute to weight gain are unknown and under investigation. In addition to HIV-related effects (CD4 nadir, level of viral load), social/ environmental contributors, and genetic factors on weight gain, there may also be effects of newer, bettertolerated ARV agents, that better target the catabolic effects of HIV.
# MENOPAUSE
Recommendation:
- When systemic menopausal hormone therapy or non-hormonal medications are indicated for PLWH experiencing menopausal symptoms, potential drug interactions with ART should be considered. (B)
# Evidence:
An increasing number of WLWH are living past menopausal age. In Canada in 2018, 22.2% of cisgender women newly diagnosed with HIV were over 50 years of age.(1) Aging with HIV is an emerging field, and it is now expected that newly diagnosed individuals whose HIV is well controlled will have life expectancies similar to the general population.
In Canadian WLWH, the average age for the onset of menopause is 48 years, which is 3 years earlier than women in the general Canadian population. (48) Earlier menopause observed in PLWH may be multifactorial. (49) There are conflicting data on the effect of HIV on menopausal age and symptoms. (50) Factors that can influence menopausal symptoms, including smoking, stress, drug use, depression, low BMI, and race/ethnicity, are also relatively more prevalent among PLWH. Occasionally, symptoms of menopause may be difficult to distinguish from symptoms related to HIV, including fatigue, sleep disturbances, night sweats, achiness, and mental health effects. (50) Sexual practices in menopausal WLWH are not well described. It is important for health care providers to discuss safer sex practices with PLWH of all ages. However, providers need to take into consideration that there are significant power imbalances for many WLWH that may compromise their ability to have safe sex and expose them to potential intimate partner violence.
There are currently no randomized controlled trials delineating the use of menopausal hormone therapy (MHT) in PLWH. As in the general population, MHT can be considered within 5-10 years of starting menopause in PLWH with severe vasomotor symptoms if the individual is below the age of 60.
For those aged 60 years and over, the risk outweighs the benefits, and MHT is not recommended. (51,52) Contraindications for MHT include unexplained vaginal bleeding, severe liver disease, breast or endometrial cancer, congestive heart failure, stroke, dementia, high risk of venous thromboembolism, hypertriglyceridemia, and severe migraine headaches. In individuals with a uterus, the proliferative effects of systemic estrogen on the endometrium must be countered by an appropriate dose of progestogen, to lower risk of cancer, i.e. combination MHT containing two hormones (estrogen and progestogen). For MHT recommendations, see: .
There may be drug interactions of MHT with ART(53, 54) (see / uploads/2019/09/Hormonal-therapy_contraceptives-HRT_Eng.pdf). Levels of estradiol and progestogens may be increased by CYP3A4 inhibitors, especially cobicistat, potentially increasing MHT side effects and long-term thromboembolic risk. Ritonavir-boosted PIs and older non-nucleoside reverse transcriptase inhibitors (NNRTIs, such as efavirenz, etravirine, nevirapine) may change hormone levels, but the role of MHT dose adjustment has not been studied. Consultation with an HIV-experienced pharmacist, HIV gynecologist, or HIV specialist is recommended.
Hot flashes and night sweats related to menopause may also be managed by non-hormonal medications (e.g. venlafaxine, paroxetine, fluoxetine, gabapentin, or clonidine). (51,52) As with MHT, drug interactions with ART should be considered (see DDI Booklet 2019_English.pdf (hivclinic.ca)) and expert guidance sought as necessary. For urogenital symptoms related to menopause, low-dose vaginal estrogen therapy should be considered.( 55) It has limited systemic absorption and therefore has less systemic side effects/ risks, lower interaction potential with ART, and has been shown to improve symptoms.
# BONE HEALTH
# Evidence:
Women have an increased risk of premature bone loss (osteopenia and osteoporosis), particularly during and after menopause, and this risk is exacerbated by HIV and ART. (56,57) The prevalence of osteoporosis in WLWH is three times greater compared with HIV-uninfected women in the same age group in the United States.( 58)
The pathogenesis of reduced bone mineral density (BMD) noted in PLWH is multi-factorial, with increased risk associated with some
# SPECIAL CONSIDERATIONS FOR TRANSGENDER † INDIVIDUALS LIVING WITH HIV
Recommendations:
- Endocrine therapy for transgender individuals living with HIV should be provided in consultation with an endocrinologist or other clinician who has experience providing endocrine care to transgender individuals. (D)
# Evidence:
Transgender populations are disproportionately affected by HIV. In a systematic review and meta-analysis among the United States (US) transgender population between 2006 and 2017, the estimated prevalence of HIV infection overall was 9.2% (compared to 13.3 per 100,000 in the US general population in 2018) and was higher among transgender women (14.1%, vs. 4.8 per 100,000) than transgender men (3.2%, vs. 22.1 per 100,000).(1, 2) Numerous challenges can affect health outcomes for transgender people, including socioeconomic factors, mental health issues, substance use, abuse and trauma, stigma, discrimination, social rejection, and exclusion. (3,4) Lack of knowledge of transgender issues among health care providers and prior negative experiences in the health care system may constitute barriers to the transgender person's ability to access and maintain HIV care. Providers should be aware that transgender people may prioritize other health concerns over HIV (e.g. gender-affirming and non-discriminatory care, hormone therapy and its side effects, mental health care including trauma recovery), potentially leading to challenges with adherence to antiretroviral therapy (ART). (4,5) In BC, the care of transgender individuals is provided through a decentralized community-based model of care. While HIV treatment and gender-affirming endocrine therapy may be administered by different providers, transgender people living with HIV (PLWH) should have access to all facets of health care in a safe, welcoming, and respectful clinic environment. For information on the care of transgender individuals, clinicians can refer to Gender-affirming Care for Trans, Two-spirit, and Gender Diverse Patients in BC: A Primary Care Toolkit (September 2019) (/ †Note: In this document, transgender includes any person whose gender identity or expression is different from their sex assigned at birth. Transfeminine is used to mean people who were assigned male sex at birth and transmasculine is used to mean people who were assigned female sex at birth and both have gender identity or expression that do not align with their sex assigned at birth.
HealthProf/Primary-Care-Toolkit.pdf). Additional resources for primary care providers are available at: .
Gender-affirming endocrine therapy, which allows the acquisition of secondary sex characteristics aligned with the individual's gender identity, should be provided in consultation with an endocrinologist or other clinician who has experience and expertise in this area. The general approach of feminizing hormone therapy is to combine an estrogen (transdermal, injectable , or oral 17-beta estradiol) with an androgen antagonist (spironolactone, cyproterone acetate, bicalutamide, dutasteride), and in some cases a progestin (micronized progesterone or medroxyprogesterone).( 6) Masculinizing hormone therapy involves the use of one of several forms of testosterone (e.g. injected, transdermal patch or gel, intranasal).( 6) There is considerable variation in the medications that are used for gender affirmation depending on provider and patient preference.
Estradiol, cyproterone, bicalutamide, dutasteride, progestins, and testosterone are substrates of CYP3A4 and may have clinically significant drug interactions with certain ARVs. (7,8) No significant drug interactions are expected between ARVs and spironolactone or finasteride. Estradiol levels may be increased with concomitant cobicistat, increased or decreased with ritonavir, and decreased with efavirenz, etravirine, or nevirapine. Levels of cyproterone, bicalutamide, dutasteride, progestins, and testosterone may be increased with concomitant cobicistat or ritonavir, and decreased with concomitant efavirenz, etravirine, or nevirapine. In transgender individuals receiving endocrine therapy, ART should be chosen to include a non-interacting agent such as doravirine, rilpivirine, or an unboosted integrase inhibitor (raltegravir, dolutegravir, or bictegravir). Otherwise, hormone efficacy and toxicity should be monitored and the hormone doses should be adjusted as necessary.( 7)
BC Cancer provides guidance for healthcare professionals regarding breast/chest screening for transgender, gender diverse, and non-binary people (). Transmasculine individuals who have not had bilateral mastectomy and transfeminine individuals between the ages of 40 and 74 who have taken estrogen-based hormone therapy for more than 5 years should be screened according to the BC Cancer breast screening policy for cisgender (non-transgender) persons (/ breast/eligibility). Transfeminine individuals who have never taken estrogen-based hormone therapy or have taken hormones for fewer than five years do not need to be screened regularly for breast cancer.
For information regarding cervical cancer screening for transgender PLWH with a cervix, see Section 7.10, page 93, of this document. For further guidelines on cervical cancer screening among transgender individuals, see the BC Cancer website: GuidelinesManual-ScreeningForCancerOfTheCervix.pdf.
For Trans Care BC recommendations regarding sexual health screening and pelvic examinations, see: .
# COMMON NON-INFEC TIOUS CO-MORBIDITIES 7.1 INTRODUCTION
A number of conditions not traditionally associated with AIDS, including cardiovascular and renal disease, are exacerbated in the presence of uncontrolled HIV replication.(1) Therefore, despite the potential for long-term complications due to chronic antiretroviral therapy (ART), the benefits outweigh the potential risks in people living with HIV (PLWH) who are appropriately treated and monitored.(2) To this end, clinical and laboratory assessment of relevant co-morbid conditions should be performed at baseline before initiation of ART and during follow-up. Screening for non-infectious comorbid conditions is described in Appendix 3, page 114.
The frequency of lab monitoring for antiretroviral toxicity depends on the known potential toxicities of specific drugs, concomitant medications, and underlying co-morbid conditions. Lab monitoring may occur every 4 weeks after initiation of therapy, decreasing to up to every 6 months after stabilization of the patient on their antiretroviral (ARV) regimen.(3) In most cases, the timing of safety laboratory monitoring can be coordinated with monitoring of HIV RNA and CD4 cell counts. For details regarding laboratory monitoring for individuals receiving ART, see Chapter 3 of the BC-CfE Guidelines for Antiretroviral ARV Treatment of Adult HIV Infection | (bccfe.ca).
# CARDIOVASCULAR DISEASE
# Recommendations:
- All PLWH should be screened for risk of cardiovascular disease at least annually, and modifiable cardiovascular risk factors should be addressed where possible. (D)
- Blood pressure should be measured at least annually and at each visit (at least every 6 months) if abnormal. (D)
- Assess lipids (total, HDL, and LDL cholesterol, and triglycerides) and/or apolipoprotein B at baseline and every 6-12 months once patient begins antiretroviral therapy. (B)
- An electrocardiogram (ECG) should be considered at baseline and periodically (at intervals determined by the degree of risk) in patients taking protease inhibitors and/or rilpivirine with other PR-or QTc-prolonging drugs. (D)
# Evidence:
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the general population.
HIV infection is associated with a doubling of the risk of CVD, including acute myocardial infarction (MI), stroke, peripheral arterial disease, heart failure, and sudden cardiac death.(4-6) Globally, the burden of HIV-associated CVD has tripled over the last 20 years.( 4)
The mechanisms underlying the increased CVD risk in PLWH include a preponderance of traditional risk factors in this population, including smoking, hypertension, dyslipidemia, diabetes, and metabolic syndrome. (4,5) In addition, uncontrolled HIV infection, including during ART interruption, is associated with chronic inflammation and an increased risk of cardiovascular events. (1,7) Even in the setting of controlled HIV viremia, underlying chronic vascular inflammation directly contributes to accelerated atherosclerosis and endothelial dysfunction. Elevated levels of some inflammatory biomarkers, notably high-sensitivity C-reactive protein (hsCRP), are independently associated with a higher risk of MI in PLWH, as in the general population. (8,9) However, the interpretation of hsCRP and other inflammatory biomarkers can be complicated in the setting of the chronic inflammatory state associated with HIV infection. Although ART reduces the levels of these biomarkers, they can remain elevated compared with those of HIV-negative individuals. The clinical utility of these biomarkers for initiation or monitoring therapy in PLWH is unknown.
While virally suppressive ART reduces risk of clinical CVD events,(1) specific ARV agents can be associated with increased CVD risk. In the D:A:D observational cohort from 1999 to 2005, the rate of CV events increased by 16% per year of exposure to ART regimens including older protease inhibitors (PIs). (10) However, more recently, the rate of MI in PLWH has plateaued, attributable at least in part to the use of contemporary PIs; in the D:A:D study from 2009 to 2016, use of darunavir/ritonavir was associated with an increase in CVD risk (59% per 5 years additional use), while use of atazanavir/ritonavir was not.
(11) Although rates of MI are declining in recent years, PLWH receiving newer ART regimens remain at an increased risk of other forms of CVD, notably atrial fibrillation and heart failure. (5) The association between recent use of abacavir and acute MI remains controversial, but most current guidelines recommend avoidance of this agent in people with established CVD or who are at a high risk for CVD.
(5, 12) Some ARV agents such as efavirenz may contribute to CVD risk through their detrimental effect on serum lipids (especially triglycerides and LDL cholesterol), while other have beneficial effects on lipid profiles, including tenofovir DF (compared to tenofovir AF) and unboosted integrase inhibitors. (13)(14)(15)(16) The Canadian Cardiovascular Society Guidelines () recognizes HIV as a significant risk factor for premature CVD and an indication for screening for cardiovascular risk factors, including lipids, regardless of age.(17) Screening for lipids (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides) and apolipoprotein B (apoB) can be done non-fasting, except in individuals with a history of triglycerides >4.5 mmol/L, where these tests should be performed in a fasting state. ApoB measurement is subject to less laboratory error than LDL cholesterol, particularly in patients with hypertriglyceridemia (as often seen in HIV). LDL cholesterol is currently recommended as the primary treatment target, but apoB and/or non-HDL cholesterol are alternatives and may be the preferred treatment targets in the future. (17) Lipids and apoB should be measured annually, and monitoring frequency should be increased to every 6 months if abnormalities are detected.
Despite the impact of ART and HIV infection itself, traditional CVD risk factors (including age and smoking) remain the most important contributors to CVD in PLWH. (17,18) A modified Framingham Risk Score (FRS) (), where the 10-year FRS percentage is doubled for a family history of premature CVD, is the recommended tool for assessing total 10-year CVD risk in the general population; (17) 21) a switch to a more lipid-friendly ART regimen may also be a consideration.(5) When needed, statins can be used safely for the treatment of dyslipidemia in HIV,( 22) but potentially significant drug-drug interactions between lipid-lowering agents and antiretrovirals (e.g. statins and PIs) must be taken into account (www.hiv-druginteractions.org) (DDI Booklet 2019_ENG DIGITAL.pdf (hivclinic.ca)). Of note, PLWH may not reach desirable lipid targets with conventional statin therapy and combination therapy may be necessary. (23,24) Some older HIV PIs (specifically saquinavir and lopinavir/ritonavir) were associated with PR interval prolongation or QTc interval prolongation. (25)(26)(27) Case reports have also described QTc prolongation and torsades de pointes in association with atazanavir(28) and efavirenz.(29) Cardiac conduction abnormalities may become clinically significant when a ritonavir-boosted PI is co-administered with one or more QTc-prolonging drugs such as methadone, quetiapine, macrolides, quinolones, and/or azoles (for a full list, see the CredibleMeds website at ), or PR-prolonging drugs, such as digitalis, calcium channel blockers, anti-arrhythmics, and beta-blockers. Rilpivirine was associated with QTc prolongation at daily doses of 75 mg or 150 mg, although this does not appear to be a problem at the 25 mg daily dose currently in use. (30)(31)(32) An electrocardiogram (ECG) should be considered at baseline before starting a ritonavir-boosted PI and/or rilpivirine with one or more PR-or QTc-prolonging drugs. A repeat ECG should be performed approximately five half-lives after starting the relevant drug, i.e. approximately 2 days after starting atazanavir/ritonavir, 3 days after starting darunavir/ ritonavir, or 10 days after starting rilpivirine. In addition, an ECG should be done after the addition or dose increase of any other QTc-prolonging drug and at times of increased risk (e.g. hypokalemia, hypomagnesemia). Repeat ECG monitoring should be performed at intervals determined by the degree of risk, i.e. whether the QTc is short (0.45 seconds).(33)
# INSULIN RESISTANCE (IR) AND DIABETES MELLITUS (DM)
Recommendations:
- Fasting blood glucose (FBG) and/or glycated hemoglobin (HbA1C) should be performed in all PLWH at baseline and at 6-to 12-month intervals during antiretroviral therapy. Abnormalities in fasting glucose and/or HbA1C should be evaluated and managed according to the Diabetes Canada guidelines (/). (A)
- Initial management of blood glucose abnormalities in PLWH involves lifestyle changes (weight loss, diet, exercise). (A)
- Oral anti-glycemic agents and injectable anti-glycemic agents should be used as required, keeping in mind drug interactions with some antiretrovirals. (A)
Evidence:
HIV and its treatment increase the risk of insulin resistance (IR) and diabetes mellitus (DM) by approximately 1.5-to 4-fold compared to the general population, (34,35) and the risk is greater with hepatitis C co-infection.(36) IR is associated with use of older nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs).( 37) Integrase inhibitors may be associated with weight gain, which in turn exacerbates the risk of diabetes, particularly in PLWH; however, an association between integrase inhibitors and clinical metabolic abnormalities has yet to be confirmed. (38,39) Traditional risk factors for DM remain relevant in PLWH.
HbA1C may be monitored as an alternative to fasting blood glucose, particularly if fasting status is difficult to ascertain; however, HbA1C can underestimate glycemia in PLWH, leading to under-diagnosis, especially in the setting of macrocytosis, lower CD4 cell counts, or certain antiretrovirals. (40)(41)(42) Fasting glucose and HbA1C should be measured annually in PLWH, with frequency of monitoring increased to every 6 months if abnormalities are detected.
In PLWH with type 2 diabetes, HbA1C should be measured every 3 months and targets should be established as per the Diabetes Canada Guidelines.(43) HbA1C targets are individualized; in most cases the target is 7%. In type 2 diabetics with CD495 fL, glucose levels should be used instead of HbA1C to guide management.
As in the general population, initial management of blood glucose abnormalities in PLWH involves lifestyle changes: maintaining healthy weight, healthy diet, and physical activity.(44) Depending on the degree of hyperglycemia at diagnosis, antihyperglycemic agents should be started concomitantly or if blood sugar targets are not met within 3 months of instituting healthy behaviour interventions.(45) Of note, in the presence of dolutegravir, metformin concentrations are increased by 79%, with a potential for increased adverse events. (46) In patients taking dolutegravir, metformin should be started at a low dose and not prescribed in doses greater than 1000 mg daily. Bictegravir increases metformin levels by 39% and no dose adjustment is required for co-administration.(47) In individuals with established cardiovascular disease with suboptimal glycemic control there is a clear role for sodium-glucose cotransporter-2 (SGLT-2) inhibitors and/or glucagon-like peptide-1 (GLP-1) receptor agonists;(45) some precautions should be noted with respect to potential drug interactions with antiretrovirals (TS_Antidiabetic_2019_Oct.pdf (liverpool-hiv-hep.s3.amazonaws.com); DDI Booklet 2019_English.pdf (hivclinic.ca).
# BONE
Recommendations:
- Clinicians should undertake preventive measures for bone loss in all PLWH, including weightbearing exercises, maintaining ideal weight, reducing smoking and alcohol consumption, and optimizing vitamin D (1000-2000 IU/day) and calcium intake (in the form of diet and/or supplements if necessary). (D)
# Evidence:
PLWH are at a greater risk of fractures than non-infected individuals. (48) The loss of bone density associated with normal aging is accelerated by HIV-associated chronic inflammation and vitamin D deficiency and by exposure to antiretrovirals. (49) The role of specific antiretrovirals in causing bone loss is controversial; however, the evidence points to tenofovir DF and ritonavir-boosted PIs as the leading culprits. (49,50) Efavirenz has also been implicated as a contributor to low bone mass, mediated through its effect on vitamin D metabolism.( 51 Preventive measures for bone loss should be implemented in all PLWH, regardless of age, following the recommendations for the general population (/). These measures include regular weight-bearing exercises, maintaining ideal weight, reducing smoking and alcohol consumption, and optimizing vitamin D and calcium intake (in the form of diet and supplements if necessary). Falls prevention strategies should be implemented for individuals with frailty or other conditions associated with a high risk of falling (https:// www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines/osteoporosis). Most PLWH have low vitamin D levels, as does the general North American population; therefore, there is insufficient evidence to support routine measurement of vitamin D levels in PLWH. (58) While there is no consensus regarding the optimal dose in the setting of HIV, supplementation with vitamin D at doses of 1000-2000 international units (IU) daily is inexpensive, safe, and not associated with known interactions with antiretroviral drugs. If dietary calcium intake is inadequate, a calcium supplement should be considered, taking into consideration potential interactions with antiretrovirals.
# RENAL DISEASE
# Recommendations:
- It is recommended that laboratory assessment of renal function (i.e. serum creatinine, estimated glomerular filtration rate , serum phosphate, urinalysis for protein and sediment, and spot urine for albumin to creatinine ratio ) should be performed in all PLWH at baseline and every 3-4 months after starting antiretrovirals, increasing to 6-month intervals when stable (depending on degree of risk). (D)
- Blood pressure should be measured at least annually and at each visit (at least every 6 months) if abnormal. (D) - Rarely, acute interstitial nephropathy with reversible acute renal failure, which has been described in association with hypersensitivity reactions to abacavir, efavirenz, and atazanavir (67) Establishing the etiology of renal dysfunction in PLWH can be difficult as it is often multi-factorial.
Referral to a nephrologist and possibly renal biopsy may be required for a definitive diagnosis, especially in cases where drug-related nephrotoxicity is suspected. Any renal function abnormalities identified at screening should be investigated and managed appropriately as in the general population. Some ARVs (specifically all NRTIs except abacavir) are renally cleared and may require dosage adjustment if renal function is abnormal.(59) For some drugs with low nephrotoxic potential (e.g. lamivudine), the beneficial effect of dose adjustment has not been proven. However, tenofovir DF is renally cleared and is also a nephrotoxin; this drug should be avoided in patients with renal disease or at high risk. If renal dysfunction occurs during ART, tenofovir DF should be discontinued if possible and replaced with another agent (e.g. abacavir if HLA-B*5701 negative or tenofovir alafenamide if eGFR >30 mL/min) rather than dose-reduced. For further information, refer to the BC-CfE Guidelines for Antiretroviral ARV Treatment of Adult HIV Infection | (bccfe.ca).
Certain ARV agents (bictegravir, dolutegravir, rilpivirine) and pharmacokinetic enhancers (cobicistat) affect renal tubular creatinine transporters resulting in decreased tubular creatinine secretion and increased serum creatinine levels. (31,32,(68)(69)(70)(71)(72)(73)(74) This is manifested as a factitious increase in serum creatinine (mean increase ~10-12 μmol/L) during the initial 2-8 weeks of therapy, without an effect on true glomerular filtration rate. After the initial increase, serum creatinine levels remain stable at the new higher level as long as the agent is continued. Decreases in eGFR that are >25% of the baseline level, that start later or continue to progress after the first 2-8 weeks of therapy, or that are accompanied by signs of renal tubular dysfunction (e.g. proteinuria) require further investigation to rule out true renal function impairment, and nephrology referral should be considered.(74)
# HYPOGONADISM
Recommendations:
- Cisgender men living with HIV presenting with symptoms of hypogonadism should be assessed with a morning serum total testosterone level; an abnormal testosterone level should be confirmed with repeat testing. (B) An estimated bioavailable testosterone measurement may be helpful to assess certain individuals, including obese cisgender men with borderline low total testosterone levels. (B)
- Testosterone replacement is indicated only for symptomatic cisgender men with total testosterone levels less than 10 mmol/L (B) and should be prescribed in consultation with a specialist. (D)
- Endocrine therapy for transgender individuals living with HIV should be provided in consultation with an endocrinologist or other clinician who has experience providing endocrine care to transgender individuals. (D)
# Evidence:
In the early ART era, hypogonadism was identified as an important contributor to loss of lean body and muscle mass, the hallmarks of AIDS-associated wasting, as well as decreased bone mineral density.(71) While less prevalent now, low testosterone levels are still present in a significant minority of cisgender men living with HIV. (75) Symptoms suggestive of testosterone deficiency include decreased libido, erectile dysfunction, hot flashes and sweats, weight loss, reduced muscle strength or exercise capacity, fragility fractures, sleep disturbance, fatigue, and depression. Cisgender men living with HIV presenting with one or more of these symptoms should be screened with a morning free testosterone level, and low levels should be confirmed on repeat testing.(76) An estimated bioavailable testosterone measurement may be helpful to assess certain individuals, specifically obese cisgender men with borderline low total testosterone levels. Normal serum testosterone levels in cisgender women are unknown.
Confirmed low testosterone levels may necessitate further investigation (including luteinizing hormone, follicle-stimulating hormone, prolactin, prostate-specific antigen) to distinguish primary (testicular) vs. secondary (pituitary/hypothalamic) hypogonadism and to rule out other clinical conditions.(77) Testosterone replacement therapy (TRT) is indicated only for cisgender men with symptomatic low testosterone levels and should be prescribed according to current guidelines, preferably in consultation with an endocrinologist or other specialist. (76,78) In cisgender men living with HIV with hypogonadism, TRT has been shown to improve mood, energy, libido, muscle strength, and body composition (specifically, decreasing fat and increasing muscle mass), without adverse effects on viral load or CD4 cell count. However, there are no reliable data demonstrating that TRT improves muscle mass, in excess of that achieved by physical exercise, or overall physical function in cisgender men living with HIV. The benefits of longer term TRT (>3-6 months) in this population have not been studied. (76) Potential side effects of TRT include acne, male pattern balding, and sleep apnea. More serious potential adverse effects include myocardial infarction (due to erythrocytosis) and prostate cancer. TRT is contraindicated in men with acute coronary syndrome or prostate cancer. The long-term safety of TRT is unknown; the need for ongoing TRT should be reassessed at least every 6 months.(76, 78)
# NEUROCOGNITIVE IMPAIRMENT
Recommendations:
- ART to suppress plasma viral load should be started early and administered continuously to prevent or minimize HIV-related neurocognitive impairment. (B)
- In PLWH presenting with cognitive complaints that affect their daily functioning, an investigation should be done to rule out relevant underlying conditions. (B)
# Evidence:
HIV can affect the central nervous system (CNS), impacting cognitive function (e.g. memory, reasoning, planning, solving problems, attention, concentration) and activities of daily living. Fortunately, the incidence of severe cognitive impairment in the form of HIV-associated dementia has declined significantly since the advent of ART. However, milder forms of neurocognitive impairment remain prevalent, even in the presence of virologic suppression, and can have a significant impact on quality of life and adherence to HIV medications. (79) PLWH with impairment in two or more cognitive domains and mild to moderate impairment in daily functioning, in the absence of confounding conditions, may be diagnosed with mild neurocognitive disorder.(80) Potential underlying conditions that need to be ruled out include:(81, 82) In the absence of relevant underlying conditions, neurocognitive impairment in HIV may be related to CSF viral "escape", i.e. presence of detectable HIV RNA in CSF despite undetectable viral load in plasma.
Limited evidence exists that adjusting the ART regimen to include agents with better CSF penetration (e.g. zidovudine, nevirapine, abacavir, emtricitabine, darunavir/ritonavir, raltegravir) can stabilize or improve neurocognitive function in this setting. (79,82) Referral to a physician with expertise in the management of HIV is advised in these situations. Full suppression of plasma viral replication remains the most important target, for both prevention and treatment of HIV-related cognitive disorders.
# LUNG DISEASE
# Recommendations:
- Smoking cessation should be strongly encouraged in all PLWH because they are at a higher risk for chronic obstructive pulmonary disease (COPD) and lung cancer than smokers who do not have HIV. (A)
- A chest X-ray should be performed at baseline in all PLWH. (D) Once infection has been treated or ruled out, patients with persistently abnormal chest X-ray findings should be investigated and referred to a respiratory specialist if necessary. (D)
# Evidence:
Compared to the general population, PLWH have a greater risk for chronic obstructive pulmonary disease (COPD) and are prone to develop it at a younger age, even taking into account the relatively high rates of smoking in this population. (83,84) COPD should be managed according to current Canadian Thoracic Society guidelines (available at /), including an aggressive plan for smoking cessation. The use of all inhaled steroids should be avoided if possible in patients receiving ritonavir or cobicistat as part of their ART regimen, due to the risk of adrenal suppression and iatrogenic Cushing's syndrome. (85,86) Beclomethasone cannot be recommended as a "safer" alternative in this setting; a systematic review showed this agent has no clinical effect in COPD. (87) If combination inhaled steroids/long-acting beta-agonist (LABA) inhalers are necessary for the management of severe COPD symptoms, consideration should be given to switching patients off of ARV regimens containing ritonavir or cobicistat. Salmeterol is not recommended with concomitant ritonavir or cobicistat in PLWH with COPD because of elevated salmeterol levels that may increase the risk of cardiovascular adverse events. (88) Formoterol can be associated with QT prolongation and should be used with caution in patients receiving QT-prolonging ARVs (rilpivirine, ritonavir-boosted lopinavir or atazanavir); however, other single-agent LABAs (e.g. indacaterol) and long-acting muscarinic antagonists (LAMAs, e.g. aclidinium, glycopyrronium, tiotropium) can be used safely in this setting.(88)
A chest X-ray should be performed at baseline in all PLWH. As HIV confers an increased risk of lung cancer, HIV care providers should have a low threshold for performing chest CT in the presence of significant respiratory symptoms, particularly in smokers. (89)(90)(91) After appropriate management of infectious etiologies, consultation with a respiratory specialist is advisable to investigate persistent symptoms or abnormal imaging findings.
# LIVER DISEASE/CIRRHOSIS
Recommendations:
- Liver enzymes and liver function should be assessed in all PLWH at baseline and every 3-4 months after starting ART, increasing to 6-month intervals when stable. (D)
# CANCER
Recommendations:
- In PLWH, screening for breast, colorectal, and prostate cancer should follow current provincial recommendations for the general population. (A)
# Evidence:
The incidence of AIDS-defining cancers, Kaposi's sarcoma, and non-Hodgkin's lymphoma has markedly decreased in the highly active ART era (with the exception of invasive cervical cancer which has remained relatively unchanged), while non-AIDS-defining cancers have become more common. (106)(107)(108) This is attributable at least in part to the increasing risk of malignancy as the PLWH population ages. 1. Mental health should be proactively assessed during clinic visits, and identified conditions should be managed using a stepped-care approach. (D)
# Evidence:
The populations at risk of HIV acquisition are also at heightened risk of anxiety, depression, and other mental health issues, including people who inject drugs (118) and cis-and transgender men who have sex with men (MSM). (119)(120)(121) Sexual minorities and transgender individuals carry a disproportionate burden of mental health challenges as indicated by higher rates of self-reported depression, anxiety, selfharm, suicidality, and substance use disorders when compared to their heterosexual counterparts. (119)(120)(121)(122) In this sense the intersecting burdens of mental illness, substance use disorders, and experiences of discrimination related to sexuality among these populations impart an increased vulnerability towards HIV acquisition.( 123)
Cisgender women living with HIV also experience high rates of anxiety, depression, and post-traumatic stress disorder (PTSD).( 124
# SPECIAL CONSIDERATIONS FOR INDIVIDUALS WITH ADVANCED HIV -OPPORTUNISTIC INFEC TION & PROPHYLAXIS
Despite efforts to expand HIV testing and the accessibility of effective antiretroviral therapy (ART) in British Columbia, just under 20% of people living with HIV (PLWH) are diagnosed at an advanced stage of HIV disease.(1) Others may not access medical care including ART or are unable to adhere to their ART regimen consistently. Such individuals may develop low CD4 cell counts, which places them at risk for opportunistic infections (OIs), and indeed an OI is often the presenting feature that brings them into medical care. Once the acute OI has been treated, primary prophylaxis for other common OIs may be appropriate if the CD4 cell count remains low. Following immune reconstitution with ART, primary prophylaxis can often be discontinued once the patient is clinically stable and has established consistent adherence. Indications for prophylaxis, agents of choice, and criteria for discontinuing and restarting primary prophylaxis for Pneumocystis jirovecii pneumonia (PJP), Toxoplasma, Mycoplasma (M.) tuberculosis, and Mycobacterium avium complex (MAC) are shown in
# HEALTH SERVICES TO OPTIMALLY ENGAGE PEOPLE LIVING WITH HIV (PLWH) IN EFFEC TIVE PRIMARY CARE
Chapter Summary:
- Optimal HIV management is facilitated by healthcare delivery models that are focused on long-term engagement and relationship-building between healthcare providers and their clients.
- Actively linking individuals newly diagnosed with HIV to clinicians who are familiar with the HIV management is preferred to passive referrals or simply providing patients information. In BC, regional public health nursing teams may be helpful in linking newly diagnosed individuals to care.
- Peer support or peer-navigation may also be helpful for linking or retaining some PLWH in care 4. Formal case management to link and/or retain PLWH in care may be needed for some individuals.
- PLWH may face additional challenges such as housing instability and food insecurity, which should be addressed through referrals to specific social services.
- Outreach support, such as those provided by public health nursing teams though health authorities, are a helpful resource in assisting PLWH to remain engaged in care.
Engaging people living with HIV (PLWH) in healthcare and ensuring client retention are key elements to providing successful treatment, ensuring adherence to antiretroviral treatments, and preventing onward disease transmission.(1, 2) However, PLWH may encounter a variety of challenges to accessing consistent and effective care. Some factors are patient-dependent, such as negative emotions associated with diagnosis(1) and a lack of adequate social supports. (1,2) Other factors are associated with health services themselves, such as negative healthcare experiences(1) and lack of culturally sensitive care for Indigenous people and other cultural minorities.(3)
Healthcare providers and staff who are perceived to be supportive and collaborative are important to establishing rapport with PLWH, and these positive relationships can, in turn, improve linkage to healthcare. (1,4,5) Moreover, supportive providers may be seen by patients as members of their supportive social network and as proxies for absent friends and family.(1) In addition, providing appropriate education around HIV, through programmes tailored for PLWH or by care providers trained/competent in providing patient education, improves patient empowerment and understanding of antiretroviral therapy (ART).(6, 7) Patients also highly value confidentiality as the fear of incidental disclosure when seeking services is a concern for many PLWH accessing care.(7) Client-centred healthcare that accounts for patient preferences and is culturally sensitive and confidential underpins the effective delivery of HIV services. (3,5,8,9) In BC, all residents are eligible for care and treatment of HIV free of charge. Care providers who are faced with challenges of caring for visitors without health insurance and/or persons residing in Canada illegally should contact the BC-CfE to advocate on the person's behalf for coverage of the cost of medical treatment.
# CHRONIC DISEASE MODEL OF CARE
As HIV is now conceptualized as a chronic, manageable condition, its optimal management is facilitated by care models that are focused on long-term engagement and relationship-building between healthcare providers and their clients. The Chronic Care Model, first formulated by Wagner et. al. in 1996(10) and recently revisited,(11) addresses relational aspects of care (Figure 9.1). At its core, the Chronic Care Model postulates that an informed and activated client, when partnered with a proactive and prepared healthcare team, will achieve optimal outcomes for chronic disease management. HIV care has been evaluated in terms of how well it incorporates aspects of the Chronic Care Model;(12-14) however, we are not aware of studies which have evaluated different service delivery models in terms of clinical outcomes. Many aspects of care related to the Chronic Care Model have recently been identified as priorities for PLWH in high-income countries.(7) These include: a strong healthcare professional-patient relationship, HIV specialist knowledge, continuity of care, ease of access to services, access to high quality information and support, effective co-ordination between HIV specialists and other healthcare professionals, and patient involvement in decisions about treatment and care. Other studies have shown that better physician-patient relationships are associated with higher rate of adherence to ART. (15) Quality improvement involves routine data collection and cycles of planning, change, and feedback to improve processes and outcomes. Incorporating quality improvement methods in HIV care can provide useful feedback throughout cycles of change, including the implementation of an intervention, and help close gaps in care.( 16) For more information on best practices for quality improvement and evaluation of HIV care and services, please consult the resources available on the HIV Continuum of Care Collaborative website (/).
# ACTIVE REFERRAL FOLLOWING DIAGNOSIS
Upon diagnosis, active guidance to set up initial clinic appointments rather than passive methods (e.g. handing out brochures) improves linkage,(1) as does scheduling clinic orientation visits. (17) In BC, regional public health teams may be helpful in linking newly diagnosed individuals to clinicians who are familiar with the management of HIV infection. A list of contact numbers can be found in the Appendix 4, page 116. As well, The Canadian AIDS Treatment and Information Exchange (, 1-800-263-1638) is a national organization that provides useful support and information regarding HIV treatment and related topics in languages accessible to most clients.
# ADDRESSING SOCIAL DETERMINANTS OF HEALTH
PLWH may face additional challenges such as housing instability and food insecurity. Stable housing among PLWH has been associated with a variety of positive clinical outcomes, including adherence to ART and improvement in overall health status, (18,19) As well, evidence from randomized trials has demonstrated that receiving assistance or other services that improve housing status has a direct impact on improved medical care and health outcomes for formerly homeless or inadequately housed PLWH. (20,21) Food insecurity has been associated with a lack of virologic suppression among PLWH receiving ART, with 37% of those with unsuppressed viral load reporting food insecurity; (22) food insecurity has also been associated with increased mortality among PLWH who use injection drugs in studies conducted in BC( 23) and New York. (22) Clinicians should actively ask PLWH about these issues and have connections to social work supports and community organizations so that they can actively assist patients in accessing appropriate programs and services.
# PEER-SUPPORT AND PATIENT OR PEER NAVIGATION
Stigma, isolation, and marginalization are common realities in the lives of PLWH. Ensuring access to social and emotional support for affected individuals is a crucial part of HIV primary care. Peer support programs can help to improve linkages and retention in care. AIDS service organizations (ASOs) are excellent starting points for many of these services. Please refer to the Contact List (Appendix 4, page 117 for a list of provincial organizations, providing support for PLWH).
Patient navigators, who may be peers with lived experience, assist in relationship-building and nonmedical support. Peer navigators may accompany clients to appointments, guide clients through the healthcare system, teach skills in communicating with providers, and provide non-clinical services such as transportation. (17,24) Peers may also provide basic information on HIV medications and support treatment adherence, including reinforcing messages regarding treatment as prevention or U=U. Peers can also provide education regarding sexually transmitted infections and other related topics. Moreover, peers can connect patients with community organizations and provide referrals to services and support groups, including addiction and mental health support. Patient and peer navigators have been found to improve linkage to and retention in healthcare by supporting clients in navigating complex medical systems to meet their care needs. (24,25) Guidelines for peer navigation services have been published by the Canadian AIDS Treatment Information Exchange. (26) In BC, several community-based organizations provide peer navigation or peer support services, including Vancouver Island PWA Society (. com/programs/peer-support/) and AIDS Vancouver (). Health care providers should contact their regional health authority's HIV program if they have clients who could benefit from peer navigation or support.
# CASE MANAGEMENT
Case management has been shown to be effective in both initial linkage to care (27) and subsequent retention in care (28,29) and often comprises a variety of interventions. Case management may consist of assistance from a healthcare worker to link PLWH to HIV care providers with time-limited follow-up to ensure that linkage and retention have occurred. Case management may also include referring clients to appropriate providers, assisting clients to prioritize personal needs, introducing HIV resources, helping to complete forms, and teaching skills about disclosure to support networks.(17) Case management activities may overlap with patient/peer navigation.(24)
# OUTREACH SERVICES
Intensive outreach services (e.g. home visits or mobile van outreach) were also found to increase retention and ART adherence, though the programs could be resource-intensive and lack long-term stability. (6,17) Outreach services can be provided by medical professionals or by peers. These programs may work better when integrated with other social services. (6) In BC, all regional health authorities have outreach nursing teams to assist PLWH who have not engaged in HIV care following diagnosis or who have fallen out of care. At Vancouver Coastal Health, these outreach personnel are known as STOP teams; they have different names in other regional health authorities. Contact information for these teams are found in Appendix 4, page 117.
The Re-Engagement and Engagement in Treatment for Antiretroviral Interrupted and Naïve populations (RETAIN) Initiative () is a partnership between the BC-CfE, Medical Health Officers from each health authority, and HIV outreach personnel throughout British Columbia. The BC-CfE sends routine alerts to physicians regarding their patients who are at least 2 months late in refilling their ART prescription. Additionally, alerts have been launched for physicians linked to patients newly diagnosed with HIV who have not yet accessed ART. Both of these alerts include contact information for local public health support.
A core component of RETAIN is the routine province-wide coordination of public health support for PLWH who have interrupted ART or who have yet to initiate therapy. PLWH will be eligible for this outreach support if: 1) they have interrupted treatment for longer than 4 months, or 2) they have not yet started treatment more than 4 months after a high plasma viral load was reported. The BC-CfE provides routine referrals for such clients to each regional health authority on a monthly basis. An evaluation of the RETAIN program demonstrated that, among individuals who had interrupted treatment for >4 months, those who interrupted their treatment in the post-RETAIN era (i.e. after June 2016) were more likely to restart ART (adjusted hazard ratio 1.50; 95% CI 1.34 -1.69), compared to earlier time periods.(30)
# OTHER SUPPORTS
In addition, supports such as counselling and use of motivational interviewing methods may improve retention and adherence to medication. (17,31) Motivational interviewing techniques can be delivered by mental health clinicians or by trained peer outreach workers.(32)
Interventions using phone text messaging can help to provide remote clinic support for individuals receiving ART. (6) In BC, the WelTel intervention has been shown to improve adherence to ART and virologic suppression among women with an unsuppressed viral load at the Oak Tree Clinic.(33, 34) | Low-density lipoprotein LTBI Latent tuberculosis (TB) infection MAC Mycobacterium avium complex MCV Mean corpuscular volume MHT Menopausal hormone therapy MI Myocardial infarction MMR Mumps, measles and rubella MRI Magnetic resonance imaging MSM Men who have sex with men MSP Medical services plan NAAT Nucleic acid amplification test NACI National Advisory Committee of Immunization (Canada) NASH Non-alcoholic steatohepatitis NNRTI Non-nucleoside reverse transcriptase inhibitor NRTI Nucleoside reverse transcriptase inhibitor NP Nurse practitioner OI Opportunistic infection# INTRODUCTION ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 22
Figure 2.
# 1: The HIV Cascade of Care •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 22
2.2 MODES OF HIV TRANSMISSION
••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••
# ••••••••••••••••• 2.3 NATURAL HISTORY OF HIV/AIDS ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• Figure 2.2: Natural history of HIV/AIDS. •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••
2.4 HIV TESTING •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••
RECOMMENDATIONS: ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 3.
# INITIAL ASSESSMENT •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• Table 3.1: Initial assessment, medical history. •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 3.2 PHYSICAL EXAMINATION ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••
Table 3.
# 2: HIV-related physical examination. ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 3.3 BASELINE LABORATORY EVALUATION •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••
Table 3.
# 3: Baseline laboratory assessment ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 3.4 COUNSELLING PLWH REGARDING HIV TRANSMISSION RISK •••••••••••••••••••••••••••••••••••••••••••••• 4 SCREENING AND IMMUNIZATION FOR SELECTED CO-MORBID INFECTIONS •••••••
# SCREENING FOR CO-MORBID INFECTIONS ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 4.2 IMMUNIZATIONS AND HIV •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 4.2.1 Recommended Vaccines ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• Table 4.1: Recommended vaccines for adults living with HIV ••••••••••••••••••••••••••••••••••••••••••••••• 4.2.2 Additional Vaccines ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 4.2.3 Contraindicated Vaccines ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 5 SPECIAL CONSIDERATIONS FOR CISGENDER WOMEN LIVING WITH HIV (WLWH)
# INTRODUCTION ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 5.2 SPECIAL CONSIDERATIONS RELATED TO ART DURING PREGNANCY AND THE POST-PARTUM PERIOD ••••••• 5.3 REPRODUCTIVE ISSUES AND GYNECOLOGIC HEALTH IN THE CONTEXT OF HIV ••••••••••••••••••••••• 5.4 ART AND WEIGHT GAIN IN WOMEN ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 5.5 MENOPAUSE ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 5.6 BONE HEALTH ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 6 SPECIAL CONSIDERATIONS FOR TRANSGENDER INDIVIDUALS LIVING WITH HIV ••••• 7 COMMON NON-INFECTIOUS CO-MORBIDITIES ••••••••••••••••••••••••••••••••••••••••••••••••••••
# INTRODUCTION ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 7.2 CARDIOVASCULAR DISEASE •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 7.3 INSULIN RESISTANCE (IR) AND DIABETES MELLITUS (DM) •••••••••••••••••••••••••••••••••••••••••••••••• 7.4 BONE ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 7.5 RENAL DISEASE ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 7.6 HYPOGONADISM ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 7.7 NEUROCOGNITIVE IMPAIRMENT ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 7.8 LUNG DISEASE ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••
7.9 LIVER DISEASE/CIRRHOSIS •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 7.
# CANCER •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 89 Table 7.1 Recommendations for cancer screening in PLWH ••••••••••••••••••••••••••••••••••••••••••••••••••• 7.11 MENTAL HEALTH •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 8 SPECIAL CONSIDERATIONS FOR INDIVIDUALS WITH ADVANCED HIV -OPPORTUNISTIC INFECTION & PROPHYLAXIS •••••••••••••••••••••••••••••••••••••••••••••••••••
••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9.1 CHRONIC DISEASE MODEL OF CARE •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9.2 ACTIVE REFERRAL FOLLOWING DIAGNOSIS•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• Figure 9
# .1: The Chronic Care Model ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 107 9.3 ADDRESSING SOCIAL DETERMINANTS OF HEALTH ••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9.4 PEER-SUPPORT AND PATIENT OR PEER NAVIGATION ••••••••••••••••••••••••••••••••••••••••••••••••••••• 9.5 CASE MANAGEMENT ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9.6 OUTREACH SERVICES •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9.7 OTHER SUPPORTS •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• APPENDIX 1: SIGNS AND SYMPTOMS ASSOCIATED WITH HIV SEROCONVERSION SYNDROME/ACUTE RETROVIRAL SYNDROME AND THEIR FREQUENCY IN SYMPTOMATIC INDIVIDUALS •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• APPENDIX 2: AIDS-DEFINING CONDITIONS •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• APPENDIX 3: SCREENING FOR NON-INFECTIOUS CO-MORBID CONDITIONS IN PEOPLE LIVING WITH HIV (PLWH) ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• APPENDIX 4: CONTACT LIST •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• PROVINCIAL AND REGIONAL HIV/AIDS SERVICE ORGANIZATIONS ••••••••••••••••••••••••••••••••••••••••••• 117 REGIONAL HEALTH AUTHORITY CONTACTS/ COMMUNICABLE DISEASE NURSING CONTACTS •••••••••• 117 APPENDIX 5: OTHER GUIDELINES RELATED TO THE CARE OF PEOPLE LIVING WITH HIV (PLWH) • DISCLAIMER
No financial or in-kind commercial support has been received for the development of these guidelines; no commercial organization has supported the development of these guidelines. The content of the guidelines has been developed by the authors and reflect best practices in HIV care in British Columbia. Both positive and negative trials are mentioned where possible. Generic names of medications are used in place of brand names where possible.
These Guidelines represent the view of the Primary Care Guidelines Writing Committee, in consultation with an external group of experts and are based on available scientific evidence current to July 31, 2021. These Guidelines may be superseded by subsequent Guidelines. Please check http://bccfe.ca/therapeuticguidelines for the most recent Guidelines. Every health care professional is responsible for exercising their own professional skill and judgment and should consider these Guidelines in the context of the individual patient's circumstances, in consultation with that patient or their guardian(s), and when appropriate, external experts (e.g., specialty consultation). These Guidelines are not medical advice nor are they intended to be the only approach to the management of a clinical problem. These Guidelines should not be relied on by any individual as a substitute for the advice or professional judgment of a health care professional.
# WHAT'S NEW IN THE GUIDELINES
# Updated: November 2022
Toxoplasma Serology Table 3.3, Toxoplasma IgG serology, has been updated for agreement with the existing recommendations provided in the body of the Primary Care Guidelines. Toxoplasma IgG serology is indicated in all persons, regardless of CD4 cell count (Table 3.3). Previous versions stated toxoplasma IgG serology is indicated in persons with CD4 cell count <200 cells/mm3.
# INTRODUC TION
There has been a significant decrease in the morbidity and mortality of people living with HIV (PLWH) in the province of British Columbia since the introduction of potent antiretroviral treatment in 1996. According to the British Columbia Centre for Excellence in HIV/AIDS (BC-CfE) HIV Quarterly Monitoring Report for the fourth quarter of 2019, there were approximately 10,603 people in the province living with HIV.(1) Among them, around 7415 were receiving antiretroviral treatment in 2020. (2) The Primary Care Guidelines for the Management of HIV/AIDS in Adults in British Columbia, along with other therapeutic guidelines, have been developed by the BC-CfE to provide support for care and treatment programs for PLWH. These guidelines also respond to the need to expand HIV treatment to meet the goals of 90-90-90 in British Columbia and respond to requests from primary care providers in the community for HIV-specific guidelines.
# OBJECTIVES
1. To provide consensus-based guidelines for the management of primary care for PLWH. 2. To provide practical and easily accessible information and resources for primary care providers of PLWH in the province of British Columbia.
# METHODS
# Process Overview and Committee Composition
An expert committee composed of primary care and infectious disease physicians, a nurse practitioner, a pharmacist, and a person living with HIV prepared the original guidelines in 2011. Since the guidelines were first published, they have been consistently reviewed and revised to ensure that the information is up-to-date. In 2014/15, the original expert committee collectively undertook a review of the 2011 guidelines. The most recent review was finalized in 2021 by a review committee consisting of primary care, public health, and infectious disease physicians (refer to above). Where applicable, the committee updated epidemiology, baseline assessment, immunizations, and co-morbidities data and added new recommendations. The revisions were sent out to subject matter experts for review where necessary.
# Consensus Development on the Basis of Evidence
The review committee met a total of eight times. Committee members developed sections, in consultation with external medical experts where appropriate, and presented their work at committee meetings, where all recommendations were discussed until consensus was reached. The final manuscript was reviewed by all committee members and then presented to and reviewed by members of the Committee for Drug Evaluation and Therapy (CDET) at the BC-CfE and reviewed by external reviewers (listed above).
Each recommendation in the guidelines has been assigned a level of evidence based on the GRADE criteria (refer to Table 1.
# 1).(3)
Note that this method of grading recommendations is different from previous versions of the BC-CfE Primary Care Guidelines.
# Quality of Evidence Definition
A High
Further research is very unlikely to change our confidence in the estimate of effect.
Several high-quality studies with consistent results
In special cases: one large, high-quality multi-centre trial
# B Moderate
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
One high-quality study Several studies with some limitations
# C Low
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
One or more studies with severe limitations
# D Very Low
Any estimate of effect is very uncertain.
# Expert opinion
No direct research evidence One or more studies with very severe limitations
# WLWH
Women living with HIV
# X-ray
Penetrating form of high-energy electromagnetic radiation
# SUMMARY OF PRIMARY CARE RECOMMENDATIONS FOR THE MANAGEMENT OF HIV/AIDS INITIAL ASSESSMENT OF PEOPLE LIVING WITH HIV (PLWH)
1. All PLWH should have timely access to a primary care clinician with knowledge in the management of HIV infection and should receive care in a culturally sensitive environment. Primary care clinicians without expertise in HIV care should consult with a physician with this expertise. (D)
2. All patients entering HIV care should have documented evidence of HIV antibody testing. If laboratory confirmation is not available, a repeat HIV antibody test should be performed. (D) 3. Clinicians should obtain a comprehensive present and past medical history, including HIV-related information, assessment of present medications, family history and psycho-social issues, and review of systems and conduct a complete physical examination upon the patient's entry into care. (D) 4. A baseline CD4 cell count (absolute and fraction) and quantitative HIV RNA (plasma viral load) should be done for all patients upon entry into care. (A) 5. All patients should be assessed for transmitted HIV drug resistance using genotypic drug resistance testing. Ideally, the drug resistance testing should be conducted on the first available sample of HIV plasma viral load. (B) 6. HLA-B*5701 testing is recommended once at baseline for all patients. HLA-B*5701-positive patients must not be given abacavir-containing regimens. (A) 7. Hematology (CBC with differential and platelet count) and comprehensive biochemistry (liver and renal function, lipid profile, fasting blood glucose and/or HbA1C) is recommended at baseline to support management of ART toxicities and to evaluate other potential co-morbidities. (D) 8. A chest X-ray should be performed at baseline in all PLWH. (D) 9. All patients should receive baseline screening for a variety of other infectious agents to assess the need for immunization, monitoring, and counselling (see Section 4, Screening and Immunization for Selected Co-Morbid Infections). (D) 10. PLWH should be advised of the risk of onward transmission, the effectiveness of HIV treatment in preventing transmission, other practices to prevent transmission, and the legal implications of HIV non-disclosure with their sexual partners. (D)
# SCREENING AND IMMUNIZATION FOR SELECTED CO-MORBID INFECTIONS
Tuberculosis Screening
1. All PLWH should be screened at baseline for Mycobacterium (M.) tuberculosis (TB) infection. (A) Screening involves reviewing history of TB exposure and/or treatment history and previous tuberculin skin test (TST) and/or interferon gamma release assay (IGRA) results. (B) A chest X-ray should be undertaken if there is history of TB exposure or positive screening test. (B) 2. In BC, the TST using 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) is the main test for diagnosing latent TB infection (LTBI), provided there are no contraindications. (B)
3. IGRAs are currently recommended as an adjunct test to TST and may be valuable in the following two situations: a) PLWH with CD4 cell count <200 cells/mm 3 who are TST-negative (if possible, the T-SPOT® assay is preferred); and b) PLWH with a history of contact with active TB and who are TST-negative. (C)
# Toxoplasmosis Screening
1. All PLWH should be screened at baseline for Toxoplasma IgG antibodies to determine prior exposure to Toxoplasma (T.) gondii. (D)
# Hepatitis Screening
1. PLWH should be screened at baseline for hepatitis A virus (HAV) using total anti-HAV antibodies. (B)
2. PLWH should be screened at baseline for hepatitis B virus (HBV) using HBsAg (hepatitis B surface antigen), anti-HBs (hepatitis B surface antibody), and anti-HBc (hepatitis B core antibody). (B)
# Screening for Syphilis and Other Sexually Transmitted Infections (STIs)
1. All PLWH should be screened for syphilis at baseline with Treponema pallidum-specific enzyme immunoassay (EIA). (B) Syphilis screening should be repeated annually, or every 3-6 months in the presence of ongoing risk behaviours, or in the presence of symptoms. (D)
2. A lumbar puncture should always be performed for patients with a reactive syphilis serology who have neurologic or ocular symptoms or signs, irrespective of past syphilis treatment history. (D)
3. All PLWH should be screened at baseline for gonorrhea and chlamydia. (B) Screening should occur every 3-6 months in the presence of ongoing risk behaviours or in the presence of symptoms. (D)
# Recommended Vaccines
Hepatitis A
1. All PLWH who are susceptible (anti-hepatitis A [HAV] negative) should be vaccinated against HAV, ideally when CD4 >200 cells/mm 3 . (B)
2. The HAV vaccine should be administered intramuscularly at the standard dose, at 0, 1, and 6 months. (B)
# Hepatitis B
1. All PLWH who are susceptible to hepatitis B virus (HBV) infection (HBsAg negative and anti-HBs less than 10 IU/mL) should be vaccinated against HBV, ideally when CD4 >200 cells/ mm 3 . (B)
2. HBV vaccination should also be offered to PLWH who have positive hepatitis B total core antibody (anti-HBc) with negative HBsAg and anti-HBs results (titre less than 10 IU/mL) and undetectable HBV DNA. (D)
3. In the situations described above, HBV vaccine should be administered intramuscularly (IM) to PLWH 20 years of age and older at a higher dose (40 mcg).
• Recombivax HB® (10 mcg/mL): give 4.0 mL IM at 0, 1, and 6 months (B)
• Recombivax HB ® Adult Dialysis formulation (40 mcg/mL) give 1.0 mL IM at 0, 1, and 6 months (B)
• Engerix®-B Adult (20 mcg/mL): give 2.0 mL IM at 0, 1, 2, and 6 months (B)
4. Post-serologic testing (using anti-HBs) within 1-6 months of completion of the vaccine series is recommended to monitor success of immune response to vaccine. (B)
# Pneumococcal Disease
1. All PLWH should be vaccinated against pneumococcal disease using standard vaccine doses (A), regardless of CD4 cell counts and according to the following schedules: (i) Individuals who have not previously received any pneumococcal vaccine: One dose of conjugate pneumococcal vaccine (Pneu-C-13) is followed at least 8 weeks later by one dose of polysaccharide pneumococcal vaccine (Pneu-P-23). (B) (ii) Individuals who have received a pneumococcal polysaccharide vaccine (Pneu-P-23) previously: The Pneu-C-13 dose should be administered at least one year after any previous dose of Pneu-P-23. (C) (iii) If re-immunization with Pneu-P-23 is needed, it should be given at least 8 weeks after the Pneu-C-13 dose and at least 5 years after the initial Pneu-P-23 dose. (C)
# Influenza
1. All PLWH should be vaccinated annually against influenza using standard doses of the inactivated vaccine, regardless of CD4 cell counts or HIV plasma viral load. (B)
# Tetanus and Diphtheria
1. All PLWH should be offered a tetanus and diphtheria (Td) toxoid booster every 10 years, ideally when CD4 >200 cells/mm 3 . (D)
# Human Papillomavirus (HPV)
1. HPV-9 vaccine is recommended for all PLWH aged 9-27 years (A) and should be strongly considered in women and MSM aged 27 years and older. (B) A three-dose series is recommended in adults.
# Additional Vaccines
Measles, Mumps, and Rubella (MMR)
1. All PLWH without evidence of immunity and with CD4 cell counts >200 cells/mm 3 should be considered for measles and/or mumps and/or rubella vaccination (given as a two-dose series of MMR vaccine). (B)
# Varicella
1. All PLWH without evidence of immunity and with CD4 cell counts >200 cells/mm 3 may be considered for varicella vaccination (given as a two-dose series of varicella vaccine given >3 months apart). (D)
Herpes Zoster
# Hypogonadism
1. Cisgender men living with HIV presenting with symptoms of hypogonadism should be assessed with a morning serum total testosterone level; an abnormal testosterone level should be confirmed with repeat testing. (B) An estimated bioavailable testosterone measurement may be helpful to assess certain individuals, including obese cisgender men with borderline low total testosterone levels. (B)
2. Testosterone replacement is indicated only for symptomatic cisgender men with total testosterone levels less than 10 mmol/L (B) and should be prescribed in consultation with a specialist. (D)
3. Endocrine therapy for transgender individuals living with HIV should be provided in consultation with an endocrinologist or other clinician who has experience providing endocrine care to transgender individuals. (D)
# Neurocognitive Impairment
1. ART to suppress plasma viral load should be started early and administered continuously to prevent or minimize HIV-related neurocognitive impairment. (B)
2. In PLWH presenting with cognitive complaints that affect their daily functioning, an investigation should be done to rule out relevant underlying conditions. (B)
# Lung Disease
1. Smoking cessation should be strongly encouraged in all PLWH because they are at a higher risk for chronic obstructive pulmonary disease (COPD) and lung cancer than smokers who do not have HIV. (A)
2. A chest X-ray should be performed at baseline in all PLWH. (D) Once infection has been treated or ruled out, patients with persistently abnormal chest X-ray findings should be investigated and referred to a respiratory specialist if necessary. (D)
# Mental Health
1. Mental health should be proactively assessed during clinic visits, and identified conditions should be managed using a stepped-care approach. (D)
# BACKGROUND
# INTRODUCTION
Today, HIV infection is a chronic manageable medical condition. Early diagnosis and initiation of potent antiretroviral therapy (ART) has dramatically improved the management of HIV infection and has led to substantial reductions in HIV-related morbidity and mortality.(1, 2) A study from 2013 estimated that a 20-year-old living with HIV and receiving ART in the U.S. or Canada could expect to live into their early 70s, a life expectancy approaching that of the general population.(3) In addition, there is now clear evidence that the widespread use of ART prevents HIV transmission at the individual (4-6) and population level. (7)(8)(9) In order for ART to be effective, individuals must be fully engaged in care, from the initial assessment following diagnosis, in order to receive timely initiation of ART and achieve long-term retention in care and virologic suppression. This concept, known as the HIV Cascade (or Continuum) of Care (10) has been adopted as the framework for assessing progress in HIV care and treatment in BC (Figure 2.1) and more generally as the 90-90-90 targets promoted by UNAIDS. (11) As of the end of 2018, an estimated 92% of people living with HIV (PLWH) in BC were diagnosed, 91% of those diagnosed were receiving ART, and of those on ART, 94% had a measured HIV viral load <200 copies/mL. (12) Providing appropriate and accessible primary care services is key to helping PLWH to remain fully engaged in HIV care and treatment.
# MODES OF HIV TRANSMISSION
The key modes of HIV transmission -sexual contact, perinatal transmission, and exposure to infected blood (e.g. through sharing of injection drug paraphernalia or receipt of contaminated blood products) -were clarified early in the AIDS epidemic. In untreated PLWH, HIV is present in significant concentrations in blood, semen, vaginal and rectal fluids, breast milk, and other body fluids contaminated with blood. However, the likelihood of HIV transmission by different routes of exposure varies markedly, as shown in
# NATURAL HISTORY OF HIV/AIDS
The mean time from HIV exposure to onset of acute seroconversion illness is generally 2-4 weeks, with a range of 5-29 days (19), and only an estimated 34% of PLWH will experience symptomatic seroconversion illness (see Appendix 1, page 112: Signs and symptoms associated with HIV Seroconversion Syndrome/ Acute Retroviral Syndrome and their frequency in symptomatic individuals). (20) During seroconversion without ART, there is an initial drop in CD4 cell counts and peak of viremia before CD4 cell counts increase (although to levels typically below pre-infection levels) and viral load decreases and stabilizes at a set point for several years (Figure 2.2). Without ART, there is considerable variability in the time of onset of further symptoms and late-stage disease. People whose CD4 cell counts stabilize above 500 cells/mm 3 may remain healthy for several years before CD4 cell counts begin to decline. In some cases, CD4 cell counts can drop rapidly after infection in the absence of ART; however, the usual scenario is that without treatment, CD4 cell counts decline over approximately 5-8 years until symptoms begin to appear. A small proportion of PLWH (5-10%), called "long-term non-progressors, " will maintain low viral load and stable CD4 cell counts for decades without specific treatment.( 21 However, timely initiation of ART will effectively prevent disease progression. In previous eras, HIV treatment was often deferred until PLWH demonstrated some degree of disease progression; however, there is now clear evidence that treating PLWH immediately after diagnosis provides substantial clinical benefits and this should be emphasized at all clinical encounters. Evidence:
# HIV TESTING
Newly diagnosed individuals should be assessed by a primary care physician or nurse practitioner (NP) within a few days of receiving a positive HIV test result (ideally less than 2 weeks) so that the baseline laboratory workup can be ordered and the individual can receive appropriate counselling and rapid initiation of antiretroviral treatment (ART
# INITIAL ASSESSMENT
Clinicians should obtain a comprehensive present and past medical history, including HIV-related information, assessment of present medications, family history and psychosocial issues and review of systems. A complete physical examination should be performed upon the patient's entry into care or as soon afterwards as possible. In the setting of rapid ART initiation, clinicians may abbreviate the initial assessment and conduct a more targeted exam. A more comprehensive assessment should be done in follow-up.
Important elements of the initial assessment are included in In the course of taking a medical history, health care providers should also assess the individual's understanding of HIV disease (including risk for HIV transmission), explore their understanding of and readiness to initiate ART, note potential barriers to treatment adherence, and identify their psychosocial needs. The baseline evaluation should also include a discussion of risk reduction and disclosure to sexual and/or needle-sharing partners, especially with individuals who are not receiving HIV treatment and are still at high risk of HIV transmission (see Section 3.4).
# PHYSICAL EXAMINATION
Clinicians should perform a comprehensive physical examination at baseline and when appropriate, with particular attention to systems potentially affected by HIV (see Table 3
# BASELINE LABORATORY EVALUATION
Two main surrogate markers are used to monitor the disease progression in PLWH: CD4 cell count to assess immune function and plasma HIV RNA (viral load) to assess level of HIV viremia.
The absolute CD4 cell count is a significant clinical indicator of immunocompetence in PLWH.( 9) It is a calculated value based on the total white blood cell (WBC) count and the percentages of total and CD4 T-lymphocytes. (10) This absolute number may fluctuate in individuals or may be influenced by factors that affect the total WBC count and lymphocyte percentages, such as the use of bone marrow-suppressive medications or the presence of acute infections. Splenectomy or co-infection with human T-lymphotropic virus type 1 (HTLV-I) may cause misleadingly elevated CD4 cell counts. These markers are used to stage HIV disease initially and are subsequently used as predictors of disease progression and survival.(11) CD4 cell counts are also used to determine the risk of opportunistic infections (OIs), the need for prophylaxis for OIs or other AIDS-defining illnesses, and when to stop prophylaxis. (12,13) HIV plasma viral load (HIV pVL) is the most important indicator of infectivity and response to ART and should be measured in all PLWH at initial assessment, at initiation of therapy and on a regular basis thereafter.(12) A patient's baseline viral load level and the magnitude of viral load decline after initiation of ART provide prognostic information about the probability of disease progression.( 14) Commercially available HIV-1 RNA assays do not detect HIV-2 viral load (for more information regarding HIV-2 refer to the HIV-2 infection chapter in the United States Department of Health and Human Services (DHHS) guidelines; https://clinicalinfo. hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf). (15) All patients should be assessed for transmitted HIV drug resistance using genotypic drug resistance testing, regardless of the estimated duration of HIV infection. Ideally, drug resistance testing should be conducted on the first available sample of HIV plasma viral load. A resistance test should be done in individuals who reengage in care and are not currently receiving ART, recognizing that the absence of resistance mutations due to lack of selective pressure may not accurately reflect drug activity.(15) Standard genotypic drug resistance testing in ART-naïve persons involves testing for mutations in the reverse transcriptase and protease genes. Although reports of transmission of virus resistant to integrase strand transfer inhibitors (INSTIs) are rare, clinicians are increasingly prescribing this class of antiretrovirals and there is potential for the transmission of INSTI-resistant virus. (16)(17)(18)(19) In BC, when HIV resistance testing is requested for a patient whose plasma viral load exceeds 250 copies/mL for the first time since diagnosis, the sample automatically undergoes testing for resistance to the INSTI class. (11) In BC, resistance testing can be requested in archived viral load samples. For more information regarding drug resistance testing, refer to the Laboratory Program tab on the BC-CfE website (http://bccfe.ca/research/laboratory-program/ laboratory-test-order-forms).
HLA-B*5701 is not a specific HIV test, but rather a genetic test. Screening for HLA-B*5701 identifies persons at a high risk for hypersensitivity reaction (HSR) to the antiretroviral agent abacavir. Screening should be performed prior to starting any patient on an abacavir-containing regimen (including fixed-dose combinations, e.g. Kivexa, Triumeq®). HSRs, including fatalities, have been documented in individuals re-challenged with abacavir after a suspected HSR. In addition, screening for HLA-B*5701 should be performed, if not done previously, for patients who are re-initiating abacavir following a gap in therapy, even if they had previously tolerated the drug, because there is a potential for HSR in this setting. (20,21) Hematological panel (CBC with differential and platelet count) should be done at baseline since anemia, leukopenia and thrombocytopenia are common in people with untreated HIV infection. A comprehensive chemistry panel (including creatinine, eGFR, serum phosphorus, urinalysis, urine albumin to creatine ratio (UACR), albumin, total bilirubin, aspartate transaminase, and alanine transaminase) is important to assess baseline renal and hepatic function and pre-existing conditions. Screening for diabetes mellitus with fasting glucose and/or hemoglobin A1C is recommended due to the increased incidence of diabetes in this population. A lipid profile should be done upon initial assessment when possible, since many ART drugs, HIV infection itself, and other host factors can increase cholesterol and triglyceride levels.
A chest radiography should be done at baseline to rule out underlying lung disease and for use as a baseline comparison in future evaluations of any respiratory illness, particularly in persons from high TB prevalence populations (see Table 3.
# 3).
All individuals should receive baseline screening for a variety of other infectious agents, including other sexually transmitted infections and hepatitis A, B, and C virus, to assess the need for treatment, immunization, monitoring, and counselling (see Section 4). Rates of sexually transmitted infections have increased significantly in men who have sex with men, and screening at baseline for gonorrhea and chlamydia in urine and other sites of contact (oral and anal) are recommended. Furthermore, all PLWH should receive a syphilis test at baseline.
# COUNSELLING PLWH REGARDING HIV TRANSMISSION RISK
Recommendation:
1. PLWH should be advised of the risk of onward transmission, practices to prevent transmission, especially the effectiveness of HIV treatment in preventing transmission, and the legal implications of HIV non-disclosure with their sexual partners.
# Evidence:
Safer sex and substance use practices to prevent onward transmission of HIV should be discussed with PLWH, and are especially important while the plasma HIV viral load is high (e.g. prior to starting ART and during the first few weeks of therapy or when there is treatment interruption). It has now been clearly demonstrated that even after repeated sexual exposures without using condoms, PLWH who are adherent to ART and have HIV plasma viral load <200 copies/mL do not transmit HIV via sexual contact. This principle of "undetectable = untransmittable" or "U=U" has been shown for both heterosexual couples and men who have sex with men.(24-28) However, the Supreme Court of Canada (2012) ruled that there is an obligation to disclose HIV-positive status in relation to vaginal or anal sex unless both of the following conditions are met: a condom is used and the PLWH has "low" viral load (<1500 copies/mL). Under these circumstances, the Supreme Court of Canada holds that there is no realistic possibility of transmission. If PLWH were to engage in sexual activity that is considered to have a "realistic possibility of HIV transmission" without first disclosing their HIV status, they can be subject to criminal prosecution (most often aggravated sexual assault). (29,30) PLWH should be advised of the legal implications of HIV non-disclosure. Further information for PLWH is available from:
# SCREENING AND IMMUNIZATION FOR SELEC TED CO-MORBID INFEC TIONS 4.1 SCREENING FOR CO-MORBID INFECTIONS
Tuberculosis Screening Recommendations:
1. All PLWH should be screened at baseline for Mycobacterium (M.) tuberculosis (TB) infection.
(A) Screening involves reviewing history of TB exposure and/or treatment history and previous tuberculin skin test (TST) and/or interferon gamma release assay (IGRA) results. (B) A chest X-ray should be undertaken if there is history of TB exposure or positive screening test. (B)
2. In BC, the TST using 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) is the main test for diagnosing latent TB infection (LTBI), provided there are no contraindications. (B) The tuberculin skin test (TST), consisting of the intradermal injection of a small amount of purified protein derived from M. tuberculosis bacteria, is the standard screening test for TB. In a person who has cell-mediated immunity to these tuberculin antigens, a cell-mediated, delayed hypersensitivity reaction will occur within 48-72 hours. The reaction will cause localized swelling and will manifest as induration of the skin at the injection site. Induration of ≥5 mm is considered significant in PLWH.(1) TST remains the standard method of diagnosing LTBI(1) in Canada, although it is recognized that TST has certain limitations. The sensitivity of the TST decreases in parallel with an individual's CD4 cell count. The TST has particularly low sensitivity in people with CD4 <200 cells/mm 3 Positive TST results should be followed by treatment for LTBI, once active TB disease is ruled out, through referral to provincial TB Services offered by the BCCDC.
# Toxoplasmosis Screening
Recommendation:
1. All PLWH should be screened at baseline for Toxoplasma IgG antibodies to determine prior exposure to Toxoplasma (T.) gondii. (D)
# Evidence:
Seroprevalence of T. gondii in North American adults is approximately 10-20%. Toxoplasma encephalitis (TE) is the most frequent clinical manifestation of central nervous system (CNS) disease in PLWH. (15) The serologic test for Toxoplasma cannot be used to diagnose or reliably exclude toxoplasmosis in PLWH. (12) Positive serology identifies individuals at a greater risk of disease. Peripheral blood serology is positive for Toxoplasma IgG (but negative for IgM) in the vast majority of patients with AIDS-related TE. However, in one study from San Francisco, 16% of those presenting with AIDS-related TE had negative serum serology for IgG by immunofluorescence.(15) Among T. gondii-infected (i.e. Toxoplasma IgG antibody positive) adult PLWH not receiving prophylaxis and with CD4 cell counts <100 cells/mm 3 , the probability of developing clinical toxoplasmosis is approximately 38%.( 12)
# Hepatitis Screening
Recommendations:
1. PLWH should be screened at baseline for hepatitis A virus (HAV) using total anti-HAV antibodies. (B) HIV and hepatitis B virus (HBV) share routes of transmission, including percutaneous (principally among people who inject drugs [PWID]), sexual (anal, vaginal, and oral) and vertical transmission. (16) The reported prevalence of HIV-HBV co-infection is between 6-10%, with higher rates observed in PWID, MSM, and individuals from endemic areas.(20) HIV-HBV co-infection is associated with an eight-fold increase in risk of mortality compared to HBV mono-infection.( 21) Therefore, traditional HBV markers, such as HBsAg (surface antigen), anti-HBs (surface antibodies), and anti-HBc (core antibodies), will assist in distinguishing individuals who are chronically infected from those who have developed a natural or acquired immune response or those susceptible to HBV infection (thus, in need of receiving immunization).
Assessment for liver disease from chronic HBV infection and screening for hepatocellular carcinoma should follow standard Canadian guidelines.( 22) However, all PLWH with chronic HBV infection should be offered ART including tenofovir disoproxil fumarate (DF) or tenofovir alafenamide (AF) in combination with emtricitabine in order to control HBV viral replication.
In Canada, the prevalence of HIV-hepatitis C (HCV) co-infection ranges from 20% to almost 90% in certain subgroups.( 23) HCV is highly prevalent among PWID; a review of international studies suggests that between 50-95% of PWID are infected with HCV. (24) Canadian studies report HCV rates as high as 82% among PWID. (25,26) If left untreated, HCV infection becomes chronic in up to 85% of co-infected individuals, potentially leading to progressive fibrosis and ultimately cirrhosis and death.(24) A metaanalysis of seventeen studies concluded that the rate of progression to hepatic fibrosis among individuals co-infected with HIV-HCV appears constant across all stages of fibrosis, and that chronic HCV outcomes are worse among co-infected individuals. Over the period studied, ART did not appear to fully reverse the adverse effect of HIV infection on HCV disease prognosis. (27) The probability of survival is also reduced among HIV-HCV co-infected individuals compared to those who are HIV mono-infected.( 28
# Screening for Syphilis and other Sexually Transmitted Infections (STIs)
Recommendations:
1. All PLWH should be screened for syphilis at baseline with Treponema pallidum-specific enzyme immunoassay (EIA). (B) Syphilis screening should be repeated annually, or every 3-6 months in the presence of ongoing risk behaviours, or in the presence of symptoms. (D)
2. A lumbar puncture should always be performed for patients with a reactive syphilis serology who have neurologic or ocular symptoms or signs, irrespective of past syphilis treatment history. (D)
3. All PLWH should be screened at baseline for gonorrhea and chlamydia. (B) Screening should occur every 3-6 months in the presence of ongoing risk behaviours or in the presence of symptoms. (D)
# Evidence:
In North America, sexual transmission is the predominant route for acquiring HIV. This has prompted the recommendation to screen all PLWH for asymptomatic sexually transmitted infections (STIs). A cohort study reported a baseline STI prevalence of 14% among PLWH (n=212, 95% confidence interval [CI] 9%-19%) and the incidence of new infections was 20.8 cases per 100 person-years (95% CI 14.8-28.4).( 31)
The prevalence of STIs in British Columbia is increasing. The provincial prevalence of infectious syphilis, as elsewhere in North America, has increased over the past fifteen years. With the exception of a short period of decline in 2009-2010, infectious syphilis rates have increased steadily to 14. A lumbar puncture should always be performed for patients with a reactive syphilis serology who have neurologic or ocular symptoms or signs, irrespective of past syphilis treatment history. In asymptomatic patients, a lumbar puncture may be considered for those patients with an RPR titre of > 1:32 or a CD4 of < 350 cell/mm 3 , which are laboratory criteria that improve the ability to identify asymptomatic neurosyphilis.(34) However, studies defining the clinical outcomes associated with a broader versus more narrow utilization of lumbar puncture in asymptomatic PLWH with syphilis have not been conducted.
For gonorrhea and chlamydia, a Nucleic Acid Amplification Test (NAAT) should be conducted at baseline in all PLWH using first-catch urine specimen and site-specific testing as indicated (oropharyngeal and rectal swabs) for MSM and others with potential sexual exposure at these sites. The validated multisite APTIMA swab is recommended for use (as opposed to the urethral/cervical swab). In PLWH who have a cervix, a cervical swab could be taken. Although not validated, vaginal swabs can be used for screening in transfeminine individuals who are post-operative (i.e. after gender-affirming surgery). In cases of possible sexual assault, pharyngeal, anal, and/or vaginal swabs should be taken. (35) Prevalent and incident asymptomatic STIs are common among MSM living with HIV, and thus increasing the frequency of screening to every 3-6 months is warranted for those with ongoing risk for infection (i.e. ongoing sexual activity with casual or multiple partners).
# IMMUNIZATIONS AND HIV
Prevention of intercurrent illness is a crucial aspect of HIV care. (29,36) The use of vaccines provides an opportunity to prevent infectious diseases in PLWH, who are more susceptible to these diseases. (17) Immunosuppression can reduce the effectiveness of vaccines and increase the risks associated with live vaccines. (17,19,37) CD4 cell counts are an important measure that can be used to help optimize the timing of immunizations and predict patient response to vaccines -in general, if a PLWH has a CD4 cell count ≥200 cells/mm 3 they will have a better response to vaccination.
General principles that primary care providers can follow for PLWH are shown below (adapted from the BCCDC Immunization Guide and the Canadian Immunization Guide)(17):
• Immunize at the time when maximum immune response can be anticipated (i.e. early in the course of HIV disease or following CD4 recovery with antiretroviral therapy).
• It is safer, and likely more effective, to immunize when CD4 cell counts are >200 cells/mm 3 .
• Use caution in the use of live vaccines based on CD4 cell counts.
• Use of the measles, mumps, and rubella (MMR) and varicella vaccines in those with CD4 <200 cells/mm 3 is not recommended.
• There is no contraindication to the use of inactivated or component vaccines at any CD4 level.
# RECOMMENDED VACCINES
# Hepatitis A
Recommendations:
1. All PLWH who are susceptible (anti-hepatitis A [HAV] negative) should be vaccinated against HAV, ideally when CD4 >200 cells/mm 3 . (B)
2. The HAV vaccine should be administered intramuscularly at the standard dose, at 0, 1, and 6 months. (B)
# Evidence:
Serologic response rates of all HAV vaccines are between 95-100% amongst HIV-negative individuals.(17) Seroconversion rates are lower among PLWH for many vaccines and HAV seroconversion is no exception, with rates ranging from 48-64% (depending on the timing of measurement of serological response). (38,39) A meta-analysis reported an overall response rate of 64% for PLWH.(40) A three-dose regimen (at 0, 1, 6 months) has been shown to have better results than a two-dose regimen (at 0 and 6 months) among PLWH, with one comparative study reporting seroconversion rates of 78% and 61%, respectively.(41) The standard HAV vaccination doses are 1.0 mL intramuscularly (IM).( 37)
# Hepatitis B
Recommendations:
1. All PLWH who are susceptible to hepatitis B virus (HBV) infection (HBsAg negative and anti-HBs less than 10 IU/mL) should be vaccinated against HBV, ideally when CD4 >200 cells/ mm 3 . (B)
2. HBV vaccination should also be offered to PLWH who have positive hepatitis B total core antibody (anti-HBc) with negative HBsAg and anti-HBs results (titre less than 10 IU/mL) and undetectable HBV DNA. (D)
3. In the situations described above, HBV vaccine should be administered intramuscularly (IM) to PLWH 20 years of age and older at a higher dose (40 mcg).
•
# Evidence:
The overall seroconversion rate (defined as Anti-HBs >10 mIU/mL) to standard HBV vaccine dosing (10 mcg of Recombivax HB® or 20 mcg of Engerix®-B IM [deltoid]) following a 0, 1, and 6 month dosing regimen appears to be on the order of 26-65%. (17,(42)(43)(44) The etiology of poor seroconversion rates in PLWH is multi-factorial and not completely elucidated. Contributing factors may include age, sex, race, CD4 cell count (both nadir and at time of vaccination), HIV viral load, treatment with antiretrovirals, smoking and alcohol abuse. The benefit of using higher doses of HBV vaccine in immunocompromised individuals is now well-established, both in HIV and in other immunodeficiency states. (42,45,46) In particular, higher HBV seroconversion rates are reported in PLWH on antiretroviral therapy (ART) with low HIV plasma viral load and high CD4 cell counts. The low seroconversion rate is an indication to conduct post-vaccination testing (HBsAg and anti-HBs) on one occasion, between 1 and 6 months after the completion of the initial vaccination series. (47) PLWH with isolated antibody to hepatitis B core antigen (HBsAg negative and surface antibody titre <10 IU/mL and no detectable HBV DNA) may also benefit from HBV vaccination. (48) Once an anti-HBs antibody titre of >10 IU/mL has been documented, no further testing or vaccination is required, even if a later measurement is found to be <10 IU/mL.
Vaccine non-responders following the first series should receive a complete second series of three doses.
If they fail to respond to a second series, they should be recorded as susceptible and receive hepatitis B immune globulin (HBIg) following a high risk hepatitis B exposure.( 49)
# Pneumococcal Disease
Recommendations:
1. All PLWH should be vaccinated against pneumococcal disease using standard vaccine doses (A), regardless of CD4 cell counts and according to the following schedules: While one study comparing Pneu-C-7 to Pneu-P-23 found that the conjugated vaccine elicited better serologic response,( 66) other studies have looked into possible synergistic effect of a dual vaccination regimen that incorporates both the conjugate and the polysaccharide vaccines, with the conjugate vaccine used first as an immune primer. (67)(68)(69)(70)(71) In addition, the sequence of vaccination is important, as initial receipt of Pneu-P-23 followed by conjugate vaccine results in lower antibody levels than initial vaccination with the conjugate vaccine.( 72) PLWH who receive the polysaccharide vaccine first should have delayed administration of the conjugate vaccine at least 12 months later. The National Advisory Committee on Immunization (NACI) concluded that there is good evidence to recommend the use of Pneu-C-13 for PLWH, given the efficacy and immunogenicity of Pneu-C-7.(73) The Pneu-C-13 vaccination dose is 0.5 mL IM and the Pneu-P-23 vaccination dose is 0.5 mL (subcutaneously [SC] or IM), although SC administration is associated with more discomfort at the injection site.(37)
# Influenza
Recommendation:
1. All PLWH should be vaccinated annually against influenza using standard doses of the inactivated vaccine, regardless of CD4 cell counts or HIV plasma viral load. (B)
# Evidence:
Caused by influenza A and B viruses, influenza occurs in Canada every year, generally during late fall and the winter months. Influenza A viruses are the most common cause of annual influenza epidemics. (17) The annual incidence of influenza varies widely, depending on the virulence of circulating strains and the susceptibility of the population, which is affected by antigenic changes in the virus, vaccine match, and vaccine coverage.(17) PLWH form part of the group at the greatest risk of serious infections, complications, hospitalizations, and/or death from influenza. (17,74) In PLWH, influenza vaccine reduces the incidence of respiratory illnesses from 49% to 29% and of laboratory-confirmed influenza from 21% to 0%. (75) As is the case with other vaccines, influenza vaccine efficacy is impaired in PLWH. One study estimated that vaccine efficacy decreased from 65% in PLWH with CD4 cell counts >100 cells/mm 3 to 11% in those with lower CD4 cell counts.(76) However, the benefits of the influenza vaccine in preventing severe illness and hospital/intensive care unit admissions prompted the US Centers for Disease Control (CDC) to recommend the use of the vaccine in PLWH, regardless of CD4 cell counts or HIV plasma viral load. (77) A single annual IM dose of 0.5 mL is currently recommended. (17,37) There is no indication for pre-or post-immunization serology testing.(17) Inactivated influenza vaccine is recommended and live attenuated intranasal vaccine should not be used in this population. (19,29,37,78) Influenza vaccines publicly funded in British Columbia vary year to year. For details of which vaccines are being used in any given season, refer to the BCCDC's Immunization Manual (http://www.bccdc.ca/discond/comm-manual/CDManualChap2.htm).( 79)
# Tetanus and Diphtheria
Recommendation:
1. All PLWH should be offered a tetanus and diphtheria (Td) toxoid booster every 10 years, ideally when CD4 >200 cells/mm 3 . (D)
# Evidence:
The recommendation above is based on the assumption that the diphtheria vaccine is being offered to an adult who has completed a primary series of childhood vaccinations. Routine immunization against diphtheria in infancy and childhood is a common practice throughout the world and has contributed to a significant decline in morbidity and mortality from this disease.(80) Serosurveys of healthy adult populations in Canada indicate that approximately 20% of those surveyed (higher in some age groups) do not have protective levels of antibody to diphtheria. Thus, the potential for re-emergence of this disease exists.( 81)
The immunity conferred by diphtheria vaccine is antitoxic, not antibacterial. Vaccination thus protects against the systemic effects of diphtheria toxin but not directly against local infection.(81) After the primary vaccination series in immunocompetent individuals, over 99% develop antibody levels that are considered protective against disease. (80) The antitoxin is believed to persist at protective levels for 10 years or more. Titres decline slowly with time but are boosted by additional vaccine doses. (80) Tetanus is rare in Canada. However, serosurveys suggest that a substantial proportion of Canadians have non-protective tetanus antitoxin levels. Factors associated with lack of immunity to tetanus include increasing age, birth outside Canada, and absence of immunization records. (81) The antibody response to tetanus boosters given to adults living with HIV or other humoral immune deficiencies is suboptimal.(80)
# Human Papillomavirus (HPV)
Recommendation:
1. HPV-9 vaccine is recommended for all PLWH aged 9-27 years (A) and should be strongly considered in women and MSM aged 27 years and older. (B) A three-dose series is recommended in adults.
# Evidence:
Human papillomavirus (HPV) is a sexually transmitted pathogen that causes ano-genital disease in all sexes. HIV-mediated immune suppression appears to facilitate HPV persistence and its oncogenic potential. In part, this appears to be due to direct enhancement of HPV integration in the presence of HIV.( 82)
In an international study, 77% of women living with HIV (WLWH) had HPV detected at least once (incident infection). HPV 16 was the most frequent genotype, with mixed infection seen in 26%.( 83
# ADDITIONAL VACCINES
Note: This guideline does not provide an exhaustive list of vaccines available to PLWH, including travel vaccines or additional vaccines that may be appropriate in specific circumstances. Please see NACI guidelines for further information regarding additional vaccines for PLWH: https://www. canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html#a29
# Measles, Mumps and Rubella (MMR)
Recommendation:
1. All PLWH without evidence of immunity and with CD4 cell counts >200 cells/mm 3 should be considered for measles and/or mumps and/or rubella vaccination (given as a two-dose series of MMR vaccine). (B)
# Evidence:
In general, live-virus vaccines should not be used among PLWH. In severely immunocompromised populations, measles can present critically and in a prolonged fashion, with a high risk for severe complications.(92-95) Measles, Mumps, Rubella (MMR) vaccination in PLWH with CD4 cell counts >200 cells/mm 3 appears to be safe with no serious adverse events reported.(96-98) Thus, all PLWH without severe immunosuppression (i.e. with CD4 cell count >200 cells/mm 3 ) and no evidence of immunity to measles, mumps, or rubella should be considered for the MMR vaccine.(29, 99) Evidence of immunity includes being born before 1970 or having previously received two doses of measles-or mumps-containing vaccine. All PLWH born before 1957 or who have previously received one dose of rubella-containing vaccine, have serologic proof of immunity, or have had prior lab confirmed rubella disease, are considered to have immunity against rubella. Thus, serological testing may be indicated to confirm the diagnosis of measles, mumps, or rubella or to determine immune status. Serologic testing is not recommended before or after receiving measles-, mumps-or rubella-containing vaccine. If serology is inadvertently done subsequent to appropriate MMR immunization and does not demonstrate immunity, re-immunization is not necessary.(100)
# Varicella
Recommendation:
1. All PLWH without evidence of immunity and with CD4 cell counts >200 cells/mm 3 may be considered for varicella vaccination (given as a two-dose series of varicella vaccine given >3 months apart). (D)
# Evidence:
At the time of publication of these guidelines, there were no published data on varicella vaccination among susceptible PLWH. However, based on expert opinion, varicella vaccine may be safe to offer to susceptible individuals with CD4 counts >200 cells/mm 3 . Live attenuated varicella vaccine remains contraindicated in PLWH with CD4 counts <200 cells/mm 3 . The varicella vaccine is administered as two doses >3 months apart.
A varicella susceptible person is defined as someone who does not have a history of varicella or herpes zoster after 12 months of age and who does not have a history of age-appropriate varicella immunization.
A self-reported history of varicella is adequate for those born before 2004; for those born in 2004 and later, history of a diagnosis by a health care provider is required for reliability. Children who have a history of either physician-diagnosed herpes zoster or lab-confirmed varicella after their first dose of vaccine do not require a second dose. If disease history is uncertain, provide a second dose.( 101)
# Herpes Zoster
Recommendation:
1. The use of inactivated herpes zoster vaccine for prevention of shingles in PLWH over age 50 can now be considered. (D) Dosage and schedule: 0.5mL IM at 0 and 2-6 months. No requirement for repeat dosing currently exists. (D)
# Evidence:
Herpes zoster, commonly known as shingles, is a cutaneous manifestation of the reactivation of the varicella zoster virus (VZV), which causes chickenpox. Manifestations increase after age 50 in the general population and include complications such as post-herpetic neuralgia.
# COVID-19
Recommendation:
# Evidence:
PLWH aged 18 years or older should be vaccinated for COVID-19 if they have no contraindications (see below). These vaccines are not expected to be associated with more serious or different adverse events among PLWH or other immunocompromised individuals. While the evidence is mixed, PLWH may be at increased risk of serious illness due to COVID-19, and in the absence of contraindications should receive any of the COVID-19 vaccines currently approved in Canada as appropriate for their age group, regardless of CD4 count (i.e.: Pfizer-BioNTech, Moderna, AstraZeneca, and Janssen vaccines).
PLWH who have CD4 counts <200 cells/mm 3 or are not virologically suppressed should be counselled regarding the unknown efficacy and safety of the vaccines given that such subjects were not included in the vaccine licensing studies. For more information, visit the BC-CfE Committee for Drug Evaluation and Therapy (CDET) statement on the use of COVID-19 mRNA vaccines in PLWH: http://bccfe.ca/ therapeutic-guidelines/healthcare-providers/therapeutic-guidelines/bc-centre-excellence-hivaids-cdetcommittee-statement.
# CONTRAINDICATED VACCINES
Recommendation:
1. The following live vaccines are contraindicated in PLWH: oral polio, live intranasal influenza vaccine, and BCG (Bacillus Calmette-Guérin). (B)
# Evidence:
For PLWH, additional live vaccines (often used in the context of foreign travel) are either contraindicated or should be used with caution in circumstances where the benefits of a live vaccination are likely to outweigh the risks. Primary care providers may wish to consult with a physician with expertise in HIV or immunization about offering such vaccines to PLWH.(106)
# SPECIAL CONSIDERATIONS FOR CISGENDER WOMEN* LIVING WITH HIV (WLWH)
Note: Guidelines and resources specific to pregnancy and post-partum care, and infant care can be found on the Oak Tree Clinic/BC Women's Hospital and Health Centre website: http://www.bcwomens.ca/ health-professionals/professional-resources/hiv-aids-resources.
# INTRODUCTION
In Canada in 2018, 29% of newly diagnosed HIV cases were in women,( 1) and among the estimated 63,110 people living with HIV (PLWH) in Canada in 2016, 23 % were women. (2) The majority of women living with HIV (WLWH) acquired the disease via heterosexual contact (64%). This holds true for women born in Canada or other non-endemic countries, as well as immigrants from HIV-endemic countries. Injection drug use is the second most common means of transmission for women (28%).( 3) In BC, the proportion of women affected by HIV is smaller than for the country as a whole: 8% of British Columbians newly diagnosed with HIV in 2017 were women.(4) Similar to national trends, heterosexual contact is the most common route of HIV transmission for women in BC, followed by injection drug use.
Frequently, women are caretakers for children/partners/parents and extended family members/ friends, and they may not give sufficient priority to their own medical/psychosocial care and wellbeing. Furthermore, women frequently face unequal power and socioeconomic relationships with their partners. These social factors may increase women's isolation and depression and compromise their adherence to medical care and their antiretroviral therapy (ART). Continued gender inequities with regard to the social determinants of health, particularly poverty and unstable housing, are significant factors disproportionately impacting women and their ability to participate in HIV care. Women who are Indigenous or from other racialized groups and sex workers are especially vulnerable due to multiple intersecting barriers. WLWH in Canada have very high rates of trauma and post-traumatic stress.(5) Many women are affected by multiple forms of trauma, including adverse childhood events, intergenerational trauma, historical trauma, institutional trauma, and stigma. Refugee women have commonly experienced severe trauma related to armed conflict in their country of origin and sexual assault. Based on data from the Canadian HIV Women's Sexual & Reproductive Health Cohort Study (CHIWOS) study, which included more than 1440 WLWH from three Canadian provinces, more than 79% of WLWH reported experiencing violence in adulthood -four times higher than the prevalence among the general population of women in Canada.(6, 7)
Since trauma is recognized as a root cause of multiple health challenges and is an important social determinant of health, in order to be successful in the care of WLWH, clinicians should address at each HIV visit the social determinants of health, including the person's current personal safety and food and * In this chapter, the term women refers to any persons whose gender identity or expression (i.e. woman) coincides with their sex assigned at birth (i.e. female), also referred to as cisgender women. For a discussion of terms used to describe persons whose gender identity or expression do not coincide with their sex assigned at birth, see the footnote on page 75.
housing security, using a trauma informed care model (https://www.traumainformedcare.chcs.org/whatis-trauma-informed-care/).( 8)
A useful Canadian resource for women-centred HIV care is available at: https://whai.ca/resource/caringfor-women-living-with-hiv-women-centred-hiv-care-toolkit/.
It should be noted that not all individuals with a cervix or with pregnancy potential self-identify as women, and not all individuals who self-identify as women have a cervix or have childbearing potential.
For this reason, all recommendations are written using gender inclusive language.
It is important for clinicians to provide trauma-informed care and communicate clearly and respectfully with PLWH, to ensure that they receive care that is appropriate to their needs and life circumstances without judgment, assumptions, or unwanted disclosure with respect to their life, gender, and sexuality. This includes respecting the gender identity and expression of individuals (e.g. using their preferred pronoun and name in conversations and in emails and letters from the clinic addressed to the patient), and creating a safe, non-judgmental space for the person to discuss issues related to their sexual, reproductive, and general health. Cultivating this cultural safety for all, including transgender and non-binary individuals, is also an important part of trauma-informed care.
# SPECIAL CONSIDERATIONS RELATED TO ART DURING PREGNANCY AND THE POST-PARTUM PERIOD
Recommendations:
1. All pregnant PLWH should be treated with ART for their HIV infection, regardless of their immunologic or virologic status, to prevent infection of their fetus. (A)
2. Clinicians should review the latest recommendations regarding ART for individuals who are pregnant or of childbearing potential, since some drugs may be contraindicated or should be used with the guidance of specialized care providers. (D)
# Evidence:
The indications for and goals of ART are the same for all PLWH. Pregnancy plans and wishes should be discussed with all PLWH in reproductive age potential, in each HIV visit. If pregnancy is desired, preconception counselling should be offered, including education around the importance of attaining maximal and sustained viral suppression before attempting conception and maintaining it throughout pregnancy and delivery, for the health of the pregnant person, to prevent sexual HIV transmission to partners without HIV, and to minimize the risk of HIV transmission to the infant. ART regimen selection preconception and during pregnancy should be made in accordance with current BC Guidelines for the Care of HIV Positive Pregnant Women (http://www.bcwomens.ca/health-professionals/professionalresources/hiv-aids-resources), and in consultation with providers who have expertise in this area.
When providing care for individuals planning pregnancy and any individuals of childbearing potential who are not using effective and consistent contraception, providers should carefully review all medications (antiretrovirals [ARVs] and concomitant medications) and avoid drugs with potential reproductive toxicity. The time of greatest developmental risk to the fetus is the first trimester, often before pregnancy is even recognized.
Like many other chronic conditions (e.g. diabetes), HIV can affect the medical management of pregnancy. Nausea and vomiting during early pregnancy can affect ART adherence. Therefore, pregnancy in PLWH is considered high risk and complex. Consultation with an obstetrician specialising in the management of HIV is recommended. In BC, preconception counselling, ARV regimen guidance, and specialized obstetrical services can be obtained from the Oak Tree Clinic in Vancouver: http://www.bcwomens.ca/ourservices/specialized-services/oak-tree-clinic or 604-875-2212; a referral form is available on their website (http://www.bcwomens.ca/health-professionals/refer-a-patient/oak-tree-clinic-hiv-care).
Following delivery, clinical, immunologic, and virologic follow-up should continue as recommended for non-pregnant adults and adolescents. ART should be continued post-partum for the optimal health of the individual. Several studies have demonstrated that adherence to ART may worsen in the post-partum period.(9, 10) Clinicians caring for postpartum individuals should specifically address ART adherence, including an evaluation of specific facilitators and barriers to adherence.
Because use of ART during lactation reduces but does not eliminate the risk of transmission of HIV in breast milk, PLWH in BC should be counselled to avoid breastfeeding, where safe alternatives can be provided. (11) In BC, free formula is provided for all babies born to mothers living with HIV for one year, coordinated by the Oak Tree Clinic. PLWH should avoid pre-mastication of food fed to their infants because the practice has been associated with transmission of HIV from parent to child.(12)
# REPRODUCTIVE ISSUES AND GYNECOLOGIC HEALTH IN THE CONTEXT OF HIV
Recommendations:
1. Contraception needs and pregnancy plans should be discussed with all individuals of childbearing potential (aged 15-50 years) upon initiation of HIV care and routinely thereafter, as pregnancy may affect the choice and timing of antiretrovirals. (D)
2. Selection of a contraceptive method should take into account the PLWH's desires about family planning and preferred contraceptive method, ART regimen, other medications, and co-morbid conditions. (D) Intrauterine devices (IUDs) can be considered as a safe and effective contraception option for PLWH. (B)
3. When prescribing ART, clinicians should take into account that some ARVs have significant pharmacokinetic (PK) interactions with hormonal contraceptives; other effective contraception options should be considered to prevent unplanned pregnancy. (B) Switching to an ARV drug that does not have interactions with hormonal contraceptives may also be considered. (B)
# Evidence:
The incidence and prevalence of gynecological problems are high among WLWH throughout the course of their HIV disease.( 13
# ART AND WEIGHT GAIN IN WOMEN
# Evidence:
Various studies have suggested that sex assigned at birth may influence the frequency, presentation, and severity of some ART-related adverse events, including metabolic complications.(31) Pharmacokinetics of antiretroviral drugs may differ between cisgender men and women, (32) due to factors such as body weight, plasma volume, hormones, gastric emptying time, plasma protein levels, cytochrome P (CYP) 450 activity, drug transporter function, and excretion activity. (33)(34)(35) Several studies indicate that cisgender women experience metabolic complications associated with ART use differently than cisgender men. WLWH are more likely to experience increases in central fat and are at a higher risk of developing particular patterns of lipodystrophy than men living with HIV. Initiation of ART often leads to weight gain. While some of this weight gain may be an appropriate "return-to-health" effect, excessive increases in weight may lead to obesity. Recent data suggest greater weight gain occurs on ART initiation among women than men, especially with the use of integrase strand transfer inhibitors and tenofovir alafenamide (AF). (44)(45)(46)(47) Other factors associated with greater weight gain on ART include black race and lower baseline CD4 cell count. (44,47) The mechanisms by which certain ARV agents differentially contribute to weight gain are unknown and under investigation. In addition to HIV-related effects (CD4 nadir, level of viral load), social/ environmental contributors, and genetic factors on weight gain, there may also be effects of newer, bettertolerated ARV agents, that better target the catabolic effects of HIV.
# MENOPAUSE
Recommendation:
1. When systemic menopausal hormone therapy or non-hormonal medications are indicated for PLWH experiencing menopausal symptoms, potential drug interactions with ART should be considered. (B)
# Evidence:
An increasing number of WLWH are living past menopausal age. In Canada in 2018, 22.2% of cisgender women newly diagnosed with HIV were over 50 years of age.(1) Aging with HIV is an emerging field, and it is now expected that newly diagnosed individuals whose HIV is well controlled will have life expectancies similar to the general population.
In Canadian WLWH, the average age for the onset of menopause is 48 years, which is 3 years earlier than women in the general Canadian population. (48) Earlier menopause observed in PLWH may be multifactorial. (49) There are conflicting data on the effect of HIV on menopausal age and symptoms. (50) Factors that can influence menopausal symptoms, including smoking, stress, drug use, depression, low BMI, and race/ethnicity, are also relatively more prevalent among PLWH. Occasionally, symptoms of menopause may be difficult to distinguish from symptoms related to HIV, including fatigue, sleep disturbances, night sweats, achiness, and mental health effects. (50) Sexual practices in menopausal WLWH are not well described. It is important for health care providers to discuss safer sex practices with PLWH of all ages. However, providers need to take into consideration that there are significant power imbalances for many WLWH that may compromise their ability to have safe sex and expose them to potential intimate partner violence.
There are currently no randomized controlled trials delineating the use of menopausal hormone therapy (MHT) in PLWH. As in the general population, MHT can be considered within 5-10 years of starting menopause in PLWH with severe vasomotor symptoms if the individual is below the age of 60.
For those aged 60 years and over, the risk outweighs the benefits, and MHT is not recommended. (51,52) Contraindications for MHT include unexplained vaginal bleeding, severe liver disease, breast or endometrial cancer, congestive heart failure, stroke, dementia, high risk of venous thromboembolism, hypertriglyceridemia, and severe migraine headaches. In individuals with a uterus, the proliferative effects of systemic estrogen on the endometrium must be countered by an appropriate dose of progestogen, to lower risk of cancer, i.e. combination MHT containing two hormones (estrogen and progestogen). For MHT recommendations, see: https://www.sigmamenopause.com/sites/default/files/pdf/publications/Final-Pocket%20Guide.pdf.
There may be drug interactions of MHT with ART(53, 54) (see https://hivclinic.ca/wp-content/ uploads/2019/09/Hormonal-therapy_contraceptives-HRT_Eng.pdf). Levels of estradiol and progestogens may be increased by CYP3A4 inhibitors, especially cobicistat, potentially increasing MHT side effects and long-term thromboembolic risk. Ritonavir-boosted PIs and older non-nucleoside reverse transcriptase inhibitors (NNRTIs, such as efavirenz, etravirine, nevirapine) may change hormone levels, but the role of MHT dose adjustment has not been studied. Consultation with an HIV-experienced pharmacist, HIV gynecologist, or HIV specialist is recommended.
Hot flashes and night sweats related to menopause may also be managed by non-hormonal medications (e.g. venlafaxine, paroxetine, fluoxetine, gabapentin, or clonidine). (51,52) As with MHT, drug interactions with ART should be considered (see DDI Booklet 2019_English.pdf (hivclinic.ca)) and expert guidance sought as necessary. For urogenital symptoms related to menopause, low-dose vaginal estrogen therapy should be considered.( 55) It has limited systemic absorption and therefore has less systemic side effects/ risks, lower interaction potential with ART, and has been shown to improve symptoms.
# BONE HEALTH
# Evidence:
Women have an increased risk of premature bone loss (osteopenia and osteoporosis), particularly during and after menopause, and this risk is exacerbated by HIV and ART. (56,57) The prevalence of osteoporosis in WLWH is three times greater compared with HIV-uninfected women in the same age group in the United States.( 58)
The pathogenesis of reduced bone mineral density (BMD) noted in PLWH is multi-factorial, with increased risk associated with some
# SPECIAL CONSIDERATIONS FOR TRANSGENDER † INDIVIDUALS LIVING WITH HIV
Recommendations:
1. Endocrine therapy for transgender individuals living with HIV should be provided in consultation with an endocrinologist or other clinician who has experience providing endocrine care to transgender individuals. (D)
# Evidence:
Transgender populations are disproportionately affected by HIV. In a systematic review and meta-analysis among the United States (US) transgender population between 2006 and 2017, the estimated prevalence of HIV infection overall was 9.2% (compared to 13.3 per 100,000 in the US general population in 2018) and was higher among transgender women (14.1%, vs. 4.8 per 100,000) than transgender men (3.2%, vs. 22.1 per 100,000).(1, 2) Numerous challenges can affect health outcomes for transgender people, including socioeconomic factors, mental health issues, substance use, abuse and trauma, stigma, discrimination, social rejection, and exclusion. (3,4) Lack of knowledge of transgender issues among health care providers and prior negative experiences in the health care system may constitute barriers to the transgender person's ability to access and maintain HIV care. Providers should be aware that transgender people may prioritize other health concerns over HIV (e.g. gender-affirming and non-discriminatory care, hormone therapy and its side effects, mental health care including trauma recovery), potentially leading to challenges with adherence to antiretroviral therapy (ART). (4,5) In BC, the care of transgender individuals is provided through a decentralized community-based model of care. While HIV treatment and gender-affirming endocrine therapy may be administered by different providers, transgender people living with HIV (PLWH) should have access to all facets of health care in a safe, welcoming, and respectful clinic environment. For information on the care of transgender individuals, clinicians can refer to Gender-affirming Care for Trans, Two-spirit, and Gender Diverse Patients in BC: A Primary Care Toolkit (September 2019) (http://www.phsa.ca/transcarebc/Documents/ †Note: In this document, transgender includes any person whose gender identity or expression is different from their sex assigned at birth. Transfeminine is used to mean people who were assigned male sex at birth and transmasculine is used to mean people who were assigned female sex at birth and both have gender identity or expression that do not align with their sex assigned at birth.
HealthProf/Primary-Care-Toolkit.pdf). Additional resources for primary care providers are available at: http://www.phsa.ca/transcarebc/health-professionals/clinical-resources.
Gender-affirming endocrine therapy, which allows the acquisition of secondary sex characteristics aligned with the individual's gender identity, should be provided in consultation with an endocrinologist or other clinician who has experience and expertise in this area. The general approach of feminizing hormone therapy is to combine an estrogen (transdermal, injectable [subcutaneous or intramuscular], or oral 17-beta estradiol) with an androgen antagonist (spironolactone, cyproterone acetate, bicalutamide, dutasteride), and in some cases a progestin (micronized progesterone or medroxyprogesterone).( 6) Masculinizing hormone therapy involves the use of one of several forms of testosterone (e.g. injected, transdermal patch or gel, intranasal).( 6) There is considerable variation in the medications that are used for gender affirmation depending on provider and patient preference.
Estradiol, cyproterone, bicalutamide, dutasteride, progestins, and testosterone are substrates of CYP3A4 and may have clinically significant drug interactions with certain ARVs. (7,8) No significant drug interactions are expected between ARVs and spironolactone or finasteride. Estradiol levels may be increased with concomitant cobicistat, increased or decreased with ritonavir, and decreased with efavirenz, etravirine, or nevirapine. Levels of cyproterone, bicalutamide, dutasteride, progestins, and testosterone may be increased with concomitant cobicistat or ritonavir, and decreased with concomitant efavirenz, etravirine, or nevirapine. In transgender individuals receiving endocrine therapy, ART should be chosen to include a non-interacting agent such as doravirine, rilpivirine, or an unboosted integrase inhibitor (raltegravir, dolutegravir, or bictegravir). Otherwise, hormone efficacy and toxicity should be monitored and the hormone doses should be adjusted as necessary.( 7)
BC Cancer provides guidance for healthcare professionals regarding breast/chest screening for transgender, gender diverse, and non-binary people (http://www.bccancer.bc.ca/screening/Documents/Breast-Screening-Transgender-Patients-Provider-Guide.pdf). Transmasculine individuals who have not had bilateral mastectomy and transfeminine individuals between the ages of 40 and 74 who have taken estrogen-based hormone therapy for more than 5 years should be screened according to the BC Cancer breast screening policy for cisgender (non-transgender) persons (http://www.bccancer.bc.ca/screening/health-professionals/ breast/eligibility). Transfeminine individuals who have never taken estrogen-based hormone therapy or have taken hormones for fewer than five years do not need to be screened regularly for breast cancer.
For information regarding cervical cancer screening for transgender PLWH with a cervix, see Section 7.10, page 93, of this document. For further guidelines on cervical cancer screening among transgender individuals, see the BC Cancer website: http://www.bccancer.bc.ca/screening/Documents/CCSP_ GuidelinesManual-ScreeningForCancerOfTheCervix.pdf.
For Trans Care BC recommendations regarding sexual health screening and pelvic examinations, see: http://www.phsa.ca/transcarebc/Documents/HealthProf/Sexual_Health_Screening_and_Pelvic_Exam.pdf .
# COMMON NON-INFEC TIOUS CO-MORBIDITIES 7.1 INTRODUCTION
A number of conditions not traditionally associated with AIDS, including cardiovascular and renal disease, are exacerbated in the presence of uncontrolled HIV replication.(1) Therefore, despite the potential for long-term complications due to chronic antiretroviral therapy (ART), the benefits outweigh the potential risks in people living with HIV (PLWH) who are appropriately treated and monitored.(2) To this end, clinical and laboratory assessment of relevant co-morbid conditions should be performed at baseline before initiation of ART and during follow-up. Screening for non-infectious comorbid conditions is described in Appendix 3, page 114.
The frequency of lab monitoring for antiretroviral toxicity depends on the known potential toxicities of specific drugs, concomitant medications, and underlying co-morbid conditions. Lab monitoring may occur every 4 weeks after initiation of therapy, decreasing to up to every 6 months after stabilization of the patient on their antiretroviral (ARV) regimen.(3) In most cases, the timing of safety laboratory monitoring can be coordinated with monitoring of HIV RNA and CD4 cell counts. For details regarding laboratory monitoring for individuals receiving ART, see Chapter 3 of the BC-CfE Guidelines for Antiretroviral ARV Treatment of Adult HIV Infection | (bccfe.ca).
# CARDIOVASCULAR DISEASE
# Recommendations:
1. All PLWH should be screened for risk of cardiovascular disease at least annually, and modifiable cardiovascular risk factors should be addressed where possible. (D)
2. Blood pressure should be measured at least annually and at each visit (at least every 6 months) if abnormal. (D)
3. Assess lipids (total, HDL, and LDL cholesterol, and triglycerides) and/or apolipoprotein B at baseline and every 6-12 months once patient begins antiretroviral therapy. (B)
4. An electrocardiogram (ECG) should be considered at baseline and periodically (at intervals determined by the degree of risk) in patients taking protease inhibitors and/or rilpivirine with other PR-or QTc-prolonging drugs. (D)
# Evidence:
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the general population.
HIV infection is associated with a doubling of the risk of CVD, including acute myocardial infarction (MI), stroke, peripheral arterial disease, heart failure, and sudden cardiac death.(4-6) Globally, the burden of HIV-associated CVD has tripled over the last 20 years.( 4)
The mechanisms underlying the increased CVD risk in PLWH include a preponderance of traditional risk factors in this population, including smoking, hypertension, dyslipidemia, diabetes, and metabolic syndrome. (4,5) In addition, uncontrolled HIV infection, including during ART interruption, is associated with chronic inflammation and an increased risk of cardiovascular events. (1,7) Even in the setting of controlled HIV viremia, underlying chronic vascular inflammation directly contributes to accelerated atherosclerosis and endothelial dysfunction. Elevated levels of some inflammatory biomarkers, notably high-sensitivity C-reactive protein (hsCRP), are independently associated with a higher risk of MI in PLWH, as in the general population. (8,9) However, the interpretation of hsCRP and other inflammatory biomarkers can be complicated in the setting of the chronic inflammatory state associated with HIV infection. Although ART reduces the levels of these biomarkers, they can remain elevated compared with those of HIV-negative individuals. The clinical utility of these biomarkers for initiation or monitoring therapy in PLWH is unknown.
While virally suppressive ART reduces risk of clinical CVD events,(1) specific ARV agents can be associated with increased CVD risk. In the D:A:D observational cohort from 1999 to 2005, the rate of CV events increased by 16% per year of exposure to ART regimens including older protease inhibitors (PIs). (10) However, more recently, the rate of MI in PLWH has plateaued, attributable at least in part to the use of contemporary PIs; in the D:A:D study from 2009 to 2016, use of darunavir/ritonavir was associated with an increase in CVD risk (59% per 5 years additional use), while use of atazanavir/ritonavir was not.
(11) Although rates of MI are declining in recent years, PLWH receiving newer ART regimens remain at an increased risk of other forms of CVD, notably atrial fibrillation and heart failure. (5) The association between recent use of abacavir and acute MI remains controversial, but most current guidelines recommend avoidance of this agent in people with established CVD or who are at a high risk for CVD.
(5, 12) Some ARV agents such as efavirenz may contribute to CVD risk through their detrimental effect on serum lipids (especially triglycerides and LDL cholesterol), while other have beneficial effects on lipid profiles, including tenofovir DF (compared to tenofovir AF) and unboosted integrase inhibitors. (13)(14)(15)(16) The Canadian Cardiovascular Society Guidelines (https://www.onlinecjc.ca/action/showPdf?pii=S0828-282X%2816%2930732-2) recognizes HIV as a significant risk factor for premature CVD and an indication for screening for cardiovascular risk factors, including lipids, regardless of age.(17) Screening for lipids (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides) and apolipoprotein B (apoB) can be done non-fasting, except in individuals with a history of triglycerides >4.5 mmol/L, where these tests should be performed in a fasting state. ApoB measurement is subject to less laboratory error than LDL cholesterol, particularly in patients with hypertriglyceridemia (as often seen in HIV). LDL cholesterol is currently recommended as the primary treatment target, but apoB and/or non-HDL cholesterol are alternatives and may be the preferred treatment targets in the future. (17) Lipids and apoB should be measured annually, and monitoring frequency should be increased to every 6 months if abnormalities are detected.
Despite the impact of ART and HIV infection itself, traditional CVD risk factors (including age and smoking) remain the most important contributors to CVD in PLWH. (17,18) A modified Framingham Risk Score (FRS) (http://www.ccs.ca/en/guidelines/guideline-resources), where the 10-year FRS percentage is doubled for a family history of premature CVD, is the recommended tool for assessing total 10-year CVD risk in the general population; (17) 21) a switch to a more lipid-friendly ART regimen may also be a consideration.(5) When needed, statins can be used safely for the treatment of dyslipidemia in HIV,( 22) but potentially significant drug-drug interactions between lipid-lowering agents and antiretrovirals (e.g. statins and PIs) must be taken into account (www.hiv-druginteractions.org) (DDI Booklet 2019_ENG DIGITAL.pdf (hivclinic.ca)). Of note, PLWH may not reach desirable lipid targets with conventional statin therapy and combination therapy may be necessary. (23,24) Some older HIV PIs (specifically saquinavir and lopinavir/ritonavir) were associated with PR interval prolongation or QTc interval prolongation. (25)(26)(27) Case reports have also described QTc prolongation and torsades de pointes in association with atazanavir(28) and efavirenz.(29) Cardiac conduction abnormalities may become clinically significant when a ritonavir-boosted PI is co-administered with one or more QTc-prolonging drugs such as methadone, quetiapine, macrolides, quinolones, and/or azoles (for a full list, see the CredibleMeds website at https://www.crediblemeds.org/index.php), or PR-prolonging drugs, such as digitalis, calcium channel blockers, anti-arrhythmics, and beta-blockers. Rilpivirine was associated with QTc prolongation at daily doses of 75 mg or 150 mg, although this does not appear to be a problem at the 25 mg daily dose currently in use. (30)(31)(32) An electrocardiogram (ECG) should be considered at baseline before starting a ritonavir-boosted PI and/or rilpivirine with one or more PR-or QTc-prolonging drugs. A repeat ECG should be performed approximately five half-lives after starting the relevant drug, i.e. approximately 2 days after starting atazanavir/ritonavir, 3 days after starting darunavir/ ritonavir, or 10 days after starting rilpivirine. In addition, an ECG should be done after the addition or dose increase of any other QTc-prolonging drug and at times of increased risk (e.g. hypokalemia, hypomagnesemia). Repeat ECG monitoring should be performed at intervals determined by the degree of risk, i.e. whether the QTc is short (<0.41 seconds), borderline (0.42-0.44 seconds), or prolonged (>0.45 seconds).(33)
# INSULIN RESISTANCE (IR) AND DIABETES MELLITUS (DM)
Recommendations:
1. Fasting blood glucose (FBG) and/or glycated hemoglobin (HbA1C) should be performed in all PLWH at baseline and at 6-to 12-month intervals during antiretroviral therapy. Abnormalities in fasting glucose and/or HbA1C should be evaluated and managed according to the Diabetes Canada guidelines (http://guidelines.diabetes.ca/). (A)
2. Initial management of blood glucose abnormalities in PLWH involves lifestyle changes (weight loss, diet, exercise). (A)
3. Oral anti-glycemic agents and injectable anti-glycemic agents should be used as required, keeping in mind drug interactions with some antiretrovirals. (A)
Evidence:
HIV and its treatment increase the risk of insulin resistance (IR) and diabetes mellitus (DM) by approximately 1.5-to 4-fold compared to the general population, (34,35) and the risk is greater with hepatitis C co-infection.(36) IR is associated with use of older nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs).( 37) Integrase inhibitors may be associated with weight gain, which in turn exacerbates the risk of diabetes, particularly in PLWH; however, an association between integrase inhibitors and clinical metabolic abnormalities has yet to be confirmed. (38,39) Traditional risk factors for DM remain relevant in PLWH.
HbA1C may be monitored as an alternative to fasting blood glucose, particularly if fasting status is difficult to ascertain; however, HbA1C can underestimate glycemia in PLWH, leading to under-diagnosis, especially in the setting of macrocytosis, lower CD4 cell counts, or certain antiretrovirals. (40)(41)(42) Fasting glucose and HbA1C should be measured annually in PLWH, with frequency of monitoring increased to every 6 months if abnormalities are detected.
In PLWH with type 2 diabetes, HbA1C should be measured every 3 months and targets should be established as per the Diabetes Canada Guidelines.(43) HbA1C targets are individualized; in most cases the target is 7%. In type 2 diabetics with CD4<500 cells/mm 3 or mean corpuscular volume (MCV) >95 fL, glucose levels should be used instead of HbA1C to guide management.
As in the general population, initial management of blood glucose abnormalities in PLWH involves lifestyle changes: maintaining healthy weight, healthy diet, and physical activity.(44) Depending on the degree of hyperglycemia at diagnosis, antihyperglycemic agents should be started concomitantly or if blood sugar targets are not met within 3 months of instituting healthy behaviour interventions.(45) Of note, in the presence of dolutegravir, metformin concentrations are increased by 79%, with a potential for increased adverse events. (46) In patients taking dolutegravir, metformin should be started at a low dose and not prescribed in doses greater than 1000 mg daily. Bictegravir increases metformin levels by 39% and no dose adjustment is required for co-administration.(47) In individuals with established cardiovascular disease with suboptimal glycemic control there is a clear role for sodium-glucose cotransporter-2 (SGLT-2) inhibitors and/or glucagon-like peptide-1 (GLP-1) receptor agonists;(45) some precautions should be noted with respect to potential drug interactions with antiretrovirals (TS_Antidiabetic_2019_Oct.pdf (liverpool-hiv-hep.s3.amazonaws.com); DDI Booklet 2019_English.pdf (hivclinic.ca).
# BONE
Recommendations:
1. Clinicians should undertake preventive measures for bone loss in all PLWH, including weightbearing exercises, maintaining ideal weight, reducing smoking and alcohol consumption, and optimizing vitamin D (1000-2000 IU/day) and calcium intake (in the form of diet and/or supplements if necessary). (D)
# Evidence:
PLWH are at a greater risk of fractures than non-infected individuals. (48) The loss of bone density associated with normal aging is accelerated by HIV-associated chronic inflammation and vitamin D deficiency and by exposure to antiretrovirals. (49) The role of specific antiretrovirals in causing bone loss is controversial; however, the evidence points to tenofovir DF and ritonavir-boosted PIs as the leading culprits. (49,50) Efavirenz has also been implicated as a contributor to low bone mass, mediated through its effect on vitamin D metabolism.( 51 Preventive measures for bone loss should be implemented in all PLWH, regardless of age, following the recommendations for the general population (https://osteoporosis.ca/health-care-professionals/clinicalpractice-guidelines/osteoporosis-guidelines/). These measures include regular weight-bearing exercises, maintaining ideal weight, reducing smoking and alcohol consumption, and optimizing vitamin D and calcium intake (in the form of diet and supplements if necessary). Falls prevention strategies should be implemented for individuals with frailty or other conditions associated with a high risk of falling (https:// www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines/osteoporosis). Most PLWH have low vitamin D levels, as does the general North American population; therefore, there is insufficient evidence to support routine measurement of vitamin D levels in PLWH. (58) While there is no consensus regarding the optimal dose in the setting of HIV, supplementation with vitamin D at doses of 1000-2000 international units (IU) daily is inexpensive, safe, and not associated with known interactions with antiretroviral drugs. If dietary calcium intake is inadequate, a calcium supplement should be considered, taking into consideration potential interactions with antiretrovirals.
# RENAL DISEASE
# Recommendations:
1. It is recommended that laboratory assessment of renal function (i.e. serum creatinine, estimated glomerular filtration rate [eGFR], serum phosphate, urinalysis for protein and sediment, and spot urine for albumin to creatinine ratio [UACR]) should be performed in all PLWH at baseline and every 3-4 months after starting antiretrovirals, increasing to 6-month intervals when stable (depending on degree of risk). (D)
2. Blood pressure should be measured at least annually and at each visit (at least every 6 months) if abnormal. (D) • Rarely, acute interstitial nephropathy with reversible acute renal failure, which has been described in association with hypersensitivity reactions to abacavir, efavirenz, and atazanavir (67) Establishing the etiology of renal dysfunction in PLWH can be difficult as it is often multi-factorial.
Referral to a nephrologist and possibly renal biopsy may be required for a definitive diagnosis, especially in cases where drug-related nephrotoxicity is suspected. Any renal function abnormalities identified at screening should be investigated and managed appropriately as in the general population. Some ARVs (specifically all NRTIs except abacavir) are renally cleared and may require dosage adjustment if renal function is abnormal.(59) For some drugs with low nephrotoxic potential (e.g. lamivudine), the beneficial effect of dose adjustment has not been proven. However, tenofovir DF is renally cleared and is also a nephrotoxin; this drug should be avoided in patients with renal disease or at high risk. If renal dysfunction occurs during ART, tenofovir DF should be discontinued if possible and replaced with another agent (e.g. abacavir if HLA-B*5701 negative or tenofovir alafenamide [AF] if eGFR >30 mL/min) rather than dose-reduced. For further information, refer to the BC-CfE Guidelines for Antiretroviral ARV Treatment of Adult HIV Infection | (bccfe.ca).
Certain ARV agents (bictegravir, dolutegravir, rilpivirine) and pharmacokinetic enhancers (cobicistat) affect renal tubular creatinine transporters resulting in decreased tubular creatinine secretion and increased serum creatinine levels. (31,32,(68)(69)(70)(71)(72)(73)(74) This is manifested as a factitious increase in serum creatinine (mean increase ~10-12 μmol/L) during the initial 2-8 weeks of therapy, without an effect on true glomerular filtration rate. After the initial increase, serum creatinine levels remain stable at the new higher level as long as the agent is continued. Decreases in eGFR that are >25% of the baseline level, that start later or continue to progress after the first 2-8 weeks of therapy, or that are accompanied by signs of renal tubular dysfunction (e.g. proteinuria) require further investigation to rule out true renal function impairment, and nephrology referral should be considered.(74)
# HYPOGONADISM
Recommendations:
1. Cisgender men living with HIV presenting with symptoms of hypogonadism should be assessed with a morning serum total testosterone level; an abnormal testosterone level should be confirmed with repeat testing. (B) An estimated bioavailable testosterone measurement may be helpful to assess certain individuals, including obese cisgender men with borderline low total testosterone levels. (B)
2. Testosterone replacement is indicated only for symptomatic cisgender men with total testosterone levels less than 10 mmol/L (B) and should be prescribed in consultation with a specialist. (D)
3. Endocrine therapy for transgender individuals living with HIV should be provided in consultation with an endocrinologist or other clinician who has experience providing endocrine care to transgender individuals. (D)
# Evidence:
In the early ART era, hypogonadism was identified as an important contributor to loss of lean body and muscle mass, the hallmarks of AIDS-associated wasting, as well as decreased bone mineral density.(71) While less prevalent now, low testosterone levels are still present in a significant minority of cisgender men living with HIV. (75) Symptoms suggestive of testosterone deficiency include decreased libido, erectile dysfunction, hot flashes and sweats, weight loss, reduced muscle strength or exercise capacity, fragility fractures, sleep disturbance, fatigue, and depression. Cisgender men living with HIV presenting with one or more of these symptoms should be screened with a morning free testosterone level, and low levels should be confirmed on repeat testing.(76) An estimated bioavailable testosterone measurement may be helpful to assess certain individuals, specifically obese cisgender men with borderline low total testosterone levels. Normal serum testosterone levels in cisgender women are unknown.
Confirmed low testosterone levels may necessitate further investigation (including luteinizing hormone, follicle-stimulating hormone, prolactin, prostate-specific antigen) to distinguish primary (testicular) vs. secondary (pituitary/hypothalamic) hypogonadism and to rule out other clinical conditions.(77) Testosterone replacement therapy (TRT) is indicated only for cisgender men with symptomatic low testosterone levels and should be prescribed according to current guidelines, preferably in consultation with an endocrinologist or other specialist. (76,78) In cisgender men living with HIV with hypogonadism, TRT has been shown to improve mood, energy, libido, muscle strength, and body composition (specifically, decreasing fat and increasing muscle mass), without adverse effects on viral load or CD4 cell count. However, there are no reliable data demonstrating that TRT improves muscle mass, in excess of that achieved by physical exercise, or overall physical function in cisgender men living with HIV. The benefits of longer term TRT (>3-6 months) in this population have not been studied. (76) Potential side effects of TRT include acne, male pattern balding, and sleep apnea. More serious potential adverse effects include myocardial infarction (due to erythrocytosis) and prostate cancer. TRT is contraindicated in men with acute coronary syndrome or prostate cancer. The long-term safety of TRT is unknown; the need for ongoing TRT should be reassessed at least every 6 months.(76, 78)
# NEUROCOGNITIVE IMPAIRMENT
Recommendations:
1. ART to suppress plasma viral load should be started early and administered continuously to prevent or minimize HIV-related neurocognitive impairment. (B)
2. In PLWH presenting with cognitive complaints that affect their daily functioning, an investigation should be done to rule out relevant underlying conditions. (B)
# Evidence:
HIV can affect the central nervous system (CNS), impacting cognitive function (e.g. memory, reasoning, planning, solving problems, attention, concentration) and activities of daily living. Fortunately, the incidence of severe cognitive impairment in the form of HIV-associated dementia has declined significantly since the advent of ART. However, milder forms of neurocognitive impairment remain prevalent, even in the presence of virologic suppression, and can have a significant impact on quality of life and adherence to HIV medications. (79) PLWH with impairment in two or more cognitive domains and mild to moderate impairment in daily functioning, in the absence of confounding conditions, may be diagnosed with mild neurocognitive disorder.(80) Potential underlying conditions that need to be ruled out include:(81, 82) In the absence of relevant underlying conditions, neurocognitive impairment in HIV may be related to CSF viral "escape", i.e. presence of detectable HIV RNA in CSF despite undetectable viral load in plasma.
Limited evidence exists that adjusting the ART regimen to include agents with better CSF penetration (e.g. zidovudine, nevirapine, abacavir, emtricitabine, darunavir/ritonavir, raltegravir) can stabilize or improve neurocognitive function in this setting. (79,82) Referral to a physician with expertise in the management of HIV is advised in these situations. Full suppression of plasma viral replication remains the most important target, for both prevention and treatment of HIV-related cognitive disorders.
# LUNG DISEASE
# Recommendations:
1. Smoking cessation should be strongly encouraged in all PLWH because they are at a higher risk for chronic obstructive pulmonary disease (COPD) and lung cancer than smokers who do not have HIV. (A)
2. A chest X-ray should be performed at baseline in all PLWH. (D) Once infection has been treated or ruled out, patients with persistently abnormal chest X-ray findings should be investigated and referred to a respiratory specialist if necessary. (D)
# Evidence:
Compared to the general population, PLWH have a greater risk for chronic obstructive pulmonary disease (COPD) and are prone to develop it at a younger age, even taking into account the relatively high rates of smoking in this population. (83,84) COPD should be managed according to current Canadian Thoracic Society guidelines (available at https://cts-sct.ca/guideline-library/), including an aggressive plan for smoking cessation. The use of all inhaled steroids should be avoided if possible in patients receiving ritonavir or cobicistat as part of their ART regimen, due to the risk of adrenal suppression and iatrogenic Cushing's syndrome. (85,86) Beclomethasone cannot be recommended as a "safer" alternative in this setting; a systematic review showed this agent has no clinical effect in COPD. (87) If combination inhaled steroids/long-acting beta-agonist (LABA) inhalers are necessary for the management of severe COPD symptoms, consideration should be given to switching patients off of ARV regimens containing ritonavir or cobicistat. Salmeterol is not recommended with concomitant ritonavir or cobicistat in PLWH with COPD because of elevated salmeterol levels that may increase the risk of cardiovascular adverse events. (88) Formoterol can be associated with QT prolongation and should be used with caution in patients receiving QT-prolonging ARVs (rilpivirine, ritonavir-boosted lopinavir or atazanavir); however, other single-agent LABAs (e.g. indacaterol) and long-acting muscarinic antagonists (LAMAs, e.g. aclidinium, glycopyrronium, tiotropium) can be used safely in this setting.(88)
A chest X-ray should be performed at baseline in all PLWH. As HIV confers an increased risk of lung cancer, HIV care providers should have a low threshold for performing chest CT in the presence of significant respiratory symptoms, particularly in smokers. (89)(90)(91) After appropriate management of infectious etiologies, consultation with a respiratory specialist is advisable to investigate persistent symptoms or abnormal imaging findings.
# LIVER DISEASE/CIRRHOSIS
Recommendations:
1. Liver enzymes and liver function should be assessed in all PLWH at baseline and every 3-4 months after starting ART, increasing to 6-month intervals when stable. (D)
# CANCER
Recommendations:
1. In PLWH, screening for breast, colorectal, and prostate cancer should follow current provincial recommendations for the general population. (A)
# Evidence:
The incidence of AIDS-defining cancers, Kaposi's sarcoma, and non-Hodgkin's lymphoma has markedly decreased in the highly active ART era (with the exception of invasive cervical cancer which has remained relatively unchanged), while non-AIDS-defining cancers have become more common. (106)(107)(108) This is attributable at least in part to the increasing risk of malignancy as the PLWH population ages. 1. Mental health should be proactively assessed during clinic visits, and identified conditions should be managed using a stepped-care approach. (D)
# Evidence:
The populations at risk of HIV acquisition are also at heightened risk of anxiety, depression, and other mental health issues, including people who inject drugs (118) and cis-and transgender men who have sex with men (MSM). (119)(120)(121) Sexual minorities and transgender individuals carry a disproportionate burden of mental health challenges as indicated by higher rates of self-reported depression, anxiety, selfharm, suicidality, and substance use disorders when compared to their heterosexual counterparts. (119)(120)(121)(122) In this sense the intersecting burdens of mental illness, substance use disorders, and experiences of discrimination related to sexuality among these populations impart an increased vulnerability towards HIV acquisition.( 123)
Cisgender women living with HIV also experience high rates of anxiety, depression, and post-traumatic stress disorder (PTSD).( 124
# SPECIAL CONSIDERATIONS FOR INDIVIDUALS WITH ADVANCED HIV -OPPORTUNISTIC INFEC TION & PROPHYLAXIS
Despite efforts to expand HIV testing and the accessibility of effective antiretroviral therapy (ART) in British Columbia, just under 20% of people living with HIV (PLWH) are diagnosed at an advanced stage of HIV disease.(1) Others may not access medical care including ART or are unable to adhere to their ART regimen consistently. Such individuals may develop low CD4 cell counts, which places them at risk for opportunistic infections (OIs), and indeed an OI is often the presenting feature that brings them into medical care. Once the acute OI has been treated, primary prophylaxis for other common OIs may be appropriate if the CD4 cell count remains low. Following immune reconstitution with ART, primary prophylaxis can often be discontinued once the patient is clinically stable and has established consistent adherence. Indications for prophylaxis, agents of choice, and criteria for discontinuing and restarting primary prophylaxis for Pneumocystis jirovecii pneumonia (PJP), Toxoplasma, Mycoplasma (M.) tuberculosis, and Mycobacterium avium complex (MAC) are shown in
# HEALTH SERVICES TO OPTIMALLY ENGAGE PEOPLE LIVING WITH HIV (PLWH) IN EFFEC TIVE PRIMARY CARE
Chapter Summary:
1. Optimal HIV management is facilitated by healthcare delivery models that are focused on long-term engagement and relationship-building between healthcare providers and their clients.
2. Actively linking individuals newly diagnosed with HIV to clinicians who are familiar with the HIV management is preferred to passive referrals or simply providing patients information. In BC, regional public health nursing teams may be helpful in linking newly diagnosed individuals to care.
3. Peer support or peer-navigation may also be helpful for linking or retaining some PLWH in care 4. Formal case management to link and/or retain PLWH in care may be needed for some individuals.
5. PLWH may face additional challenges such as housing instability and food insecurity, which should be addressed through referrals to specific social services.
6. Outreach support, such as those provided by public health nursing teams though health authorities, are a helpful resource in assisting PLWH to remain engaged in care.
Engaging people living with HIV (PLWH) in healthcare and ensuring client retention are key elements to providing successful treatment, ensuring adherence to antiretroviral treatments, and preventing onward disease transmission.(1, 2) However, PLWH may encounter a variety of challenges to accessing consistent and effective care. Some factors are patient-dependent, such as negative emotions associated with diagnosis(1) and a lack of adequate social supports. (1,2) Other factors are associated with health services themselves, such as negative healthcare experiences(1) and lack of culturally sensitive care for Indigenous people and other cultural minorities.(3)
Healthcare providers and staff who are perceived to be supportive and collaborative are important to establishing rapport with PLWH, and these positive relationships can, in turn, improve linkage to healthcare. (1,4,5) Moreover, supportive providers may be seen by patients as members of their supportive social network and as proxies for absent friends and family.(1) In addition, providing appropriate education around HIV, through programmes tailored for PLWH or by care providers trained/competent in providing patient education, improves patient empowerment and understanding of antiretroviral therapy (ART).(6, 7) Patients also highly value confidentiality as the fear of incidental disclosure when seeking services is a concern for many PLWH accessing care.(7) Client-centred healthcare that accounts for patient preferences and is culturally sensitive and confidential underpins the effective delivery of HIV services. (3,5,8,9) In BC, all residents are eligible for care and treatment of HIV free of charge. Care providers who are faced with challenges of caring for visitors without health insurance and/or persons residing in Canada illegally should contact the BC-CfE to advocate on the person's behalf for coverage of the cost of medical treatment.
# CHRONIC DISEASE MODEL OF CARE
As HIV is now conceptualized as a chronic, manageable condition, its optimal management is facilitated by care models that are focused on long-term engagement and relationship-building between healthcare providers and their clients. The Chronic Care Model, first formulated by Wagner et. al. in 1996(10) and recently revisited,(11) addresses relational aspects of care (Figure 9.1). At its core, the Chronic Care Model postulates that an informed and activated client, when partnered with a proactive and prepared healthcare team, will achieve optimal outcomes for chronic disease management. HIV care has been evaluated in terms of how well it incorporates aspects of the Chronic Care Model;(12-14) however, we are not aware of studies which have evaluated different service delivery models in terms of clinical outcomes. Many aspects of care related to the Chronic Care Model have recently been identified as priorities for PLWH in high-income countries.(7) These include: a strong healthcare professional-patient relationship, HIV specialist knowledge, continuity of care, ease of access to services, access to high quality information and support, effective co-ordination between HIV specialists and other healthcare professionals, and patient involvement in decisions about treatment and care. Other studies have shown that better physician-patient relationships are associated with higher rate of adherence to ART. (15) Quality improvement involves routine data collection and cycles of planning, change, and feedback to improve processes and outcomes. Incorporating quality improvement methods in HIV care can provide useful feedback throughout cycles of change, including the implementation of an intervention, and help close gaps in care.( 16) For more information on best practices for quality improvement and evaluation of HIV care and services, please consult the resources available on the HIV Continuum of Care Collaborative website (http://stophivaids.ca/hiv-continuum-collaborative/).
# ACTIVE REFERRAL FOLLOWING DIAGNOSIS
Upon diagnosis, active guidance to set up initial clinic appointments rather than passive methods (e.g. handing out brochures) improves linkage,(1) as does scheduling clinic orientation visits. (17) In BC, regional public health teams may be helpful in linking newly diagnosed individuals to clinicians who are familiar with the management of HIV infection. A list of contact numbers can be found in the Appendix 4, page 116. As well, The Canadian AIDS Treatment and Information Exchange (http://catie.ca, 1-800-263-1638) is a national organization that provides useful support and information regarding HIV treatment and related topics in languages accessible to most clients.
# ADDRESSING SOCIAL DETERMINANTS OF HEALTH
PLWH may face additional challenges such as housing instability and food insecurity. Stable housing among PLWH has been associated with a variety of positive clinical outcomes, including adherence to ART and improvement in overall health status, (18,19) As well, evidence from randomized trials has demonstrated that receiving assistance or other services that improve housing status has a direct impact on improved medical care and health outcomes for formerly homeless or inadequately housed PLWH. (20,21) Food insecurity has been associated with a lack of virologic suppression among PLWH receiving ART, with 37% of those with unsuppressed viral load reporting food insecurity; (22) food insecurity has also been associated with increased mortality among PLWH who use injection drugs in studies conducted in BC( 23) and New York. (22) Clinicians should actively ask PLWH about these issues and have connections to social work supports and community organizations so that they can actively assist patients in accessing appropriate programs and services.
# PEER-SUPPORT AND PATIENT OR PEER NAVIGATION
Stigma, isolation, and marginalization are common realities in the lives of PLWH. Ensuring access to social and emotional support for affected individuals is a crucial part of HIV primary care. Peer support programs can help to improve linkages and retention in care. AIDS service organizations (ASOs) are excellent starting points for many of these services. Please refer to the Contact List (Appendix 4, page 117 for a list of provincial organizations, providing support for PLWH).
Patient navigators, who may be peers with lived experience, assist in relationship-building and nonmedical support. Peer navigators may accompany clients to appointments, guide clients through the healthcare system, teach skills in communicating with providers, and provide non-clinical services such as transportation. (17,24) Peers may also provide basic information on HIV medications and support treatment adherence, including reinforcing messages regarding treatment as prevention or U=U. Peers can also provide education regarding sexually transmitted infections and other related topics. Moreover, peers can connect patients with community organizations and provide referrals to services and support groups, including addiction and mental health support. Patient and peer navigators have been found to improve linkage to and retention in healthcare by supporting clients in navigating complex medical systems to meet their care needs. (24,25) Guidelines for peer navigation services have been published by the Canadian AIDS Treatment Information Exchange. (26) In BC, several community-based organizations provide peer navigation or peer support services, including Vancouver Island PWA Society (https://vpwas. com/programs/peer-support/) and AIDS Vancouver (https://www.aidsvancouver.org/peer-navigationprogram). Health care providers should contact their regional health authority's HIV program if they have clients who could benefit from peer navigation or support.
# CASE MANAGEMENT
Case management has been shown to be effective in both initial linkage to care (27) and subsequent retention in care (28,29) and often comprises a variety of interventions. Case management may consist of assistance from a healthcare worker to link PLWH to HIV care providers with time-limited follow-up to ensure that linkage and retention have occurred. Case management may also include referring clients to appropriate providers, assisting clients to prioritize personal needs, introducing HIV resources, helping to complete forms, and teaching skills about disclosure to support networks.(17) Case management activities may overlap with patient/peer navigation.(24)
# OUTREACH SERVICES
Intensive outreach services (e.g. home visits or mobile van outreach) were also found to increase retention and ART adherence, though the programs could be resource-intensive and lack long-term stability. (6,17) Outreach services can be provided by medical professionals or by peers. These programs may work better when integrated with other social services. (6) In BC, all regional health authorities have outreach nursing teams to assist PLWH who have not engaged in HIV care following diagnosis or who have fallen out of care. At Vancouver Coastal Health, these outreach personnel are known as STOP teams; they have different names in other regional health authorities. Contact information for these teams are found in Appendix 4, page 117.
The Re-Engagement and Engagement in Treatment for Antiretroviral Interrupted and Naïve populations (RETAIN) Initiative (http://bccfe.ca/stop-hiv-aids/retain) is a partnership between the BC-CfE, Medical Health Officers from each health authority, and HIV outreach personnel throughout British Columbia. The BC-CfE sends routine alerts to physicians regarding their patients who are at least 2 months late in refilling their ART prescription. Additionally, alerts have been launched for physicians linked to patients newly diagnosed with HIV who have not yet accessed ART. Both of these alerts include contact information for local public health support.
A core component of RETAIN is the routine province-wide coordination of public health support for PLWH who have interrupted ART or who have yet to initiate therapy. PLWH will be eligible for this outreach support if: 1) they have interrupted treatment for longer than 4 months, or 2) they have not yet started treatment more than 4 months after a high plasma viral load was reported. The BC-CfE provides routine referrals for such clients to each regional health authority on a monthly basis. An evaluation of the RETAIN program demonstrated that, among individuals who had interrupted treatment for >4 months, those who interrupted their treatment in the post-RETAIN era (i.e. after June 2016) were more likely to restart ART (adjusted hazard ratio 1.50; 95% CI 1.34 -1.69), compared to earlier time periods.(30)
# OTHER SUPPORTS
In addition, supports such as counselling and use of motivational interviewing methods may improve retention and adherence to medication. (17,31) Motivational interviewing techniques can be delivered by mental health clinicians or by trained peer outreach workers.(32)
Interventions using phone text messaging can help to provide remote clinic support for individuals receiving ART. (6) In BC, the WelTel intervention has been shown to improve adherence to ART and virologic suppression among women with an unsuppressed viral load at the Oak Tree Clinic.(33, 34) | None | None |
fe5556c4264960378c449228713470110f4a177a | cma | None | Major planning directives related to the COVID-19 pandemic are coordinated through Ontario Health,#
COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease of Nirmatrelvir dose and (b) that there is no known dose-related toxicity with Nirmatrelvir, suggesting the benefits of treatment are maintained with minimal increase in unintended harm. 6. Further studies on the safety of Paxlovid in advanced CKD are not likely to be available in any relevant time frame so we need to act on present available information, however limited. 7. On the basis of the above risks of serious morbidity and mortality from COVID-19 infection in patients with advanced CKD, and the small estimated incremental risks from extending the use of Paxlovid to these patients, we suggest providing Paxlovid after discussing these aspects with the patient.
# COVID-19 and Chronic Kidney Disease (CKD)
As of March 31, 2022, there have been 6.14 million deaths globally from Coronavirus disease (COVID- 19) due to the Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2), of which 37,653 have occurred in Canada . Additionally, there are other longer term consequences from COVID-19, including post critical illness syndromes, auto-immune diseases, cardiovascular disease, and other physical and neurocognitive sequelae . These numbers are expected to grow over the next few years and will have a major impact on life expectancy and healthcare utilization.
The burden of morbidity and mortality of COVID-19 is higher in immunocompromised patients including those with advanced CKD (stages 4 and 5) and those with end stage kidney disease (ESKD), receiving dialysis. Hemodialysis patients cannot self-isolate, usually receiving their life-sustaining treatment three times a week in a congregate setting. Kidney transplant recipients are immunosuppressed and have other comorbid conditions making them more susceptible as well. Presently, about 3 million people receive dialysis worldwide, 23,708 of them in Canada, and 13,330 in Ontario ; . Excluding Quebec, there are 18,052 kidney transplant recipients in Canada .
In the first year after the declaration of the pandemic, in the United States alone, the year-over-year decline in the dialysis census was 1.6%, representing a deficit of 3.8%, relative to the forecasted increasing trend . In Ontario over the first 5 months of the pandemic in 2020, 187 (1.5%) of 12,501 patients undergoing dialysis were diagnosed with SARS-CoV-2 infection. Of these, 117 (62.6%) were admitted to hospital and the case fatality rate was 28.3% . These data predate the availability of vaccination. While case fatality rates for patients on dialysis have fallen in more recent waves in Ontario (18% in Wave 3 and 6% in Wave 5) and are 12% overall during the pandemic, they remain markedly higher than those in the general population ; . Patients with advanced CKD, who attend Multi-Care Kidney Clinics (MCKCs) in Ontario have an even higher mortality rate of 18% overall during the pandemic.
The vaccines for COVID-19 are remarkably effective. However, their effectiveness is lower in the dialysis and transplant populations . The pooled estimate of early antibody formation in dialysis patients was 89% (95% confidence interval 85 to 91%) relative to healthy controls, thus conferring incomplete protection which wanes over time . For kidney transplant recipients, these figures are much lower at 8% (95% CI 5 -15%) and 35% (95% CI 29 -42%) with multiple dosing resulting in progressively smaller incremental antibody responses . For newer variants (such as Omicron), which COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease require higher antibody titres for viral neutralization, a corollary is that vaccines alone will not be sufficient for protection against infection and disease in dialysis patients .
# 'Renalism' and CKD
Patients with CKD, especially those with glomerular filtration rate (GFR) < 30, patients on dialysis and kidney transplant recipients are frequently excluded from clinical trials, in particular those evaluating investigational drugs. Proposed explanations for this have included the high comorbidity burden and high complication rates with competing events, and in particular the concern with decreased renal clearance for newer drugs making dosing decisions difficult for a phase 3 trial. The consequence is that CKD patients are excluded initially at time of drug approval, and therapeutic nihilism occurs, whereby these patients are denied effective therapies until data emerges several years later on safety and efficacy . This phenomenon has been termed 'renalism', and has unfortunately recurred with COVID-19. A rapid review of trial registries with COVID-19 reported that 218 of 484 trials (45%) had an exclusion based on CKD status which was often poorly defined (such as 'kidney dysfunction' without a GFR cutoff) .
Several therapeutic options have been investigated, and some have been approved for early treatment of COVID-19, notably remdesivir (Velkury, Gilead Inc.) and nirmatrelvir/ritonavir (Paxlovid, Pfizer Inc.). However, patients with low GFR have been excluded from all clinical trials of nirmatrelvir/ritonavir (Paxlovid), and theoretical concerns about drug dosing and safety have led to GFR < 30 being labeled as a contraindication in the product monograph.
# Paxlovid Efficacy
Nirmatrelvir (PF-07321332) is an orally administered antiviral agent targeting the SARS-CoV-2 3chymotrypsin-like cysteine protease enzyme (Mpro). Coadministration of nirmatrelvir with a low dose (100 mg) of ritonavir, a CYP3A4 inhibitor, enhances nirmatrelvir concentration, allowing required therapeutic concentrations to be achieved (see next section for details). The EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) evaluated the safety and efficacy of nirmatrelvir plus ritonavir in non-hospitalized adults with mild-to-moderate COVID-19 at high risk for progression to severe disease .
The incidence of COVID-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval , −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%). There were 13 deaths, all in the placebo group. Patients with CKD were excluded from this trial. The Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-SR) trial in 1140 patients at standard risk has finished enrolment with results expected in a few months.
On this basis, Paxlovid is indicated for the treatment of mild-to-moderate COVID-19 (i.e. for outpatient treatment) in adults with positive SARS-CoV-2 viral testing, and who are at high risk for progression to COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease severe COVID-19, including hospitalization or death. It is not recommended for those with 'serious renal impairment (eGFR < 30)'.
# Paxlovid Pharmacology
# Pharmacodynamics
Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication.
Nirmatrelvir was shown to be an inhibitor of SARS-CoV-2 Mpro (at a Ki=3.1 nM, or IC50=19.2 nM) in a biochemical enzymatic assay (in vitro) . Ki refers to how well the drug inhibits the enzyme (lower values are indicative of greater inhibition) and IC50 to the concentration required to inhibit 50% of the enzyme over baseline (lower is better). Nirmatrelvir is a competitive inhibitor, and the EC50 (i.e. effective concentration) may be more important, which was measured at 3 times higher, i.e. 61.8 nM. However, in a study in mice, it was reported that EC90 correlated with efficacy, and this concentration was 181nM (292 ng/mL). Hence the desired dose of nirmatrelvir is that which maintains a trough level above the required EC90 concentration of 292 ng/mL. This was the basis of the use of the 300 mg dose in the EPIC-HR trial (see figure 1).
# Pharmacokinetics
Nirmatrelvir has a molecular weight of 499.5 Da, is about 35% renally excreted and is 70% protein bound. Ritonavir is mostly hepatically metabolized and is 99% protein bound. Hence it is expected that nirmatrelvir will accumulate with decreasing kidney function, while ritonavir will not. A small proportion of nirmatrelvir will be removed with dialysis as well.
# Paxlovid Pharmacokinetic Data in CKD
Study C4671005 included 8 patients with serious renal impairment (defined as GFR < 30, not on dialysis). After a single dose of 100 mg nirmatrelvir, the overall concentration at 24 hours was 694.2 (42) ng/mL , over 2 times the required 292 ng/mL (Table 1 and Figure 2).
# Paxlovid Adverse Effects
From animal data, no adverse effects were observed at 1000 mg/kg/day, which correspond to an exposure approximately 8 times higher than clinical exposures at the authorized human dose. Nirmatrelvir-related findings following repeat oral dosing in monkeys at up to 600 mg/kg/day were limited to emesis, increase in fibrinogen, as well as increases in ALT and AST levels. These findings completely reversed at the end of the 2-week recovery period. In the EPIC-HR trial, serious adverse events were lower with Paxlovid (1.6%) compared to placebo (6.6%). Adverse events reported by more than 1% of the participants were dysgeusia, nausea, vomiting, headache, diarrhea and fever. In study C 2/8 (25%) reported dysgeusia and dry mouth compared to none in the other arms with higher renal function. One patient did report several serious adverse events (SAEs), namely acute kidney injury, pulmonary edema, and pneumonia, which were likely related to COVID-19 infection rather than the medication. Overall, Paxlovid has a favorable safety profile, with no evidence of dose-dependent toxicity. COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease
# Rationale for Dosing of Paxlovid in CKD and Dialysis Patients
A single dose of nirmatrelvir 100 mg provided adequate concentration of drug to inhibit Mpro enzymatic activity at 24 hours, based on study C4671005 in non-dialysis CKD patients with GFR < 30. Similar concentrations would be seen in dialysis, and it is expected that there will be some clearance of nirmatrelvir with hemodialysis, given its molecular size, 70% protein binding and volume of distribution. The safety profile of nirmatrelvir is quite favorable, with few SAEs, with the animal data not indicative of a higher dose dependent toxicity. Nirmatrelvir is currently formulated as a 150 mg tablet and dosed at 300 mg with 100 mg ritonavir twice a day for patients with normal kidney function, and at 150 mgs with 100 mg ritonavir twice a day in those with eGFR 30-60. A dose of 300 mg (with 100 mg ritonavir) followed by 150 mg daily, administered after hemodialysis on days of dialysis is predicted to provide effective blood concentrations for enzyme inhibition (figure 3). Minimal drug accumulation is expected based on the short duration of therapy and single dose pharmacokinetics. A lower dose of 150 mg every 48 hours could be considered for patients less than 40 kgs.
Patients receiving peritoneal dialysis often have greater residual renal function compared to those receiving hemodialysis and may therefore have slightly higher endogenous clearance of nirmatrelvir. However, the dialytic removal with peritoneal dialysis will be lower compared with hemodialysis. Hence similar doses to those discussed above for hemodialysis are expected to achieve effective concentrations in these patients. Additional considerations of drug interactions are also important, since ritonavir is a potent CYP3A4 inhibitor. Commonly used drugs with important drug interactions in CKD and dialysis patients include direct acting oral anticoagulants, some statins, calcium channel blockers and alpha-adrenergic antagonists. These interactions however, are not a contraindication to therapy, and may be mitigated with support from clinicians and pharmacy and temporary suspension or dose reduction of these medications, depending on the clinical context (see table 3).
We suggest that patients with advanced CKD (eGFR < 30) and those on dialysis who contract COVID-19 be offered the low dose nirmatrelvir/ritonavir (Paxlovid) regimens. Since the current product monograph does not recommend the use of nirmatrelvir/ritonavir (Paxlovid) in these patients, this should be preceded by a discussion between the prescribing physician and the patient emphasizing that the potential benefits of the treatment substantially exceed the theoretical risks of toxicity.
# Rationale for Dosing of Paxlovid in Kidney Transplant Recipients
In patients with a kidney transplant, drug-drug interactions are as much or more of a concern than the kidney function. The inhibition of drug metabolism due to ritonavir can result in extremely toxic levels (10-fold higher) of calcineurin inhibitors (CNIs), and prolonged half-life. To a lesser extent, levels of mycophenolic acid and sirolimus may also be affected (see table 3 for details). Hence even with eGFR > 30, CNIs must be held, and close monitoring of CNI levels is required even after the therapy is complete to decide on timing of restarting. Given this interaction, the use of nirmatrelvir/ritonavir (Paxlovid) in kidney transplant recipients with eGFR < 30 should be considered very cautiously. Though not discussed separately, similar considerations would also apply to patients with CKD due to glomerulonephritis receiving these immunosuppressive drugs.
# Summary
Patients with advanced CKD (stages 4 and 5) and patients on dialysis who contract COVID-19, are at markedly higher risk of developing severe symptomatic disease and of dying. They have a lower and less sustained immune response to vaccination and need access to potentially lifesaving medications. Nirmatrelvir/ritonavir (Paxlovid) is a very effective therapy in the early management of high risk patients with symptomatic disease; however it is renally cleared and is currently not recommended for those with GFR < 30. On the basis of available data and pharmacological principles, an adjusted dose given at a lower frequency is proposed for use in people with GFR < 30 and in those on dialysis after appropriate evaluation and discussion of risks and benefits with the patient. | Major planning directives related to the COVID-19 pandemic are coordinated through Ontario Health,#
COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease of Nirmatrelvir dose and (b) that there is no known dose-related toxicity with Nirmatrelvir, suggesting the benefits of treatment are maintained with minimal increase in unintended harm. 6. Further studies on the safety of Paxlovid in advanced CKD are not likely to be available in any relevant time frame so we need to act on present available information, however limited. 7. On the basis of the above risks of serious morbidity and mortality from COVID-19 infection in patients with advanced CKD, and the small estimated incremental risks from extending the use of Paxlovid to these patients, we suggest providing Paxlovid after discussing these aspects with the patient.
# COVID-19 and Chronic Kidney Disease (CKD)
As of March 31, 2022, there have been 6.14 million deaths globally from Coronavirus disease (COVID- 19) due to the Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2), of which 37,653 have occurred in Canada [1]. Additionally, there are other longer term consequences from COVID-19, including post critical illness syndromes, auto-immune diseases, cardiovascular disease, and other physical and neurocognitive sequelae [2][3][4]. These numbers are expected to grow over the next few years and will have a major impact on life expectancy and healthcare utilization.
The burden of morbidity and mortality of COVID-19 is higher in immunocompromised patients including those with advanced CKD (stages 4 and 5) and those with end stage kidney disease (ESKD), receiving dialysis. Hemodialysis patients cannot self-isolate, usually receiving their life-sustaining treatment three times a week in a congregate setting. Kidney transplant recipients are immunosuppressed and have other comorbid conditions making them more susceptible as well. Presently, about 3 million people receive dialysis worldwide, 23,708 of them in Canada, and 13,330 in Ontario [5,6]; [7]. Excluding Quebec, there are 18,052 kidney transplant recipients in Canada [CORR data, 2020].
In the first year after the declaration of the pandemic, in the United States alone, the year-over-year decline in the dialysis census was 1.6%, representing a deficit of 3.8%, relative to the forecasted increasing trend [8]. In Ontario over the first 5 months of the pandemic in 2020, 187 (1.5%) of 12,501 patients undergoing dialysis were diagnosed with SARS-CoV-2 infection. Of these, 117 (62.6%) were admitted to hospital and the case fatality rate was 28.3% [9]. These data predate the availability of vaccination. While case fatality rates for patients on dialysis have fallen in more recent waves in Ontario (18% in Wave 3 and 6% in Wave 5) and are 12% overall during the pandemic, they remain markedly higher than those in the general population [Internal ORN Data]; [10]. Patients with advanced CKD, who attend Multi-Care Kidney Clinics (MCKCs) in Ontario have an even higher mortality rate of 18% overall during the pandemic.
The vaccines for COVID-19 are remarkably effective. However, their effectiveness is lower in the dialysis and transplant populations [11]. The pooled estimate of early antibody formation in dialysis patients was 89% (95% confidence interval [CI] 85 to 91%) [12] relative to healthy controls, thus conferring incomplete protection which wanes over time [12][13][14]. For kidney transplant recipients, these figures are much lower at 8% (95% CI 5 -15%) and 35% (95% CI 29 -42%) with multiple dosing resulting in progressively smaller incremental antibody responses [15]. For newer variants (such as Omicron), which COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease require higher antibody titres for viral neutralization, a corollary is that vaccines alone will not be sufficient for protection against infection and disease in dialysis patients [16].
# 'Renalism' and CKD
Patients with CKD, especially those with glomerular filtration rate (GFR) < 30, patients on dialysis and kidney transplant recipients are frequently excluded from clinical trials, in particular those evaluating investigational drugs. Proposed explanations for this have included the high comorbidity burden and high complication rates with competing events, and in particular the concern with decreased renal clearance for newer drugs making dosing decisions difficult for a phase 3 trial. The consequence is that CKD patients are excluded initially at time of drug approval, and therapeutic nihilism occurs, whereby these patients are denied effective therapies until data emerges several years later on safety and efficacy [17,18]. This phenomenon has been termed 'renalism', and has unfortunately recurred with COVID-19. A rapid review of trial registries with COVID-19 reported that 218 of 484 trials (45%) had an exclusion based on CKD status which was often poorly defined (such as 'kidney dysfunction' without a GFR cutoff) [19].
Several therapeutic options have been investigated, and some have been approved for early treatment of COVID-19, notably remdesivir (Velkury, Gilead Inc.) and nirmatrelvir/ritonavir (Paxlovid, Pfizer Inc.). However, patients with low GFR have been excluded from all clinical trials of nirmatrelvir/ritonavir (Paxlovid), and theoretical concerns about drug dosing and safety have led to GFR < 30 being labeled as a contraindication in the product monograph.
# Paxlovid Efficacy
Nirmatrelvir (PF-07321332) is an orally administered antiviral agent targeting the SARS-CoV-2 3chymotrypsin-like cysteine protease enzyme (Mpro). Coadministration of nirmatrelvir with a low dose (100 mg) of ritonavir, a CYP3A4 inhibitor, enhances nirmatrelvir concentration, allowing required therapeutic concentrations to be achieved (see next section for details). The EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) evaluated the safety and efficacy of nirmatrelvir plus ritonavir in non-hospitalized adults with mild-to-moderate COVID-19 at high risk for progression to severe disease [20].
The incidence of COVID-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%). There were 13 deaths, all in the placebo group. Patients with CKD were excluded from this trial. The Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-SR) trial in 1140 patients at standard risk has finished enrolment with results expected in a few months.
On this basis, Paxlovid is indicated for the treatment of mild-to-moderate COVID-19 (i.e. for outpatient treatment) in adults with positive SARS-CoV-2 viral testing, and who are at high risk for progression to COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease severe COVID-19, including hospitalization or death. It is not recommended for those with 'serious renal impairment (eGFR < 30)'.
# Paxlovid Pharmacology
# Pharmacodynamics
Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication.
Nirmatrelvir was shown to be an inhibitor of SARS-CoV-2 Mpro (at a Ki=3.1 nM, or IC50=19.2 nM) in a biochemical enzymatic assay (in vitro) [21,22]. Ki refers to how well the drug inhibits the enzyme (lower values are indicative of greater inhibition) and IC50 to the concentration required to inhibit 50% of the enzyme over baseline (lower is better). Nirmatrelvir is a competitive inhibitor, and the EC50 (i.e. effective concentration) may be more important, which was measured at 3 times higher, i.e. 61.8 nM. However, in a study in mice, it was reported that EC90 correlated with efficacy, and this concentration was 181nM (292 ng/mL). Hence the desired dose of nirmatrelvir is that which maintains a trough level above the required EC90 concentration of 292 ng/mL. This was the basis of the use of the 300 mg dose in the EPIC-HR trial (see figure 1).
# Pharmacokinetics
Nirmatrelvir has a molecular weight of 499.5 Da, is about 35% renally excreted and is 70% protein bound. Ritonavir is mostly hepatically metabolized and is 99% protein bound. Hence it is expected that nirmatrelvir will accumulate with decreasing kidney function, while ritonavir will not. A small proportion of nirmatrelvir will be removed with dialysis as well.
# Paxlovid Pharmacokinetic Data in CKD
Study C4671005 included 8 patients with serious renal impairment (defined as GFR < 30, not on dialysis). After a single dose of 100 mg nirmatrelvir, the overall concentration at 24 hours was 694.2 (42) ng/mL [geometric mean (coefficient of variation)], over 2 times the required 292 ng/mL (Table 1 and Figure 2).
# Paxlovid Adverse Effects
From animal data, no adverse effects were observed at 1000 mg/kg/day, which correspond to an exposure approximately 8 times higher than clinical exposures at the authorized human dose. Nirmatrelvir-related findings following repeat oral dosing in monkeys at up to 600 mg/kg/day were limited to emesis, increase in fibrinogen, as well as increases in ALT and AST levels. These findings completely reversed at the end of the 2-week recovery period. In the EPIC-HR trial, serious adverse events were lower with Paxlovid (1.6%) compared to placebo (6.6%). Adverse events reported by more than 1% of the participants were dysgeusia, nausea, vomiting, headache, diarrhea and fever. In study C 2/8 (25%) reported dysgeusia and dry mouth compared to none in the other arms with higher renal function. One patient did report several serious adverse events (SAEs), namely acute kidney injury, pulmonary edema, and pneumonia, which were likely related to COVID-19 infection rather than the medication. Overall, Paxlovid has a favorable safety profile, with no evidence of dose-dependent toxicity. COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease
# Rationale for Dosing of Paxlovid in CKD and Dialysis Patients
A single dose of nirmatrelvir 100 mg provided adequate concentration of drug to inhibit Mpro enzymatic activity at 24 hours, based on study C4671005 in non-dialysis CKD patients with GFR < 30. Similar concentrations would be seen in dialysis, and it is expected that there will be some clearance of nirmatrelvir with hemodialysis, given its molecular size, 70% protein binding and volume of distribution. The safety profile of nirmatrelvir is quite favorable, with few SAEs, with the animal data not indicative of a higher dose dependent toxicity. Nirmatrelvir is currently formulated as a 150 mg tablet and dosed at 300 mg with 100 mg ritonavir twice a day for patients with normal kidney function, and at 150 mgs with 100 mg ritonavir twice a day in those with eGFR 30-60. A dose of 300 mg (with 100 mg ritonavir) followed by 150 mg daily, administered after hemodialysis on days of dialysis is predicted to provide effective blood concentrations for enzyme inhibition (figure 3). Minimal drug accumulation is expected based on the short duration of therapy and single dose pharmacokinetics. A lower dose of 150 mg every 48 hours could be considered for patients less than 40 kgs.
Patients receiving peritoneal dialysis often have greater residual renal function compared to those receiving hemodialysis and may therefore have slightly higher endogenous clearance of nirmatrelvir. However, the dialytic removal with peritoneal dialysis will be lower compared with hemodialysis. Hence similar doses to those discussed above for hemodialysis are expected to achieve effective concentrations in these patients. Additional considerations of drug interactions are also important, since ritonavir is a potent CYP3A4 inhibitor. Commonly used drugs with important drug interactions in CKD and dialysis patients include direct acting oral anticoagulants, some statins, calcium channel blockers and alpha-adrenergic antagonists. These interactions however, are not a contraindication to therapy, and may be mitigated with support from clinicians and pharmacy and temporary suspension or dose reduction of these medications, depending on the clinical context (see table 3).
We suggest that patients with advanced CKD (eGFR < 30) and those on dialysis who contract COVID-19 be offered the low dose nirmatrelvir/ritonavir (Paxlovid) regimens. Since the current product monograph does not recommend the use of nirmatrelvir/ritonavir (Paxlovid) in these patients, this should be preceded by a discussion between the prescribing physician and the patient emphasizing that the potential benefits of the treatment substantially exceed the theoretical risks of toxicity.
# Rationale for Dosing of Paxlovid in Kidney Transplant Recipients
In patients with a kidney transplant, drug-drug interactions are as much or more of a concern than the kidney function. The inhibition of drug metabolism due to ritonavir can result in extremely toxic levels (10-fold higher) of calcineurin inhibitors (CNIs), and prolonged half-life. To a lesser extent, levels of mycophenolic acid and sirolimus may also be affected (see table 3 for details). Hence even with eGFR > 30, CNIs must be held, and close monitoring of CNI levels is required even after the therapy is complete to decide on timing of restarting. Given this interaction, the use of nirmatrelvir/ritonavir (Paxlovid) in kidney transplant recipients with eGFR < 30 should be considered very cautiously. Though not discussed separately, similar considerations would also apply to patients with CKD due to glomerulonephritis receiving these immunosuppressive drugs.
# Summary
Patients with advanced CKD (stages 4 and 5) and patients on dialysis who contract COVID-19, are at markedly higher risk of developing severe symptomatic disease and of dying. They have a lower and less sustained immune response to vaccination and need access to potentially lifesaving medications. Nirmatrelvir/ritonavir (Paxlovid) is a very effective therapy in the early management of high risk patients with symptomatic disease; however it is renally cleared and is currently not recommended for those with GFR < 30. On the basis of available data and pharmacological principles, an adjusted dose given at a lower frequency is proposed for use in people with GFR < 30 and in those on dialysis after appropriate evaluation and discussion of risks and benefits with the patient. | None | None |
3e2d0755adce66f250e40e74b0bbbd02726d5f11 | cma | None | The same can be said regarding the frequency of chest imaging, which varied from for-cause to once a year (Expert opinion). 23. Patients with RCC who have undergone definitive treatment should be followed with routine chest and abdominal imaging to rule out recurrence or progression to metastasis (Adopted from CUA guideline for followup of patients after treatment of non-metastatic RCC; expert opinion). 24. Patients with an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m 2 or with progressive chronic kidney disease following definitive treatment should be considered for a referral to a nephrologist (or their general practitioner), especially if associated with proteinuria (Adopted from CUA guideline for followup of patients after treatment of non-metastatic RCC; conditional recommendation, low certainty in evidence of effects).# Summary of recommendations
- Patients diagnosed with SRM should undergo routine laboratory investigations, including at a minimum a serum creatinine and glomerular filtration rate (Clinical principle).
# Patients with SRM incidentally discovered on routine
imaging should be investigated with a multiphasic, contrast-enhanced abdominal computed tomography (CT) or magnetic resonance imaging (MRI) scan (Clinical principle). 3. For patients with suspected renal malignancy, a baseline chest X-ray is suggested to assess for pulmonary metastases (Conditional recommendation, low certainty in evidence of effects). 4. Patients with SRM and pre-existing renal dysfunction in whom a radical nephrectomy is being considered, may be offered renal scintigraphy when the result may alter their management (Clinical principle). 5. Patients with SRM should be offered a renal mass biopsy when the result of the biopsy may alter their management (Adopted from Kidney Cancer Research Network of Canada consensus on the role of renal mass biopsy in the management of kidney cancer; expert opinion). 6. Patients with features suspicious of hereditary renal cell carcinoma (RCC) should be offered genetic counselling (Adopted from CUA guideline on genetic screening for hereditary RCC; expert opinion). 7. For patients with SRM suspicious for renal malignancy AND significant comorbidities and/or limited life expectancy, observation (or watchful waiting) is recommended as the preferred strategy for patients (Strong recommendation, high certainty in evidence of effects). 8. For patients with a suspected renal malignancy measuring <2 cm in diameter, active surveillance is suggested as the preferred strategy, given their slow growth rate and low probability of aggressive histology (Conditional recommendation, moderate certainty in evidence of effects). 9. For patients with a suspected renal malignancy measuring 2-4 cm in diameter, active surveillance and definitive treatment (partial nephrectomy or percutaneous thermal ablation) are suggested as management options (Conditional recommendation, low certainty in evidence of effects). 10. For patients with a suspected renal malignancy, the choice of treatment should be personalized using a shared decision-making approach, after proper counselling and while taking into account tumor characteristics, patient factors, and patient preferences and values (Expert opinion).
Richard et al 11. For patients with a suspected renal malignancy who prefer management by upfront definitive treatment, surgery or percutaneous thermal ablation are suggested (Conditional recommendation, low certainty in evidence of effects). 12. Patients with a suspected renal malignancy who prefer management by upfront definitive treatment should be informed of the higher uncertainty surrounding the data on the efficacy and harms of percutaneous thermal ablation treatment compared to surgery (Expert opinion). 13. Patients with a suspected renal malignancy who opt to be treated by percutaneous thermal ablation should have a renal mass biopsy performed prior to, or at the time of thermal ablation (Adopted from KCRNC consensus on the role of renal mass biopsy in the management of kidney cancer; expert consensus) 14. For patients with suspected malignant SRM undergoing surgery, partial nephrectomy is recommended over radical nephrectomy (Strong recommendation, moderate certainty in evidence of effects). 15. For patients with suspected renal malignancy undergoing partial nephrectomy, a minimally invasive approach (robotic-assisted or conventional laparoscopy) is suggested over an open approach, when technically feasible and oncologically safe (Conditional recommendation, moderate certainty in evidence of effects). 16. For patients with suspected renal malignancy undergoing radical nephrectomy, a conventional laparoscopic approach is recommended over open or robotic-assisted approaches (Strong recommendation, moderate certainty in evidence of effects). 17. For patients undergoing percutaneous thermal ablation for a suspected renal malignancy, cryoablation and radio-frequency ablation are both suggested as options for management, as they yield similar oncological outcomes and adverse events (Conditional recommendation, moderate certainty in evidence of effects). 18. Patients under active surveillance should be monitored until the oncological risk increases, they select intervention, or the benefits of treatment outweigh the competing risks. The factors that define oncological risk are not completely elucidated but the most well-accepted factors are: growth of tumor to >4 cm, consecutive growth rate >0.5 cm/year, progression to metastases, and patient's choice (Clinical principle). 19. Patients with suspected tumor growth on ultrasound imaging should undergo cross-sectional imaging to confirm growth prior to intervention (Expert opinion). 20. For patients with suspected renal malignancy who opted to be managed by active surveillance, routine abdominal ultrasound (assuming good visualization and good agreement in size measurements between ultrasound and cross-sectional imaging) is suggested until definitive treatments are no longer considered (i.e., watchful waiting) (Conditional recommendation, low certainty in evidence of effects). 21. For patients with suspected renal malignancy who opted to be managed by active surveillance, chest X-ray imaging is suggested until definitive treatments are no longer considered (i.e., watchful waiting) (Conditional recommendation, low certainty in evidence of effects). 22. The panel was unable to achieve a consensus as to the frequency of abdominal imaging, which varied from at least once every 3-6 months for the first year and then once every 6-12 months if the lesion remains stable.
# Introduction
The incidence of small renal masses (SRM) is increasing around the world largely due to the increasing use of abdominal imaging. 1,2 Although 10-30% of these SRM are benign, the increase in SRM detection has also led to an increase in the detection of renal cell carcinoma (RCC). In 2020, it was estimated that approximately 7500 Canadians would be diagnosed with a kidney cancer. 6 There are several well-accepted treatment strategies available to manage SRM, and in the absence of high-quality evidence comparing each option, the best treatment strategy remains debated and may vary by patient. The most accepted treatment modalities include surgical excision (partial/radical nephrectomy), thermal ablation (cryoablation/radio-frequency ablation), and active surveillance. Even though many small cancers behave in an indolent fashion and have a low metastatic potential, the vast majority of patients receive invasive treatments. 3,7 In an attempt to decrease overtreatment of patients with SRM, renal mass biopsies have been proposed as a diagnostic test that may help guide management. 8 There is no "one-size-fits-all" strategy to the management of patients with SRM; shared decision-making must consider Guideline: SRM tumor characteristics, competing medical risks (age, renal function, comorbidities, etc.), and patient values and preferences to produce individualized management plans, recognizing gaps remaining in the natural history of observed renal masses. The objective of this guideline is to provide evidence-based recommendations to help clinicians and patients in the evaluation and management of SRM.
# Definition of small renal masses
For the purpose of this guideline, the panel has focused their recommendations on the management small, solid, enhancing renal masses measuring ≤4 cm on cross-sectional imaging and with features suspicious of a cT1a RCC (i.e., no radiographical evidence of tumor thrombus, renal fat, and/ or renal sinus fat invasion).
As the management of cystic renal lesions and angiomyolipomas are already the topic of separate guidelines, the review of these entities was not included in the current document. 9,10
# Methods
In October 2020, the guideline panel met and discussed key components of the guideline. Several questions were prioritized and were chosen to be developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. 11 A comprehensive literature search was completed in Medline, Embase, and PubMed to identify existing systematic reviews and meta-analyses on the topic, as well as additional relevant observational or randomized controlled studies. Recommendations were based on the most recent and most comprehensive meta-analyses available. When meta-analyses were not available, questions were answered based on selected observational or randomized controlled studies. The evidence was presented in evidence profiles and evidence-to-decision tables using GRADEpro.
The guideline panel developed the recommendations by majority during four teleconference meetings. The panel considered the tradeoff between undesirable and desirable effects of each management strategy, the required resources, and the economical impact of each intervention. In the absence of evidence on the topic, the panel estimated the patients' values and preferences by reflecting on their own values and preferences, were they faced with the decision to choose a treatment for the management of a SRM. Two of the panelists were non-clinician patient participants. They represented the patient stakeholder group Kidney Cancer Canada.
The strength of each recommendation was rated as strong or conditional (weak) as per the GRADE framework. Strong recommendations were made when the desirable benefits of treatment outweighed the undesirable consequences (harms) and are worded as recommends. Conditional recommendations were made when the benefits of treatment probably outweighed the harms and are worded as suggests. When insufficient evidence was available for a recommendation, the panel reported additional information as clinical principle or as expert opinion. All final recommendations were reviewed and approved by all members of the guideline panel. In patients with a SRM suspicious for renal malignancy, routine blood work, such as serum Cr and GFR, is suggested to better counsel patients on the potential harms of treatments. For patients with renal impairment and for whom an invasive treatment is being considered, a urinalysis to screen for proteinuria is also suggested. 12,13 Urine albuminto-creatinine ratio may also be used. Likewise, a complete blood count and a coagulation study may also be considered for patients being considered for an invasive treatment. 14 Although uncommon, synchronous metastasis can be found in patients diagnosed with a SRM. 15 For patients with features suspicious for liver metastases, liver function tests are suggested. 16 For patients presenting with bone pain, alkaline phosphatase, serum calcium, and lactate dehydrogenase (LDH) should be ordered. 17 For patients where urothelial cancer is suspected, a urine cytology and endoscopic assessment should be performed. 18
# Diagnostic evaluation
# Imaging
# Patients with a SRM incidentally discovered on routine
imaging should be investigated with a multiphasic, contrast-enhanced, abdominal computed tomography (CT) or magnetic resonance imaging (MRI) scan (Clinical principle).
# For patients with suspected renal malignancy, a baseline chest X-ray is suggested to assess for pulmonary metastases (Conditional recommendation, low certainty in evidence of effects). 4. Patients with a SRM and pre-existing renal dysfunction
in whom a radical nephrectomy is being considered may be offered renal scintigraphy when the result may alter their management (Clinical principle).
# Richard et al
Most renal masses are incidentally discovered on routine imaging. 1 As many as 10-30% of all SRM are benign, and the majority of malignant lesions have low metastatic potential. 3 An abdominal, multiphasic, contrast-enhanced CT or MRI is mandatory to characterize the mass, as enhancement is the most important criterion to confirm its solid nature. 19 Non-contrast CT scans can also be useful to identify macroscopic fat, a feature consistent with an angiomyolipoma, a benign lesion. Alternatively, a nonenhanced CT after an ultrasound confirming the solid nature of a mass may be acceptable for patients unable to receive contrast due to advanced renal impairment.
Under 2% of malignant SRM will be metastatic at the time of diagnosis. 15 Contrast-enhanced abdominal imaging is useful to exclude the presence of visceral metastases and tumor thrombus. To complete the metastatic workup, the chest should be imaged, as the lungs are the most common site of metastases. 20 Although the sensitivity for metas-Although the sensitivity for metastases is lower with chest X-ray compared to a chest CT, 21 the panel suggests a chest X-ray as the initial imaging of choice, given the low incidence of metastasis and the lower harms and cost to the healthcare system compared to chest CT. If any abnormalities are detected on the chest X-ray, a chest CT should be performed. Bone scintigraphy and brain imaging should only be performed for-cause in patients with symptoms, as most bone/brain metastases are symptomatic at diagnosis. 22,23 Renal scintigraphy may be considered in patients with renal impairment and in whom a radical nephrectomy is considered or in whom the assessment of differential renal function could alter management. As stated previously, 10-30% of SRM will be benign and the majority of malignant lesions will be of low metastatic potential. 3 Current conventional imaging modalities and other tumor factors typically associated with increased risks of malignancy (i.e., size, growth rate, etc.) cannot reliably differentiate a benign lesion from a malignant one. Consequently, renal mass biopsies have been used as a means to identify the histology of a SRM before treatment, with the objective to inform management and decrease overtreatment. 4,24 The role of renal mass biopsy in the management of kidney cancer in Canada is the topic of a KCRNC consensus statement that has been endorsed by the Canadian Urological Association. 8 Consequently, only key components will be reviewed here.
# Role of renal mass biopsy
Like any other diagnostic test, renal mass biopsy should be offered to patients in whom the result may impact management. A renal biopsy should not be performed for patients where its outcome will not influence treatment decision (e.g., someone not fit for invasive treatment or a patient who seeks surgical removal regardless of histology). A recent meta-analysis by Marconi et al has demonstrated that biopsies yielded a median diagnostic rate of 92% (interquartile rate 80.6-96.8%), with a concordance rate for histology and grade (four-tier system) of 90.3% (IQR 84-94.4%) and 62.5% (IQR 52.1-72.1%), respectively. 24 In addition to identifying benign lesions, a renal mass biopsy can also be helpful for risk stratification. Finelli et al used an active surveillance cohort where all patients were characterized by an upfront renal mass biopsy. 25 They found growth rates varied by RCC subtype. Clear-cell RCC had the fastest growth rates (average 0.25 cm/year) and papillary type 1 tumors, the slowest (average 0.11 cm/year). 25 Renal mass biopsies have also been shown to be safe, with a median overall complication rate of 8.1% (IQR 2.7-11.1%), with the vast majority of these complications reported as Clavien-Dindo 99%). 24 Additionally, although there are some reports of biopsy tract seeding with tumor, the evidence remains controversial and this risk is likely very low. 26,27 Before proceeding with a renal mass biopsy, the panel believes it is important to inform the patients of its benefits and harms, including the non-diagnostic rate and the unknown false-negative rate; most series do not report the false-negative rate, as masses with a benign biopsy result are not generally removed. False-negative rates have been reported to be as low as 3.5% in one Canadian series and as high as 31.5% in a meta-analysis where "normal parenchyma" biopsies were considered benign histology as opposed to non-diagnostic. 28,29 The authors of this guideline feel it is also important to consider that the diagnostic test characteristics and complication rates reported above are from experienced biopsy centers, and that results may not be generalizable to less experienced centers. Additionally, biopsy outcomes may also be influenced by a number of patient and tumor factors, such as size of the mass, consistency (cystic or necrosis component), location (exophytic vs. endophytic), and skin-to-tumor distance. 5,28,30 Thus, the decision to proceed with a biopsy should be made through a shared decision-making approach after weighing the potential benefits and harms of the diagnostic test and discussing the patients' preferences and values.
# Guideline: SRM
# Role of genetic assessment
# Patients with features suspicious of hereditary RCC should
be offered genetic counselling (Adopted from Canadian Urological Association guideline on genetic screening for hereditary renal cell cancers; expert opinion)
The role of genetic testing in the management of kidney cancer is extensively discussed in a separate CUA clinical practice guideline by Reaume et al. 31 Briefly, as suggested by the aforementioned guideline and endorsed by this panel, patients with the criteria presented in Table 1 should be offered genetic counselling and referred for genetic assessment. There are currently three well-documented management options for the treatment of SRM. Current evidence comparing each of these treatment options is of low quality and no one option has been demonstrated to be superior to another in a randomized controlled trial. Thus, the choice of treatment should be personalized using a shared decisionmaking approach, after proper counselling, according to each patient's values and preferences, and while factoring the patient's competing risks and tumor characteristics (Fig. 1). A summary of characteristics that may influence treatment decision is presented in Table 2. Prediction tools to estimate risk of other-cause mortality are available (e.g., ) and can be helpful to guide management. A decision aid has also been developed to inform patients diagnosed with a SRM and may help facilitate shared decision-making (. ca/docs/das/Small_Kidney_Tumour_Treatment.pdf). 32 The evidence supporting each recommendation and the different treatment strategies are summarized below.
# Management of small renal masses
# Expectant management: Active surveillance vs. watchful waiting
Active surveillance is a strategy where patients are followed with serial, scheduled imaging to monitor the mass. With active surveillance, patients are offered a definitive treatment if there is evidence of disease progression or if their preferences change during the course of management. A comprehensive description of the indications for definitive treatment while on active surveillance is detailed below. This strategy differs from watchful waiting (the preferred strategy reserved for patients with limited life expectancy), where treatment is only considered for palliation of symptoms that may arise from disease progression rather than an attempt at cure. Patients managed by watchful waiting do not require regular imaging followup unless clinically indicated.
A meta-analysis of patients with a SRM has demonstrated that active surveillance was associated with a cancer-specific survival similar to other treatment strategies and has demonstrated a low associated risk of developing metastasis after short-to mid-term followup. 33 Results from the largest, multicenter, prospective study (Delayed Intervention and Surveillance for Small Renal Masses ) has demonstrated that most tumors grow slowly (median growth rate <0.1 cm/year) and that approximately 10-15% of patients will discontinue active surveillance in favor of definitive therapy over time. Compared to the active surveillance cohort, the immediate intervention cohort had higher quality of life scores at baseline and throughout followup, but men-
# tal health domains (including depression/anxiety domains)
were not negatively affected while on active surveillance, and even improved over time. 37 Importantly, although active surveillance was initially reserved for older, comorbid patients, recent evidence has demonstrated that this strategy is also safe among younger patients. 38 Evidence from the DISSRM registry demonstrated that there was no difference in terms of cancer-specific survival and overall survival among patients <60 years of age managed by either definitive treatment (n=156) or active surveillance (n=68). Rate of progression to definitive treatment was lower among patients that presented with a lesion <2 cm compared to patients who presented with a lesion that measured 2-4 cm (15.1% vs. 33.3%).
One caveat that should be discussed with patients about this management strategy, is that most active surveillance series are of relatively short followup (median 42 months, range 1-137 months) and based on older, more comorbid patients compared to surgical series. 39 Nevertheless, given the relatively high probability of benign histology (>20%) and indolent nature of most malignancies in this size range(>85%), 3 active surveillance is suggested as the preferred management strategy for patients with a lesion measuring <2 cm. Immediate, definitive treatment remains an option and should be discussed with patients to ensure they are fully informed. In patients with a lesion measuring 2-4 cm, there was no consensus on the preferred management strategy. Although the panel members all recognized that active surveillance should be offered as an option to these patients, nearly 40% of the panel members felt that definitive treatment (surgery or thermal ablation) should be considered as the option of choice. Given the varied Guideline: SRM growth rates by histological subtype, biopsy may also inform the management decision for patients considering active surveillance. 25 As stated, risks of active surveillance may be influenced by the characteristics presented in Table 2.
# Definitive treatments
Surgery vs. percutaneous thermal-ablation 11. For patients with a suspected renal malignancy who prefer management by upfront definitive treatment, surgery or percutaneous thermal ablation are suggested (Conditional recommendation, low certainty in evidence of effects). 12. Patients with a SRM should be informed of the higher uncertainty surrounding the data on the efficacy and harms of percutaneous thermal ablation treatment compared to surgery (Expert opinion).
# Patients with a suspected renal malignancy who opt
to be treated by percutaneous thermal ablation should have a renal mass biopsy performed prior to, or at the time of thermal ablation (Adopted from KCRNC consensus statement on the role of renal mass biopsy in the management of kidney cancer; expert consensus). 8 As stated, there is currently no randomized controlled trial comparing the outcomes of surgery and percutaneous thermal ablation for the management of patients with a SRM. A number of meta-analyses have compared the short-term and long-term outcomes of surgery and thermal ablation with the caveat that the data are based mostly on retrospective studies and are, therefore, prone to selection bias. 33, The non-randomized evidence seems to suggest that thermal ablation yields similar oncological outcomes compared to surgery. There is some evidence that seems to suggest that local recurrence is higher after thermal ablation than with partial nephrectomy; 41 however, when multiple ablative treatments were considered, local recurrence-free survival was comparable to partial nephrectomy. 47,48 The most recent meta-analysis on the topic was performed by the European Association of Urology Renal Cell Cancer Guideline Panel and reported in 2020. 41 In this meta-analysis, 26 observational studies, totalling 16 780 patients, were included. The risk of bias assessment revealed high or uncertain risk of bias across all studies, owing to the included studies being retrospective, observational studies with poorly matched controls and relatively short followups. The data seem to suggest that percutaneous ablation is safe in terms of adverse events and complications, but its long-term oncological outcome compared to partial nephrectomy is uncertain. Compared to thermal ablation, surgery also has the advantage of providing definitive pathology specimen, which may be important for genetic counselling consideration.
Nevertheless, given the evidence, the panel is unable to suggest one approach over the other in patients who choose to undergo definitive treatment. Patients with a SRM should be informed of the higher uncertainty surrounding the data on the efficacy and harms of percutaneous thermal ablation treatment compared to surgery. Thus, the choice of treatment must be individualized according to each patient's values and preferences and according to patient, tumor, and hospital-level characteristics (Table 2). Importantly, patients choosing percutaneous thermal ablation as their treatment of choice should have a renal mass biopsy performed prior to, or at the time of thermal ablation to obtain histological confirmation and to help tailor the followup strategy.
# Partial vs. radical nephrectomy
# For patients with suspected malignant SRM undergoing surgery, partial nephrectomy is recommended over radical nephrectomy (Strong recommendation; moderate certainty in evidence of effects).
Surgical removal of a localized renal mass can be done through a radical or partial nephrectomy. Current evidence is mostly based on observational studies, either retrospective or prospective in design. So far, only one randomized controlled trial which closed prematurely due to poor accrual, has compared the oncological outcomes of patients with a localized renal mass (<5 cm in diameter) treated with a radical nephrectomy or a partial nephrectomy between 1992 and 2003. The results of this study showed comparable 10-year cancer-specific survival for both options, but an improved 10-year overall survival in favor of radical nephrectomy, with only a fraction of deaths (12 of 117) due to renal cancer. 49 These results have long been debated for a number of reasons, including its poor accrual, relatively high crossover rate, incomplete central pathology review, and most importantly, the overwhelming number of observational studies favoring partial nephrectomy over radical nephrectomy. 50,51 A Cochrane review published in 2017 demonstrated that time to death of any cause was decreased using partial nephrectomy compared to radical nephrectomy (hazard ratio 1.5, 95% confidence interval 1.03-2.18). 52 This review was based on low-quality evidence, given the available data. Additionally, there was no difference identi- ). The absence of difference in the rate of significant harm with regards to both surgeries is especially true for easily resectable tumors in the presence of a normal contralateral kidney. 49 Although debated, one of the potential explanations for the improved survival is that partial nephrectomy results in an increased renal function preservation and subsequent decrease in cardiovascular events compared to radical nephrectomy. Therefore, given the overwhelming number of observational studies demonstrating equivalent oncological outcomes, increased renal function preservation, and comparable significant harms (at least in easily resectable tumors), partial nephrectomy is recommended as the preferred approach when technically feasible in expert hands.
In older patients and in those with more comorbidities/ limited life expectancy, the potential benefit of partial over radical nephrectomy is less clear. Likewise, the benefit of partial over radical nephrectomy for patients with complex renal masses is subject to some debate, given the higher incidence of significant complications and potentially higher upstaging to pT3a. Consequently, for some patients, the increased risk of harms may outweigh the potential benefits of partial nephrectomy. Thus, radical nephrectomy should be reserved for patients in whom a partial nephrectomy or percutaneous thermal ablation cannot be performed even in experienced centers or for patients who are unwilling to accept the short-term risks of partial nephrectomy/thermal ablation compared to radical nephrectomy. A consideration should also be given for a preoperative renal mass biopsy in patients for whom a radical nephrectomy is planned to avoid removal of the entire organ for a benign lesion.
Nephrometry scoring systems have been developed to aid in communicating renal tumor complexity in a standardized fashion -whether in clinical or research contexts -and to predict treatment outcomes. The most commonly used systems are the RENAL (radius, exophytic/endophytic, nearness, anterior/posterior, location), PADUA (preoperative aspects and dimensions used for an anatomical), and SPARE (Simplified PADUA Renal) nephrometry scores (Table 3). The first two nephrometry scoring systems are the most extensively studied and have been shown to be predictive of length of hospital stay, tumor pathology, surgical margins, tumor growth rate, renal function outcomes, and survival. 59 The RENAL nephrometry score has also been shown to be useful for predicting outcomes and complications following percutaneous ablation. 58,60 One caveat of using these scoring systems includes interobserver variability in assessments and inconsistent associations with outcome measures. 66 Further work is needed to determine to what extent formal nephrometry scores improve upon subjective estimation of tumor complexity by individual surgeons. Nonetheless, nephrom-etry scoring systems represent a common language that can standardize classification of renal tumor complexity, allow for comparison of surgical outcomes, improve patient coun- Partial nephrectomy can be performed through different approaches -open, conventional laparoscopy, or roboticassisted. A number of meta-analyses have compared open to minimally invasive partial nephrectomy. All three techniques seem to offer similar oncological outcomes; however, minimally invasive techniques are generally associated with significantly less blood loss (and blood transfusion), shorter hospitalization stay, less severe postoperative complications, and potentially, better renal function preservation. There does not seem to be any clinically significant difference between conventional laparoscopy and robotic-assisted partial nephrectomy in terms of oncological and functional outcomes, although robotic-assisted surgery is potentially associated with higher incidence of major bleed and shorter ischemia time, albeit early in the robotic experience era. Thus, given the evidence, when technically feasible and oncologically safe, minimally invasive techniques -conventional laparoscopy or robotic-assisted partial nephrectomy -should be favored over open partial nephrectomy. However, open partial nephrectomy remains appropriate for complex SRM, if the alternative is radical nephrectomy.
If a radical nephrectomy is to be performed, a minimally invasive approach is favored over open surgery. Results from a recent meta-analysis showed that minimally invasive approaches offer key advantages over an open approach, such as decreased hospitalization stay and fewer complications, while providing similar oncological outcomes. 70 Conventional laparoscopy and robot-assisted radical nephrectomy seem to result in similar surgical outcomes, but owing to the higher total cost, higher equity, and the lower surgical complexity of a radical nephrectomy (compared to a partial nephrectomy), conventional laparoscopic radical nephrectomy is strongly favored over robotic radical nephrectomy. 71 Percutaneous cryotherapy vs. percutaneous radio-frequency ablation 17. For patients undergoing percutaneous thermal ablation for a suspected renal malignancy, cryoablation and radio-frequency ablation are both suggested as options for management, as they yield similar oncological outcomes and adverse events (Conditional recommendation, moderate certainty in evidence of effects).
Percutaneous ablation of a SRM is most commonly performed using cryoablation (tissue damage by freezing) or radio-frequency ablation (tissue damage by heat). A number of retrospective studies have compared both these ablative techniques and have concluded that both yield similar oncological outcomes and adverse events. 44, Consequently, as both techniques have their own advantages and disadvantages, the choice of approach should be based on availability, provider's experience, and tumor-related factors (size, location, adjacent structures, etc.). Regardless on the type of technique chosen, it is the panel's opinion that a renal tumor biopsy should be performed prior to ablation (in a separate setting or at the time of ablation), as this will achieve histological confirmation and will help tailor the frequency of followup imaging. It is also important to note that most series reported their outcomes for tumors <3 cm in size.
Even though the treatment of 3-4 cm tumors is possible, patients should be appropriately counselled as to the higher likelihood of complications and local recurrence compared to <3 cm tumors. 58, For these patients, although the literature is prone to biases and subject to debate among experts, there is some evidence suggesting that cryoablation leads to lower cancer-specific mortality compared to radio-frequency ablation. 80,81 Thus, when both ablation approaches are available, it would seem reasonable to favor cryoablation for tumors 3-4 cm. Delayed intervention, including partial or radical nephrectomy, or percutaneous ablation, is instituted in 0-30% of Richard et al patients on active surveillance. 82 Indications for intervention vary and involve an assessment of the competing risks of RCC progression vs. other causes of mortality, factoring in patient values and preferences through shared decision-making.
# Indications for definitive treatment while on active surveillance
Common reasons for intervention include tumor growth rate and absolute tumor size attained. Both maximum linear tumor diameter and volumetric measurements can be used during surveillance. Volumetric assessments may be more accurate, given that tumors are not always spherical, but at the same time, are less practical and less familiar to clinicians. It is, however, important to note that none of these indications have been validated.
Average growth rate for a SRM during surveillance is typically 0.1-0.25 cm per year. Aggressive tumors have a faster growth rate. For example, in a pooled analysis of patients who had metastatic progression on surveillance, average growth rate was 0.8 cm per year. 87 As such, rapid growth rate is an indication for intervention, with important additional considerations, such as age, comorbidities, patient's preference, etc. (Table 2). The DISSRM registry used growth rate >0.5 cm per year as a criterion for progression, while the Renal Cell Carcinoma Consortium of Canada used doubling of calculated tumor volume within 12 months as part of their definition of progression. 25,84 Several limitations of growth rate assessments are important. First, growth rates should be assessed cautiously in patients who would require comparisons of tumor size measured using different imaging modalities. If tumor growth is suspected based on ultrasound, this should be confirmed with cross-sectional imaging prior to intervention. Second, tumor growth may be exponential, and therefore, tumor growth may increase over time. Third, intra-and inter-observer variability in the measurement of tumor diameter on imaging exist and must be considered. 89 Fourth, some tumors may exhibit stochastic growth, further contributing to variability. 25 For patients on active surveillance with concerning tumor growth and without a prior renal mass biopsy, one can be considered if it will change management.
Tumor size is associated with risk of harboring malignancy, the risk of aggressive histology, including high-grade disease, 90,91 the risk of developing metastatic disease, and survival outcomes. 95 The Renal Cell Carcinoma Consortium of Canada and the DISSRM registry consider tumor diameter >4 cm as a criterion for progression. 83,84 A larger tumor size and/ or change in tumor complexity (as reflected by the nephrometry score) may also limit the feasibility of certain interventions. Clinicians should review images in each instance to ensure a window of treatment opportunity is not inadvertently missed; this should be factored into decision-making.
Several patient factors may also influence decisions on delayed interventions. 96 Patient age, frailty, and comorbidities should all be factored into estimating risk of mortality for competing medical conditions. In elderly, frail, and/or comorbid patients, the risks of intervention are not trivial and there is a stronger rationale for deferring intervention or perhaps for transitioning to watchful waiting. Patient anxiety should also be factored into decision-making, although it should not be the sole criterion for intervention. It is the role of the clinician to provide appropriate counselling to address anxiety, which may include the use of decision aids. 32 One study found that depression and anxiety were not adversely affected while on active surveillance for a renal mass, and in fact, improved with time. 97 The objective of active surveillance is to delay treatment until evidence of disease progression. To do so, it is important to obtain routine abdominal imaging during followup. Several imaging modalities may be used, such as ultrasound, CT scan, and MRI. Cross-sectional imaging using CT or MRI provides the most accurate assessment of the size and complexity of a SRM. Ultrasound is an alternative for imaging surveillance, as it is cost-effective, offers adequate assessment of growth, avoids ionizing radiation, and is more readily accessible/available than CT and MRI. For these reasons, abdominal ultrasound is suggested as the imaging of choice during followup for patients on active surveillance. One caveat of ultrasound is that it is operator-dependent and cross-modality comparisons of size measurements with CT/MRI can sometimes be challenging. Therefore, if tumor growth is suspected on surveillance ultrasound or the mass cannot be reliably identified Guideline: SRM by ultrasound, an abdominal cross-sectional imaging (CT or MRI) for confirmation is required.
# Followup
Although a rare event, patients on active surveillance may develop distant metastases. For this reason, most renal mass active surveillance series include chest X-rays as part of their surveillance protocols, while none performed CT scans of the chest routinely. 82 Asymptomatic patients with tumors <4 cm in size have a <1% probability of harboring pulmonary metastases, as assessed by CT chest, 98,99 and data from the DISSRM registry has revealed that all abnormalities noted on the chest X-ray either at baseline or during surveillance were not metastasis-related. 100 The low prevalence of pulmonary metastases combined with the suboptimal sensitivity and specificity limit the utility and cost-effectiveness of chest X-ray surveillance in patients undergoing active surveillance for SRM. Nevertheless, despite its limitation, the panel suggests performing chest X-ray imaging during followup, as the members placed a higher importance on finding metastases than on the potential harms and cost of chest imaging.
Followup schedules for active surveillance are heterogeneous between studies and even within series. To date, the optimal schedule has not been agreed upon. 82 Nevertheless, the panel members believed that patients should be followed with abdominal imaging every 3-6 months for the first year and then every 6-12 months, if the lesion remains stable. Frequency of imaging should be increased for patients demonstrating tumor growth if the patient remains on active surveillance. Patients should be followed with abdominal imaging until definitive treatments are no longer considered. Likewise, there is no agreed-upon optimal followup schedule for chest imaging. The panel members were nearly evenly split as to the frequency of chest imaging and thus, they were not able to achieve a consensus as to its frequency, which varied from for-cause (52.6% of members) to once a year (47.4% of members).
# Followup after definitive treatment
# Patients with a RCC who have undergone definitive
treatment should be followed with routine chest and abdominal imaging to rule out recurrence or progression to metastasis (Adopted from CUA guideline for followup of patients after treatment of non-metastatic renal cell carcinoma; expert opinion). 24. Patients with an estimated GFR <45 ml/min/1.73m 2 or with progressive chronic kidney disease following definitive treatment should be considered for a referral to a nephrologist (or their general practitioner), especially if associated with proteinuria (Adopted from CUA guideline for followup of patients after treatment of non-metastatic renal cell carcinoma; conditional recommendation, low certainty in evidence of effects).
The readers interested in receiving in-depth guidance of the followup of patients with hereditary RCC should review the guideline by Lattouf et al. 101 Likewise, the detailed recommended followup after definitive treatment of incidental RCC is extensively reviewed in the guideline by Kassouf et al. Briefly, studies have shown that patients with pT1a RCC are at low risk of local recurrence or metastases after surgery to remove the mass (5% for recurrence or metastases). 102,103 Recommended surveillance after surgery includes: annual blood test (complete blood count, serum chemistries, and liver function test) and annual chest X-ray, as well as abdominal CT, MRI, or ultrasound at 24 and 60 months. A contrast-enhanced abdominal CT scan/MRI at 3-12 months post-treatment for patients treated with partial nephrectomy is optional to evaluate the residual baseline renal appearance. Due to the higher risk of residual disease and need for retreatment after thermal ablation, a contrast-enhanced abdominal CT scan/MRI is recommended at three, six, and 12 months post-treatment, and then annually, in addition to annual bloodwork and chest X-ray. Patients with postoperative chronic renal failure should be referred to nephrology or to their general practitioner for proper assessment, given the potentially higher risk of developing cardiovascular disorders. 57
# Future directions
# Novel non-surgical therapies
In addition to cryoablation and radio-frequency ablation, there are currently three other types of ablative therapies available to treat SRM: microwave ablation, 44, irreversible electroporation, and stereotactic body radiation therapy (SBRT)
Although promising, as long-term data on the outcomes of these techniques are lacking, the panel still considers these approaches experimental and long-term data will be required before making any recommendations on the role of these newer ablative techniques.
# Novel diagnostic imaging
MRI is an increasingly used alternative to CT scan and it is generally perceived as a comparable alternative. There are a number of reports evaluating a potential role for multiparametric MRI (mpMRI) as an imaging tool to help predict histological subtype. Recently, a clear-cell likelihood score has been proposed to determine the risk of a lesion being clear-cell RCC using a non-invasive approach. 104,110,111 This score has been proposed as a tool to reduce the number of patients who undergo routine biopsy and to help guide management, although this remains to be validated.
Like mpMRI, 99mTc-sestamibi single-photon emission computed tomography (SPECT)/CT is being evaluated for Richard et al detecting oncocytomas and other benign renal lesions. Early results appear promising but require further validation before being routinely recommended in Canada.
# Novel diagnostic biomarkers
In recent years, there has been extensive research focused on the identification of a reliable biomarker as an adjunct to imaging and an alternative to renal mass biopsy. 118,119 Several studies have evaluated the role of liquid biopsy assays, including circulating tumor cells, circulating cell-free DNA, and microRNAs, as less invasive techniques for early detection of RCC and for discrimination between benign and malignant renal masses. Although early detection of RCC through easily available circulating biomarkers is of great interest and a promising research avenue, the diversity of techniques and current lack of validation studies preclude any meaningful conclusions. The panel hopes that recommendations will be made possible by the publication of new studies on the topic for the next iteration of this guideline.
# Knowledge gaps
In addition to the lack of high-quality studies comparing the different treatment options for SRM, one other area of clear knowledge gap identified by the panel is the current lack of studies on quality-of-life outcomes and on patients' values and preferences. These types of studies are of great importance to guideline panels that must make recommendations based on the tradeoff of desirable and undesirable outcomes of the management alternatives they are considering using average or typical values and preferences. This concept is highlighted by the widely adopted GRADE framework for clinical guidelines. As values and preferences studies on the topic are currently absent, the panel had to speculate, with the help of patient representatives, on the actual patients' value and preferences for the management of SRM, speculation that may diverge substantially from the true situation. The panels hopes that studies will have attempted to fill this important knowledge gap in time for the next iteration of this guideline.
# Summary
The incidence of SRM is increasing and many of these incidentally found lesions will be either benign or of low metastatic potential. Immediate invasive treatment of all patients with SRM leads to significant overtreatment. Importantly, most of the evidence on management options for patients with SRM is based on observational data, which are subject to many biases. Thus, most recommendations are based on evidence with low certainty of effect. The panel hopes that in the near future, higher-quality studies will further refine the management of SRM. In the meantime, it is important to obtain a treatment consensus through a shared decision-making approach after weighing the pros and cons of each option according to each patient's own values and preferences.
Competing interests: Dr. Richard has been an advisory board member for Bayer, Janssen, and Sanofi; and a speakers' bureau member for Abbvie, Amgen, Astellas, Ferring, and Janssen. Dr. Bhindi has been an advisory board member for Bayer and Janssen; and has received speaker honoraria from Merck. Dr. Breau has been an advisory board member for Ferring (bladder cancer). Dr. Kassouf has been an advisory board member for EMD Serono and Pfizer; has received grants and/or honoraria from Abbvie, Astellas, BMS, Ferring, Janssen, Merck, Roche, and Sesen Bio; and has participated in clinical trials supported by Astra Zeneca, BMS, Janssen, Pfizer, Roche, Sesen Bio, and Theralase. Dr. Lavallée has participated in advisory boards for Abbvie, Bayer, Ferring, Sanofi, and Tersera; and has received an unrestricted research grant from Sanofi. Dr. Jewett has been an advisory board member for and received payment from Sesen Bio and Theralase Technologies Ltd. Dr. Kachura participated in the multicenter OPTIMA trial for liver cancer ablation supported by Celsion Inc. Dr. Pouliot has been an advisory board member for Astellas, Bayer, Esai, Janssen, Merck, Sanofi, and Tersera; holds investments in Allogene Therapeutics; and has participated in clinical trials supported by Lantheus, Merck, and Progenics. Dr. So has been an advisory board member for Abbvie, Amgen, Bayer, Ferring, Janssen, Merck, and Tersera. Dr. Rendon has been an advisory board and speakers' bureau member for and has received honoraria from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Ferring, Jansen, and Sanofi. Dr. Tanguay has participated in advisory boards for BMS, Janssen, Knight Therapeutics, Merck, and Roche; and has participated in clinical trials supported by AstraZeneca and Roche. Dr. Shayegan has been an advisory board member for Astellas, Bayer, and Janssen; and has received a research grant from Janssen. The remaining authors do not report any competing personal or financial interests related to this work. This paper has been peer-reviewed. | The same can be said regarding the frequency of chest imaging, which varied from for-cause to once a year (Expert opinion). 23. Patients with RCC who have undergone definitive treatment should be followed with routine chest and abdominal imaging to rule out recurrence or progression to metastasis (Adopted from CUA guideline for followup of patients after treatment of non-metastatic RCC; expert opinion). 24. Patients with an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m 2 or with progressive chronic kidney disease following definitive treatment should be considered for a referral to a nephrologist (or their general practitioner), especially if associated with proteinuria (Adopted from CUA guideline for followup of patients after treatment of non-metastatic RCC; conditional recommendation, low certainty in evidence of effects).# Summary of recommendations
1. Patients diagnosed with SRM should undergo routine laboratory investigations, including at a minimum a serum creatinine and glomerular filtration rate (Clinical principle).
# Patients with SRM incidentally discovered on routine
imaging should be investigated with a multiphasic, contrast-enhanced abdominal computed tomography (CT) or magnetic resonance imaging (MRI) scan (Clinical principle). 3. For patients with suspected renal malignancy, a baseline chest X-ray is suggested to assess for pulmonary metastases (Conditional recommendation, low certainty in evidence of effects). 4. Patients with SRM and pre-existing renal dysfunction in whom a radical nephrectomy is being considered, may be offered renal scintigraphy when the result may alter their management (Clinical principle). 5. Patients with SRM should be offered a renal mass biopsy when the result of the biopsy may alter their management (Adopted from Kidney Cancer Research Network of Canada [KCRNC] consensus on the role of renal mass biopsy in the management of kidney cancer; expert opinion). 6. Patients with features suspicious of hereditary renal cell carcinoma (RCC) should be offered genetic counselling (Adopted from CUA guideline on genetic screening for hereditary RCC; expert opinion). 7. For patients with SRM suspicious for renal malignancy AND significant comorbidities and/or limited life expectancy, observation (or watchful waiting) is recommended as the preferred strategy for patients (Strong recommendation, high certainty in evidence of effects). 8. For patients with a suspected renal malignancy measuring <2 cm in diameter, active surveillance is suggested as the preferred strategy, given their slow growth rate and low probability of aggressive histology (Conditional recommendation, moderate certainty in evidence of effects). 9. For patients with a suspected renal malignancy measuring 2-4 cm in diameter, active surveillance and definitive treatment (partial nephrectomy or percutaneous thermal ablation) are suggested as management options (Conditional recommendation, low certainty in evidence of effects). 10. For patients with a suspected renal malignancy, the choice of treatment should be personalized using a shared decision-making approach, after proper counselling and while taking into account tumor characteristics, patient factors, and patient preferences and values (Expert opinion).
Richard et al 11. For patients with a suspected renal malignancy who prefer management by upfront definitive treatment, surgery or percutaneous thermal ablation are suggested (Conditional recommendation, low certainty in evidence of effects). 12. Patients with a suspected renal malignancy who prefer management by upfront definitive treatment should be informed of the higher uncertainty surrounding the data on the efficacy and harms of percutaneous thermal ablation treatment compared to surgery (Expert opinion). 13. Patients with a suspected renal malignancy who opt to be treated by percutaneous thermal ablation should have a renal mass biopsy performed prior to, or at the time of thermal ablation (Adopted from KCRNC consensus on the role of renal mass biopsy in the management of kidney cancer; expert consensus) 14. For patients with suspected malignant SRM undergoing surgery, partial nephrectomy is recommended over radical nephrectomy (Strong recommendation, moderate certainty in evidence of effects). 15. For patients with suspected renal malignancy undergoing partial nephrectomy, a minimally invasive approach (robotic-assisted or conventional laparoscopy) is suggested over an open approach, when technically feasible and oncologically safe (Conditional recommendation, moderate certainty in evidence of effects). 16. For patients with suspected renal malignancy undergoing radical nephrectomy, a conventional laparoscopic approach is recommended over open or robotic-assisted approaches (Strong recommendation, moderate certainty in evidence of effects). 17. For patients undergoing percutaneous thermal ablation for a suspected renal malignancy, cryoablation and radio-frequency ablation are both suggested as options for management, as they yield similar oncological outcomes and adverse events (Conditional recommendation, moderate certainty in evidence of effects). 18. Patients under active surveillance should be monitored until the oncological risk increases, they select intervention, or the benefits of treatment outweigh the competing risks. The factors that define oncological risk are not completely elucidated but the most well-accepted factors are: growth of tumor to >4 cm, consecutive growth rate >0.5 cm/year, progression to metastases, and patient's choice (Clinical principle). 19. Patients with suspected tumor growth on ultrasound imaging should undergo cross-sectional imaging to confirm growth prior to intervention (Expert opinion). 20. For patients with suspected renal malignancy who opted to be managed by active surveillance, routine abdominal ultrasound (assuming good visualization and good agreement in size measurements between ultrasound and cross-sectional imaging) is suggested until definitive treatments are no longer considered (i.e., watchful waiting) (Conditional recommendation, low certainty in evidence of effects). 21. For patients with suspected renal malignancy who opted to be managed by active surveillance, chest X-ray imaging is suggested until definitive treatments are no longer considered (i.e., watchful waiting) (Conditional recommendation, low certainty in evidence of effects). 22. The panel was unable to achieve a consensus as to the frequency of abdominal imaging, which varied from at least once every 3-6 months for the first year and then once every 6-12 months if the lesion remains stable.
# Introduction
The incidence of small renal masses (SRM) is increasing around the world largely due to the increasing use of abdominal imaging. 1,2 Although 10-30% of these SRM are benign, the increase in SRM detection has also led to an increase in the detection of renal cell carcinoma (RCC). [3][4][5] In 2020, it was estimated that approximately 7500 Canadians would be diagnosed with a kidney cancer. 6 There are several well-accepted treatment strategies available to manage SRM, and in the absence of high-quality evidence comparing each option, the best treatment strategy remains debated and may vary by patient. The most accepted treatment modalities include surgical excision (partial/radical nephrectomy), thermal ablation (cryoablation/radio-frequency ablation), and active surveillance. Even though many small cancers behave in an indolent fashion and have a low metastatic potential, the vast majority of patients receive invasive treatments. 3,7 In an attempt to decrease overtreatment of patients with SRM, renal mass biopsies have been proposed as a diagnostic test that may help guide management. 8 There is no "one-size-fits-all" strategy to the management of patients with SRM; shared decision-making must consider Guideline: SRM tumor characteristics, competing medical risks (age, renal function, comorbidities, etc.), and patient values and preferences to produce individualized management plans, recognizing gaps remaining in the natural history of observed renal masses. The objective of this guideline is to provide evidence-based recommendations to help clinicians and patients in the evaluation and management of SRM.
# Definition of small renal masses
For the purpose of this guideline, the panel has focused their recommendations on the management small, solid, enhancing renal masses measuring ≤4 cm on cross-sectional imaging and with features suspicious of a cT1a RCC (i.e., no radiographical evidence of tumor thrombus, renal fat, and/ or renal sinus fat invasion).
As the management of cystic renal lesions and angiomyolipomas are already the topic of separate guidelines, the review of these entities was not included in the current document. 9,10 [Editor's note: The CUA guideline on the management of cystic renal lesions is currently being updated and should be available in 2022.]
# Methods
In October 2020, the guideline panel met and discussed key components of the guideline. Several questions were prioritized and were chosen to be developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. 11 A comprehensive literature search was completed in Medline, Embase, and PubMed to identify existing systematic reviews and meta-analyses on the topic, as well as additional relevant observational or randomized controlled studies. Recommendations were based on the most recent and most comprehensive meta-analyses available. When meta-analyses were not available, questions were answered based on selected observational or randomized controlled studies. The evidence was presented in evidence profiles and evidence-to-decision tables using GRADEpro.
The guideline panel developed the recommendations by majority during four teleconference meetings. The panel considered the tradeoff between undesirable and desirable effects of each management strategy, the required resources, and the economical impact of each intervention. In the absence of evidence on the topic, the panel estimated the patients' values and preferences by reflecting on their own values and preferences, were they faced with the decision to choose a treatment for the management of a SRM. Two of the panelists were non-clinician patient participants. They represented the patient stakeholder group Kidney Cancer Canada.
The strength of each recommendation was rated as strong or conditional (weak) as per the GRADE framework. Strong recommendations were made when the desirable benefits of treatment outweighed the undesirable consequences (harms) and are worded as recommends. Conditional recommendations were made when the benefits of treatment probably outweighed the harms and are worded as suggests. When insufficient evidence was available for a recommendation, the panel reported additional information as clinical principle or as expert opinion. All final recommendations were reviewed and approved by all members of the guideline panel. In patients with a SRM suspicious for renal malignancy, routine blood work, such as serum Cr and GFR, is suggested to better counsel patients on the potential harms of treatments. For patients with renal impairment and for whom an invasive treatment is being considered, a urinalysis to screen for proteinuria is also suggested. 12,13 Urine albuminto-creatinine ratio may also be used. Likewise, a complete blood count and a coagulation study may also be considered for patients being considered for an invasive treatment. 14 Although uncommon, synchronous metastasis can be found in patients diagnosed with a SRM. 15 For patients with features suspicious for liver metastases, liver function tests are suggested. 16 For patients presenting with bone pain, alkaline phosphatase, serum calcium, and lactate dehydrogenase (LDH) should be ordered. 17 For patients where urothelial cancer is suspected, a urine cytology and endoscopic assessment should be performed. 18
# Diagnostic evaluation
# Imaging
# Patients with a SRM incidentally discovered on routine
imaging should be investigated with a multiphasic, contrast-enhanced, abdominal computed tomography (CT) or magnetic resonance imaging (MRI) scan (Clinical principle).
# For patients with suspected renal malignancy, a baseline chest X-ray is suggested to assess for pulmonary metastases (Conditional recommendation, low certainty in evidence of effects). 4. Patients with a SRM and pre-existing renal dysfunction
in whom a radical nephrectomy is being considered may be offered renal scintigraphy when the result may alter their management (Clinical principle).
# Richard et al
Most renal masses are incidentally discovered on routine imaging. 1 As many as 10-30% of all SRM are benign, and the majority of malignant lesions have low metastatic potential. 3 An abdominal, multiphasic, contrast-enhanced CT or MRI is mandatory to characterize the mass, as enhancement is the most important criterion to confirm its solid nature. 19 Non-contrast CT scans can also be useful to identify macroscopic fat, a feature consistent with an angiomyolipoma, a benign lesion. Alternatively, a nonenhanced CT after an ultrasound confirming the solid nature of a mass may be acceptable for patients unable to receive contrast due to advanced renal impairment.
Under 2% of malignant SRM will be metastatic at the time of diagnosis. 15 Contrast-enhanced abdominal imaging is useful to exclude the presence of visceral metastases and tumor thrombus. To complete the metastatic workup, the chest should be imaged, as the lungs are the most common site of metastases. 20 Although the sensitivity for metas-Although the sensitivity for metastases is lower with chest X-ray compared to a chest CT, 21 the panel suggests a chest X-ray as the initial imaging of choice, given the low incidence of metastasis and the lower harms and cost to the healthcare system compared to chest CT. If any abnormalities are detected on the chest X-ray, a chest CT should be performed. Bone scintigraphy and brain imaging should only be performed for-cause in patients with symptoms, as most bone/brain metastases are symptomatic at diagnosis. 22,23 Renal scintigraphy may be considered in patients with renal impairment and in whom a radical nephrectomy is considered or in whom the assessment of differential renal function could alter management. As stated previously, 10-30% of SRM will be benign and the majority of malignant lesions will be of low metastatic potential. 3 Current conventional imaging modalities and other tumor factors typically associated with increased risks of malignancy (i.e., size, growth rate, etc.) cannot reliably differentiate a benign lesion from a malignant one. Consequently, renal mass biopsies have been used as a means to identify the histology of a SRM before treatment, with the objective to inform management and decrease overtreatment. 4,24 The role of renal mass biopsy in the management of kidney cancer in Canada is the topic of a KCRNC consensus statement that has been endorsed by the Canadian Urological Association. 8 Consequently, only key components will be reviewed here.
# Role of renal mass biopsy
Like any other diagnostic test, renal mass biopsy should be offered to patients in whom the result may impact management. A renal biopsy should not be performed for patients where its outcome will not influence treatment decision (e.g., someone not fit for invasive treatment or a patient who seeks surgical removal regardless of histology). A recent meta-analysis by Marconi et al has demonstrated that biopsies yielded a median diagnostic rate of 92% (interquartile rate [IQR] 80.6-96.8%), with a concordance rate for histology and grade (four-tier system) of 90.3% (IQR 84-94.4%) and 62.5% (IQR 52.1-72.1%), respectively. 24 In addition to identifying benign lesions, a renal mass biopsy can also be helpful for risk stratification. Finelli et al used an active surveillance cohort where all patients were characterized by an upfront renal mass biopsy. 25 They found growth rates varied by RCC subtype. Clear-cell RCC had the fastest growth rates (average 0.25 cm/year) and papillary type 1 tumors, the slowest (average 0.11 cm/year). 25 Renal mass biopsies have also been shown to be safe, with a median overall complication rate of 8.1% (IQR 2.7-11.1%), with the vast majority of these complications reported as Clavien-Dindo <2 (>99%). 24 Additionally, although there are some reports of biopsy tract seeding with tumor, the evidence remains controversial and this risk is likely very low. 26,27 Before proceeding with a renal mass biopsy, the panel believes it is important to inform the patients of its benefits and harms, including the non-diagnostic rate and the unknown false-negative rate; most series do not report the false-negative rate, as masses with a benign biopsy result are not generally removed. False-negative rates have been reported to be as low as 3.5% in one Canadian series and as high as 31.5% in a meta-analysis where "normal parenchyma" biopsies were considered benign histology as opposed to non-diagnostic. 28,29 The authors of this guideline feel it is also important to consider that the diagnostic test characteristics and complication rates reported above are from experienced biopsy centers, and that results may not be generalizable to less experienced centers. Additionally, biopsy outcomes may also be influenced by a number of patient and tumor factors, such as size of the mass, consistency (cystic or necrosis component), location (exophytic vs. endophytic), and skin-to-tumor distance. 5,28,30 Thus, the decision to proceed with a biopsy should be made through a shared decision-making approach after weighing the potential benefits and harms of the diagnostic test and discussing the patients' preferences and values.
# Guideline: SRM
# Role of genetic assessment
# Patients with features suspicious of hereditary RCC should
be offered genetic counselling (Adopted from Canadian Urological Association guideline on genetic screening for hereditary renal cell cancers; expert opinion)
The role of genetic testing in the management of kidney cancer is extensively discussed in a separate CUA clinical practice guideline by Reaume et al. 31 Briefly, as suggested by the aforementioned guideline and endorsed by this panel, patients with the criteria presented in Table 1 should be offered genetic counselling and referred for genetic assessment. There are currently three well-documented management options for the treatment of SRM. Current evidence comparing each of these treatment options is of low quality and no one option has been demonstrated to be superior to another in a randomized controlled trial. Thus, the choice of treatment should be personalized using a shared decisionmaking approach, after proper counselling, according to each patient's values and preferences, and while factoring the patient's competing risks and tumor characteristics (Fig. 1). A summary of characteristics that may influence treatment decision is presented in Table 2. Prediction tools to estimate risk of other-cause mortality are available (e.g., https://studies.fccc.edu/nomograms/3) and can be helpful to guide management. A decision aid has also been developed to inform patients diagnosed with a SRM and may help facilitate shared decision-making (https://decisionaid.ohri. ca/docs/das/Small_Kidney_Tumour_Treatment.pdf). 32 The evidence supporting each recommendation and the different treatment strategies are summarized below.
# Management of small renal masses
# Expectant management: Active surveillance vs. watchful waiting
Active surveillance is a strategy where patients are followed with serial, scheduled imaging to monitor the mass. With active surveillance, patients are offered a definitive treatment if there is evidence of disease progression or if their preferences change during the course of management. A comprehensive description of the indications for definitive treatment while on active surveillance is detailed below. This strategy differs from watchful waiting (the preferred strategy reserved for patients with limited life expectancy), where treatment is only considered for palliation of symptoms that may arise from disease progression rather than an attempt at cure. Patients managed by watchful waiting do not require regular imaging followup unless clinically indicated.
A meta-analysis of patients with a SRM has demonstrated that active surveillance was associated with a cancer-specific survival similar to other treatment strategies and has demonstrated a low associated risk of developing metastasis after short-to mid-term followup. 33 Results from the largest, multicenter, prospective study (Delayed Intervention and Surveillance for Small Renal Masses [DISSRM]) has demonstrated that most tumors grow slowly (median growth rate <0.1 cm/year) and that approximately 10-15% of patients will discontinue active surveillance in favor of definitive therapy over time. [34][35][36] Compared to the active surveillance cohort, the immediate intervention cohort had higher quality of life scores at baseline and throughout followup, but men-
# tal health domains (including depression/anxiety domains)
were not negatively affected while on active surveillance, and even improved over time. 37 Importantly, although active surveillance was initially reserved for older, comorbid patients, recent evidence has demonstrated that this strategy is also safe among younger patients. 38 Evidence from the DISSRM registry demonstrated that there was no difference in terms of cancer-specific survival and overall survival among patients <60 years of age managed by either definitive treatment (n=156) or active surveillance (n=68). Rate of progression to definitive treatment was lower among patients that presented with a lesion <2 cm compared to patients who presented with a lesion that measured 2-4 cm (15.1% vs. 33.3%).
One caveat that should be discussed with patients about this management strategy, is that most active surveillance series are of relatively short followup (median 42 months, range 1-137 months) and based on older, more comorbid patients compared to surgical series. 39 Nevertheless, given the relatively high probability of benign histology (>20%) and indolent nature of most malignancies in this size range(>85%), 3 active surveillance is suggested as the preferred management strategy for patients with a lesion measuring <2 cm. Immediate, definitive treatment remains an option and should be discussed with patients to ensure they are fully informed. In patients with a lesion measuring 2-4 cm, there was no consensus on the preferred management strategy. Although the panel members all recognized that active surveillance should be offered as an option to these patients, nearly 40% of the panel members felt that definitive treatment (surgery or thermal ablation) should be considered as the option of choice. Given the varied Guideline: SRM growth rates by histological subtype, biopsy may also inform the management decision for patients considering active surveillance. 25 As stated, risks of active surveillance may be influenced by the characteristics presented in Table 2.
# Definitive treatments
Surgery vs. percutaneous thermal-ablation 11. For patients with a suspected renal malignancy who prefer management by upfront definitive treatment, surgery or percutaneous thermal ablation are suggested (Conditional recommendation, low certainty in evidence of effects). 12. Patients with a SRM should be informed of the higher uncertainty surrounding the data on the efficacy and harms of percutaneous thermal ablation treatment compared to surgery (Expert opinion).
# Patients with a suspected renal malignancy who opt
to be treated by percutaneous thermal ablation should have a renal mass biopsy performed prior to, or at the time of thermal ablation (Adopted from KCRNC consensus statement on the role of renal mass biopsy in the management of kidney cancer; expert consensus). 8 As stated, there is currently no randomized controlled trial comparing the outcomes of surgery and percutaneous thermal ablation for the management of patients with a SRM. A number of meta-analyses have compared the short-term and long-term outcomes of surgery and thermal ablation with the caveat that the data are based mostly on retrospective studies and are, therefore, prone to selection bias. 33,[40][41][42][43][44][45][46][47] The non-randomized evidence seems to suggest that thermal ablation yields similar oncological outcomes compared to surgery. There is some evidence that seems to suggest that local recurrence is higher after thermal ablation than with partial nephrectomy; 41 however, when multiple ablative treatments were considered, local recurrence-free survival was comparable to partial nephrectomy. 47,48 The most recent meta-analysis on the topic was performed by the European Association of Urology Renal Cell Cancer Guideline Panel and reported in 2020. 41 In this meta-analysis, 26 observational studies, totalling 16 780 patients, were included. The risk of bias assessment revealed high or uncertain risk of bias across all studies, owing to the included studies being retrospective, observational studies with poorly matched controls and relatively short followups. The data seem to suggest that percutaneous ablation is safe in terms of adverse events and complications, but its long-term oncological outcome compared to partial nephrectomy is uncertain. Compared to thermal ablation, surgery also has the advantage of providing definitive pathology specimen, which may be important for genetic counselling consideration.
Nevertheless, given the evidence, the panel is unable to suggest one approach over the other in patients who choose to undergo definitive treatment. Patients with a SRM should be informed of the higher uncertainty surrounding the data on the efficacy and harms of percutaneous thermal ablation treatment compared to surgery. Thus, the choice of treatment must be individualized according to each patient's values and preferences and according to patient, tumor, and hospital-level characteristics (Table 2). Importantly, patients choosing percutaneous thermal ablation as their treatment of choice should have a renal mass biopsy performed prior to, or at the time of thermal ablation to obtain histological confirmation and to help tailor the followup strategy.
# Partial vs. radical nephrectomy
# For patients with suspected malignant SRM undergoing surgery, partial nephrectomy is recommended over radical nephrectomy (Strong recommendation; moderate certainty in evidence of effects).
Surgical removal of a localized renal mass can be done through a radical or partial nephrectomy. Current evidence is mostly based on observational studies, either retrospective or prospective in design. So far, only one randomized controlled trial which closed prematurely due to poor accrual, has compared the oncological outcomes of patients with a localized renal mass (<5 cm in diameter) treated with a radical nephrectomy or a partial nephrectomy between 1992 and 2003. The results of this study showed comparable 10-year cancer-specific survival for both options, but an improved 10-year overall survival in favor of radical nephrectomy, with only a fraction of deaths (12 of 117) due to renal cancer. 49 These results have long been debated for a number of reasons, including its poor accrual, relatively high crossover rate, incomplete central pathology review, and most importantly, the overwhelming number of observational studies favoring partial nephrectomy over radical nephrectomy. 50,51 A Cochrane review published in 2017 demonstrated that time to death of any cause was decreased using partial nephrectomy compared to radical nephrectomy (hazard ratio [HR] 1.5, 95% confidence interval [CI] 1.03-2.18). 52 This review was based on low-quality evidence, given the available data. Additionally, there was no difference identi- ). The absence of difference in the rate of significant harm with regards to both surgeries is especially true for easily resectable tumors in the presence of a normal contralateral kidney. 49 Although debated, one of the potential explanations for the improved survival is that partial nephrectomy results in an increased renal function preservation and subsequent decrease in cardiovascular events compared to radical nephrectomy. [53][54][55][56][57] Therefore, given the overwhelming number of observational studies demonstrating equivalent oncological outcomes, increased renal function preservation, and comparable significant harms (at least in easily resectable tumors), partial nephrectomy is recommended as the preferred approach when technically feasible in expert hands.
In older patients and in those with more comorbidities/ limited life expectancy, the potential benefit of partial over radical nephrectomy is less clear. Likewise, the benefit of partial over radical nephrectomy for patients with complex renal masses is subject to some debate, given the higher incidence of significant complications and potentially higher upstaging to pT3a. [58][59][60][61][62] Consequently, for some patients, the increased risk of harms may outweigh the potential benefits of partial nephrectomy. Thus, radical nephrectomy should be reserved for patients in whom a partial nephrectomy or percutaneous thermal ablation cannot be performed even in experienced centers or for patients who are unwilling to accept the short-term risks of partial nephrectomy/thermal ablation compared to radical nephrectomy. A consideration should also be given for a preoperative renal mass biopsy in patients for whom a radical nephrectomy is planned to avoid removal of the entire organ for a benign lesion.
Nephrometry scoring systems have been developed to aid in communicating renal tumor complexity in a standardized fashion -whether in clinical or research contexts -and to predict treatment outcomes. The most commonly used systems are the RENAL (radius, exophytic/endophytic, nearness, anterior/posterior, location), PADUA (preoperative aspects and dimensions used for an anatomical), and SPARE (Simplified PADUA Renal) nephrometry scores (Table 3). [63][64][65] The first two nephrometry scoring systems are the most extensively studied and have been shown to be predictive of length of hospital stay, tumor pathology, surgical margins, tumor growth rate, renal function outcomes, and survival. 59 The RENAL nephrometry score has also been shown to be useful for predicting outcomes and complications following percutaneous ablation. 58,60 One caveat of using these scoring systems includes interobserver variability in assessments and inconsistent associations with outcome measures. 66 Further work is needed to determine to what extent formal nephrometry scores improve upon subjective estimation of tumor complexity by individual surgeons. Nonetheless, nephrom-etry scoring systems represent a common language that can standardize classification of renal tumor complexity, allow for comparison of surgical outcomes, improve patient coun- Partial nephrectomy can be performed through different approaches -open, conventional laparoscopy, or roboticassisted. A number of meta-analyses have compared open to minimally invasive partial nephrectomy. All three techniques seem to offer similar oncological outcomes; however, minimally invasive techniques are generally associated with significantly less blood loss (and blood transfusion), shorter hospitalization stay, less severe postoperative complications, and potentially, better renal function preservation. [67][68][69] There does not seem to be any clinically significant difference between conventional laparoscopy and robotic-assisted partial nephrectomy in terms of oncological and functional outcomes, although robotic-assisted surgery is potentially associated with higher incidence of major bleed and shorter ischemia time, albeit early in the robotic experience era. [67][68][69] Thus, given the evidence, when technically feasible and oncologically safe, minimally invasive techniques -conventional laparoscopy or robotic-assisted partial nephrectomy -should be favored over open partial nephrectomy. However, open partial nephrectomy remains appropriate for complex SRM, if the alternative is radical nephrectomy.
If a radical nephrectomy is to be performed, a minimally invasive approach is favored over open surgery. Results from a recent meta-analysis showed that minimally invasive approaches offer key advantages over an open approach, such as decreased hospitalization stay and fewer complications, while providing similar oncological outcomes. 70 Conventional laparoscopy and robot-assisted radical nephrectomy seem to result in similar surgical outcomes, but owing to the higher total cost, higher equity, and the lower surgical complexity of a radical nephrectomy (compared to a partial nephrectomy), conventional laparoscopic radical nephrectomy is strongly favored over robotic radical nephrectomy. 71 Percutaneous cryotherapy vs. percutaneous radio-frequency ablation 17. For patients undergoing percutaneous thermal ablation for a suspected renal malignancy, cryoablation and radio-frequency ablation are both suggested as options for management, as they yield similar oncological outcomes and adverse events (Conditional recommendation, moderate certainty in evidence of effects).
Percutaneous ablation of a SRM is most commonly performed using cryoablation (tissue damage by freezing) or radio-frequency ablation (tissue damage by heat). A number of retrospective studies have compared both these ablative techniques and have concluded that both yield similar oncological outcomes and adverse events. 44,[72][73][74][75] Consequently, as both techniques have their own advantages and disadvantages, the choice of approach should be based on availability, provider's experience, and tumor-related factors (size, location, adjacent structures, etc.). Regardless on the type of technique chosen, it is the panel's opinion that a renal tumor biopsy should be performed prior to ablation (in a separate setting or at the time of ablation), as this will achieve histological confirmation and will help tailor the frequency of followup imaging. It is also important to note that most series reported their outcomes for tumors <3 cm in size.
Even though the treatment of 3-4 cm tumors is possible, patients should be appropriately counselled as to the higher likelihood of complications and local recurrence compared to <3 cm tumors. 58,[76][77][78][79][80] For these patients, although the literature is prone to biases and subject to debate among experts, there is some evidence suggesting that cryoablation leads to lower cancer-specific mortality compared to radio-frequency ablation. 80,81 Thus, when both ablation approaches are available, it would seem reasonable to favor cryoablation for tumors 3-4 cm. Delayed intervention, including partial or radical nephrectomy, or percutaneous ablation, is instituted in 0-30% of Richard et al patients on active surveillance. 82 Indications for intervention vary and involve an assessment of the competing risks of RCC progression vs. other causes of mortality, factoring in patient values and preferences through shared decision-making.
# Indications for definitive treatment while on active surveillance
Common reasons for intervention include tumor growth rate and absolute tumor size attained. Both maximum linear tumor diameter and volumetric measurements can be used during surveillance. Volumetric assessments may be more accurate, given that tumors are not always spherical, but at the same time, are less practical and less familiar to clinicians. It is, however, important to note that none of these indications have been validated.
Average growth rate for a SRM during surveillance is typically 0.1-0.25 cm per year. [83][84][85][86][87][88] Aggressive tumors have a faster growth rate. For example, in a pooled analysis of patients who had metastatic progression on surveillance, average growth rate was 0.8 cm per year. 87 As such, rapid growth rate is an indication for intervention, with important additional considerations, such as age, comorbidities, patient's preference, etc. (Table 2). The DISSRM registry used growth rate >0.5 cm per year as a criterion for progression, while the Renal Cell Carcinoma Consortium of Canada used doubling of calculated tumor volume within 12 months as part of their definition of progression. 25,84 Several limitations of growth rate assessments are important. First, growth rates should be assessed cautiously in patients who would require comparisons of tumor size measured using different imaging modalities. If tumor growth is suspected based on ultrasound, this should be confirmed with cross-sectional imaging prior to intervention. Second, tumor growth may be exponential, and therefore, tumor growth may increase over time. Third, intra-and inter-observer variability in the measurement of tumor diameter on imaging exist and must be considered. 89 Fourth, some tumors may exhibit stochastic growth, further contributing to variability. 25 For patients on active surveillance with concerning tumor growth and without a prior renal mass biopsy, one can be considered if it will change management.
Tumor size is associated with risk of harboring malignancy, the risk of aggressive histology, including high-grade disease, 90,91 the risk of developing metastatic disease, [92][93][94] and survival outcomes. 95 The Renal Cell Carcinoma Consortium of Canada and the DISSRM registry consider tumor diameter >4 cm as a criterion for progression. 83,84 A larger tumor size and/ or change in tumor complexity (as reflected by the nephrometry score) may also limit the feasibility of certain interventions. Clinicians should review images in each instance to ensure a window of treatment opportunity is not inadvertently missed; this should be factored into decision-making.
Several patient factors may also influence decisions on delayed interventions. 96 Patient age, frailty, and comorbidities should all be factored into estimating risk of mortality for competing medical conditions. In elderly, frail, and/or comorbid patients, the risks of intervention are not trivial and there is a stronger rationale for deferring intervention or perhaps for transitioning to watchful waiting. Patient anxiety should also be factored into decision-making, although it should not be the sole criterion for intervention. It is the role of the clinician to provide appropriate counselling to address anxiety, which may include the use of decision aids. 32 One study found that depression and anxiety were not adversely affected while on active surveillance for a renal mass, and in fact, improved with time. 97 The objective of active surveillance is to delay treatment until evidence of disease progression. To do so, it is important to obtain routine abdominal imaging during followup. Several imaging modalities may be used, such as ultrasound, CT scan, and MRI. Cross-sectional imaging using CT or MRI provides the most accurate assessment of the size and complexity of a SRM. Ultrasound is an alternative for imaging surveillance, as it is cost-effective, offers adequate assessment of growth, avoids ionizing radiation, and is more readily accessible/available than CT and MRI. For these reasons, abdominal ultrasound is suggested as the imaging of choice during followup for patients on active surveillance. One caveat of ultrasound is that it is operator-dependent and cross-modality comparisons of size measurements with CT/MRI can sometimes be challenging. Therefore, if tumor growth is suspected on surveillance ultrasound or the mass cannot be reliably identified Guideline: SRM by ultrasound, an abdominal cross-sectional imaging (CT or MRI) for confirmation is required.
# Followup
Although a rare event, patients on active surveillance may develop distant metastases. For this reason, most renal mass active surveillance series include chest X-rays as part of their surveillance protocols, while none performed CT scans of the chest routinely. 82 Asymptomatic patients with tumors <4 cm in size have a <1% probability of harboring pulmonary metastases, as assessed by CT chest, 98,99 and data from the DISSRM registry has revealed that all abnormalities noted on the chest X-ray either at baseline or during surveillance were not metastasis-related. 100 The low prevalence of pulmonary metastases combined with the suboptimal sensitivity and specificity limit the utility and cost-effectiveness of chest X-ray surveillance in patients undergoing active surveillance for SRM. Nevertheless, despite its limitation, the panel suggests performing chest X-ray imaging during followup, as the members placed a higher importance on finding metastases than on the potential harms and cost of chest imaging.
Followup schedules for active surveillance are heterogeneous between studies and even within series. To date, the optimal schedule has not been agreed upon. 82 Nevertheless, the panel members believed that patients should be followed with abdominal imaging every 3-6 months for the first year and then every 6-12 months, if the lesion remains stable. Frequency of imaging should be increased for patients demonstrating tumor growth if the patient remains on active surveillance. Patients should be followed with abdominal imaging until definitive treatments are no longer considered. Likewise, there is no agreed-upon optimal followup schedule for chest imaging. The panel members were nearly evenly split as to the frequency of chest imaging and thus, they were not able to achieve a consensus as to its frequency, which varied from for-cause (52.6% of members) to once a year (47.4% of members).
# Followup after definitive treatment
# Patients with a RCC who have undergone definitive
treatment should be followed with routine chest and abdominal imaging to rule out recurrence or progression to metastasis (Adopted from CUA guideline for followup of patients after treatment of non-metastatic renal cell carcinoma; expert opinion). 24. Patients with an estimated GFR <45 ml/min/1.73m 2 or with progressive chronic kidney disease following definitive treatment should be considered for a referral to a nephrologist (or their general practitioner), especially if associated with proteinuria (Adopted from CUA guideline for followup of patients after treatment of non-metastatic renal cell carcinoma; conditional recommendation, low certainty in evidence of effects).
The readers interested in receiving in-depth guidance of the followup of patients with hereditary RCC should review the guideline by Lattouf et al. 101 Likewise, the detailed recommended followup after definitive treatment of incidental RCC is extensively reviewed in the guideline by Kassouf et al. Briefly, studies have shown that patients with pT1a RCC are at low risk of local recurrence or metastases after surgery to remove the mass (5% for recurrence or metastases). 102,103 Recommended surveillance after surgery includes: annual blood test (complete blood count, serum chemistries, and liver function test) and annual chest X-ray, as well as abdominal CT, MRI, or ultrasound at 24 and 60 months. A contrast-enhanced abdominal CT scan/MRI at 3-12 months post-treatment for patients treated with partial nephrectomy is optional to evaluate the residual baseline renal appearance. Due to the higher risk of residual disease and need for retreatment after thermal ablation, a contrast-enhanced abdominal CT scan/MRI is recommended at three, six, and 12 months post-treatment, and then annually, in addition to annual bloodwork and chest X-ray. Patients with postoperative chronic renal failure should be referred to nephrology or to their general practitioner for proper assessment, given the potentially higher risk of developing cardiovascular disorders. 57
# Future directions
# Novel non-surgical therapies
In addition to cryoablation and radio-frequency ablation, there are currently three other types of ablative therapies available to treat SRM: microwave ablation, 44,[104][105][106][107] irreversible electroporation, and stereotactic body radiation therapy (SBRT)
Although promising, as long-term data on the outcomes of these techniques are lacking, the panel still considers these approaches experimental and long-term data will be required before making any recommendations on the role of these newer ablative techniques.
# Novel diagnostic imaging
MRI is an increasingly used alternative to CT scan and it is generally perceived as a comparable alternative. There are a number of reports evaluating a potential role for multiparametric MRI (mpMRI) as an imaging tool to help predict histological subtype. [108][109][110] Recently, a clear-cell likelihood score has been proposed to determine the risk of a lesion being clear-cell RCC using a non-invasive approach. 104,110,111 This score has been proposed as a tool to reduce the number of patients who undergo routine biopsy and to help guide management, although this remains to be validated.
Like mpMRI, 99mTc-sestamibi single-photon emission computed tomography (SPECT)/CT is being evaluated for Richard et al detecting oncocytomas and other benign renal lesions. [112][113][114][115][116][117] Early results appear promising but require further validation before being routinely recommended in Canada.
# Novel diagnostic biomarkers
In recent years, there has been extensive research focused on the identification of a reliable biomarker as an adjunct to imaging and an alternative to renal mass biopsy. 118,119 Several studies have evaluated the role of liquid biopsy assays, including circulating tumor cells, circulating cell-free DNA, and microRNAs, as less invasive techniques for early detection of RCC and for discrimination between benign and malignant renal masses. [120][121][122][123][124][125][126][127][128][129][130][131][132][133] Although early detection of RCC through easily available circulating biomarkers is of great interest and a promising research avenue, the diversity of techniques and current lack of validation studies preclude any meaningful conclusions. The panel hopes that recommendations will be made possible by the publication of new studies on the topic for the next iteration of this guideline.
# Knowledge gaps
In addition to the lack of high-quality studies comparing the different treatment options for SRM, one other area of clear knowledge gap identified by the panel is the current lack of studies on quality-of-life outcomes and on patients' values and preferences. These types of studies are of great importance to guideline panels that must make recommendations based on the tradeoff of desirable and undesirable outcomes of the management alternatives they are considering using average or typical values and preferences. This concept is highlighted by the widely adopted GRADE framework for clinical guidelines. As values and preferences studies on the topic are currently absent, the panel had to speculate, with the help of patient representatives, on the actual patients' value and preferences for the management of SRM, speculation that may diverge substantially from the true situation. The panels hopes that studies will have attempted to fill this important knowledge gap in time for the next iteration of this guideline.
# Summary
The incidence of SRM is increasing and many of these incidentally found lesions will be either benign or of low metastatic potential. Immediate invasive treatment of all patients with SRM leads to significant overtreatment. Importantly, most of the evidence on management options for patients with SRM is based on observational data, which are subject to many biases. Thus, most recommendations are based on evidence with low certainty of effect. The panel hopes that in the near future, higher-quality studies will further refine the management of SRM. In the meantime, it is important to obtain a treatment consensus through a shared decision-making approach after weighing the pros and cons of each option according to each patient's own values and preferences.
Competing interests: Dr. Richard has been an advisory board member for Bayer, Janssen, and Sanofi; and a speakers' bureau member for Abbvie, Amgen, Astellas, Ferring, and Janssen. Dr. Bhindi has been an advisory board member for Bayer and Janssen; and has received speaker honoraria from Merck. Dr. Breau has been an advisory board member for Ferring (bladder cancer). Dr. Kassouf has been an advisory board member for EMD Serono and Pfizer; has received grants and/or honoraria from Abbvie, Astellas, BMS, Ferring, Janssen, Merck, Roche, and Sesen Bio; and has participated in clinical trials supported by Astra Zeneca, BMS, Janssen, Pfizer, Roche, Sesen Bio, and Theralase. Dr. Lavallée has participated in advisory boards for Abbvie, Bayer, Ferring, Sanofi, and Tersera; and has received an unrestricted research grant from Sanofi. Dr. Jewett has been an advisory board member for and received payment from Sesen Bio and Theralase Technologies Ltd. Dr. Kachura participated in the multicenter OPTIMA trial for liver cancer ablation supported by Celsion Inc. Dr. Pouliot has been an advisory board member for Astellas, Bayer, Esai, Janssen, Merck, Sanofi, and Tersera; holds investments in Allogene Therapeutics; and has participated in clinical trials supported by Lantheus, Merck, and Progenics. Dr. So has been an advisory board member for Abbvie, Amgen, Bayer, Ferring, Janssen, Merck, and Tersera. Dr. Rendon has been an advisory board and speakers' bureau member for and has received honoraria from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Ferring, Jansen, and Sanofi. Dr. Tanguay has participated in advisory boards for BMS, Janssen, Knight Therapeutics, Merck, and Roche; and has participated in clinical trials supported by AstraZeneca and Roche. Dr. Shayegan has been an advisory board member for Astellas, Bayer, and Janssen; and has received a research grant from Janssen. The remaining authors do not report any competing personal or financial interests related to this work. This paper has been peer-reviewed. | None | None |
c3cbaa0668b67bd3e8154db91c09c3c5da1a8df3 | cma | None | At CancerCare Manitoba (CCMB) the Clinical Practice Guidelines Initiative (CPGI) seeks to improve patient outcomes in terms of survival and quality of life through the development, dissemination, implementation, and evaluation of guidelines for the management of common clinical scenarios encountered by cancer patients throughout the province. This clinical guide was approved by the Lymphoproliferative Disorders Disease Site Group (DSG).This document is intended as a guide to facilitate an evidence-informed, shared approach to the appropriate use of PET scan imaging in lymphoma in Manitoba. For this purpose, it may be used by qualified and licensed healthcare practitioners involved with the care of oncology patients, which may include (but is not limited to): physicians, surgeons, nurses, radiation therapists, and pharmacists at CCMB, CCPN sites, Uniting Primary Care Oncology Network (UPCON) clinics, and WRHA Community Oncology Program sites.# Disclaimer
Use of this clinical guide in any setting should not preclude use of the practitioner's independent clinical judgment; nor should it replace consultation with the appropriate oncology specialty when indicated (example: medical or radiation oncology, pharmacy, nursing, etc.). Clinicians are expected to apply the recommendations within boundaries of professional standards and scope of practice, and according to level of training and experience.
It is the responsibility of the practitioner to develop an individualized disease or symptom management plan for each patient under his/her care, and ideally this should take place within the context of an inter-professional team. The needs and preferences of the patient and the family should always be reflected in the plan of care. This clinical guide document should be viewed as an evidence-informed practice tool, and as such, it does not represent an exhaustive text on the appropriate use of PET scan imaging in lymphoma in Manitoba. Clinicians are advised to use it in their practice concomitantly with information from other evidence-informed sources.
# Background Aim and Purpose
Development of this clinical guide was undertaken for the purpose of knowledge translation of the current standards in practice for routine use of PET scan imaging in lymphoma in Manitoba. The overall aim is to improve the standard of care received by this patient population, through application of evidence-informed interventions and promotion of best practices.
# Development Process
A multidisciplinary group of medical professionals agreed by consensus to adapt a report from an international conference and to establish a clinical guide for the use of PET scan imaging for patients with lymphoma in Manitoba.
# Patient Population and Healthcare Setting
The recommendations in this clinical guide are applicable to the care of patients with lymphoma. These recommendations are intended for use in both inpatient and outpatient settings.
# End-Users
This clinical guide is written for use by healthcare professionals providing care for the above mentioned patient population. Intended primarily for use by medical clinicians, the clinical guide may be of interest to trainees, physician extenders, allied healthcare staff, healthcare administrators, policy-makers and possibly members of the general public.
# Maintenance
At CancerCare Manitoba clinical guides are considered 'living' documents which require ongoing evaluation, review and updating. Re-evaluation of this clinical guide is planned for 2020. The working group will revise and update the document as needed, with any critical new evidence brought forward before this scheduled review. | At CancerCare Manitoba (CCMB) the Clinical Practice Guidelines Initiative (CPGI) seeks to improve patient outcomes in terms of survival and quality of life through the development, dissemination, implementation, and evaluation of guidelines for the management of common clinical scenarios encountered by cancer patients throughout the province. This clinical guide was approved by the Lymphoproliferative Disorders Disease Site Group (DSG).This document is intended as a guide to facilitate an evidence-informed, shared approach to the appropriate use of PET scan imaging in lymphoma in Manitoba. For this purpose, it may be used by qualified and licensed healthcare practitioners involved with the care of oncology patients, which may include (but is not limited to): physicians, surgeons, nurses, radiation therapists, and pharmacists at CCMB, CCPN sites, Uniting Primary Care Oncology Network (UPCON) clinics, and WRHA Community Oncology Program sites.# Disclaimer
Use of this clinical guide in any setting should not preclude use of the practitioner's independent clinical judgment; nor should it replace consultation with the appropriate oncology specialty when indicated (example: medical or radiation oncology, pharmacy, nursing, etc.). Clinicians are expected to apply the recommendations within boundaries of professional standards and scope of practice, and according to level of training and experience.
It is the responsibility of the practitioner to develop an individualized disease or symptom management plan for each patient under his/her care, and ideally this should take place within the context of an inter-professional team. The needs and preferences of the patient and the family should always be reflected in the plan of care. This clinical guide document should be viewed as an evidence-informed practice tool, and as such, it does not represent an exhaustive text on the appropriate use of PET scan imaging in lymphoma in Manitoba. Clinicians are advised to use it in their practice concomitantly with information from other evidence-informed sources.
# Background Aim and Purpose
Development of this clinical guide was undertaken for the purpose of knowledge translation of the current standards in practice for routine use of PET scan imaging in lymphoma in Manitoba. The overall aim is to improve the standard of care received by this patient population, through application of evidence-informed interventions and promotion of best practices.
# Development Process
A multidisciplinary group of medical professionals agreed by consensus to adapt a report from an international conference and to establish a clinical guide for the use of PET scan imaging for patients with lymphoma in Manitoba.
# Patient Population and Healthcare Setting
The recommendations in this clinical guide are applicable to the care of patients with lymphoma. These recommendations are intended for use in both inpatient and outpatient settings.
# End-Users
This clinical guide is written for use by healthcare professionals providing care for the above mentioned patient population. Intended primarily for use by medical clinicians, the clinical guide may be of interest to trainees, physician extenders, allied healthcare staff, healthcare administrators, policy-makers and possibly members of the general public.
# Maintenance
At CancerCare Manitoba clinical guides are considered 'living' documents which require ongoing evaluation, review and updating. Re-evaluation of this clinical guide is planned for 2020. The working group will revise and update the document as needed, with any critical new evidence brought forward before this scheduled review.
# Acknowledgements
We gratefully acknowledge the support of CancerCare Manitoba, the CancerCare Manitoba Foundation, and the Provincial Oncology Clinical Practice Guidelines Initiative.
# Approved By
Dr. Bohdan Bydel, Nuclear Medicine Physician Section Head, Nuclear Medicine Co-Director PET/CT Program, HSC Winnipeg
# Contributors
| None | None |
377c12110fd15514137da90e33a1c8c7f1ffacdc | cma | None | Funded by the Canadian Institutes of Health Research (CIHR), the Canadian Research Initiative in Substance Misuse (CRISM) is a national research-practice-policy network focused on substance use disorders, comprising four large interdisciplinary regional teams (Nodes) representing British Columbia, the Prairie Provinces, Ontario, and Quebec/Atlantic. Each CRISM node includes regional research scientists, service providers, policy makers, community leaders, and people with lived experience of substance use disorders. CRISM's mission is to translate the best scientific evidence into clinical practice, health services, and policy change. More information about CRISM can be found at: document is one of a series of six national guidance documents, rapidly developed by the CRISM network at the request of the Government of Canada. Collectively, the six documents address urgent needs of people who use substances, service providers, and decision makers in relation to the COVID-19 pandemic. The urgent nature of this work required rapid development and dissemination of this guidance. This, and the continuing evolution of the knowledge base regarding COVID-19, precluded CRISM from conducting a comprehensive review of the relevant literature. However, when available, scientific evidence is cited in support of the expert advice offered herein.#
The guidance provided in this document is subject to change as new information becomes available. Readers should note that the intent of this document is to provide general guidance rather than detailed procedural and logistical advice. Readers are advised to consult local public health and medical authorities for specific input on navigating their own unique regulatory and policy environments, as necessary.
The CRISM/COVID-19 guidance documents cover the following topics: - Strategies to Help Individuals Self-Isolate for People who use Drugs Each document was developed by a core CRISM regional authorship committee, drawing on expert knowledge, available scientific evidence, and a review of relevant documentation from public health authorities. Draft documents produced by each authorship committee were reviewed by pan-Canadian panels of content and clinical experts, including people with lived and living experience of substance use. A Directed Operating Grant provided funding for this work to CRISM from the Canadian Institutes of Health Research (CIHR). | Funded by the Canadian Institutes of Health Research (CIHR), the Canadian Research Initiative in Substance Misuse (CRISM) is a national research-practice-policy network focused on substance use disorders, comprising four large interdisciplinary regional teams (Nodes) representing British Columbia, the Prairie Provinces, Ontario, and Quebec/Atlantic. Each CRISM node includes regional research scientists, service providers, policy makers, community leaders, and people with lived experience of substance use disorders. CRISM's mission is to translate the best scientific evidence into clinical practice, health services, and policy change. More information about CRISM can be found at: https://crism.ca.This document is one of a series of six national guidance documents, rapidly developed by the CRISM network at the request of the Government of Canada. Collectively, the six documents address urgent needs of people who use substances, service providers, and decision makers in relation to the COVID-19 pandemic. The urgent nature of this work required rapid development and dissemination of this guidance. This, and the continuing evolution of the knowledge base regarding COVID-19, precluded CRISM from conducting a comprehensive review of the relevant literature. However, when available, scientific evidence is cited in support of the expert advice offered herein.#
The guidance provided in this document is subject to change as new information becomes available. Readers should note that the intent of this document is to provide general guidance rather than detailed procedural and logistical advice. Readers are advised to consult local public health and medical authorities for specific input on navigating their own unique regulatory and policy environments, as necessary.
The CRISM/COVID-19 guidance documents cover the following topics: • Strategies to Help Individuals Self-Isolate for People who use Drugs Each document was developed by a core CRISM regional authorship committee, drawing on expert knowledge, available scientific evidence, and a review of relevant documentation from public health authorities. Draft documents produced by each authorship committee were reviewed by pan-Canadian panels of content and clinical experts, including people with lived and living experience of substance use. A Directed Operating Grant provided funding for this work to CRISM from the Canadian Institutes of Health Research (CIHR).
# Acknowledgements
The guidance document authorship committee members gratefully acknowledge the contributions of the external reviewers: Peter Butt, Allison Crawford, Selene Etches, S. Monty Ghosh, Scott Harrison, Bruce Hollett, Amanda Hudson, Stéphanie Marsan, Jean-François Mary, Manon Poirier, Jessica Roper, Andrea Ryan and Natasha Touesnard. The authorship committee members acknowledges the contributions of the following individuals for primary research, writing, editorial work, and administrative support: Alice Lam, Valeria Saavedra, Aïssata Sako, and Jennifer Swansburg. The committee also wishes to thank Valeria Saavedra and Kevin Hollett for their graphic design support. The committee acknowledges the contribution of Dr. Sherry Stewart for her assistance with the review process in Atlantic Canada. The committee acknowledges the assistance of the CRISM Node managers: Denise Adams, Farihah Ali, and Nirupa Goel. In addition, the committee thanks Gina Lepage of Traductions Lepage for her assistance with translating the guidance document into French.
# Disclaimer for Health Care Providers
The recommendations in this guidance document represent the view of the national guidance document authorship committee members and external reviewers, arrived at after careful consideration of the scientific evidence, available literature, and external expert peer review. The application of the recommendations in this guidance document does not override the responsibility of healthcare professionals to make decisions appropriate to the needs, preferences and values of an individual patient, in consultation with the patient (and their guardian(s) or family members, when appropriate) and, when appropriate, external experts (e.g. specialty consultation). When exercising clinical judgment in the treatment of opioid use disorder, healthcare professionals are expected to take this guidance document into account while upholding their duties to adhere to the fundamental principles and values of the Canadian Medical Association Code of Ethics, especially: compassion, beneficence, non-maleficence, respect for persons, justice and accountability, as well as the required standards for good clinical practice defined by relevant governing bodies within regional or local jurisdictions. Nothing in this guidance document should be interpreted in a way that would be inconsistent with compliance with those duties.
# Legal disclaimer
While the individuals and groups involved in the production of this document have made every effort to ensure the accuracy of the information contained in this guidance document, please note that the information is provided "as is" and that CIHR and CRISM make no representation or warranty of any kind, either expressed or implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest extent possible under applicable law, CIHR and CRISM disclaim and will not be bound by any express, implied or statutory representation or warranty (including, without limitation, representations or warranties of title or non-infringement).
This document is intended to give an understanding of the growing role of telemedicine for healthcare access during the COVID-19 pandemic. This guidance document is not intended as a substitute for the advice or professional judgment of a healthcare professional. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a local healthcare professional.
# Conflict of Interest
In accordance with the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts 1 , authorship committee members and external reviewers were asked to disclose all sources and amounts of direct and indirect (i.e., research support) remuneration from industry, for-profit enterprises, and other entities that could potentially introduce real or perceived risk of bias. In addition, authorship committee members and external reviewers were asked to report indirect sources of bias, such as academic advancement, clinical revenue, and professional or public standing that could potentially influence interpretation of research evidence and formulation of recommendations. Of note, three of the authorship committee members and external reviewers are CRISM staff members.
No authorship committee members and external reviewers were excluded from participation due to direct financial conflicts of interest. Of the nineteen authorship committee members and external reviewers, one disclosed receipt of funds prior to Guidance document involvement from a commercial entity (Indivior Inc.) that could theoretically benefit from Guidance document recommendations. Six authorship committee members and external reviewers acknowledged that their employment involved the delivery of Opioid Agonist Therapy (OAT) to patients. Eight authorship committee members and external reviewers acknowledged their employment involved the support of delivery the Opioid Agonist Therapy programs. Seven authorship committee members and external reviewers acknowledged their employment involved engagement in developing OAT practice within their respective organization. Two authorship committee members and external reviewers acknowledged that their employment involved engagement in developing telemedicine practice within their respective organizations. Two authorship committee members and external reviewers acknowledged that they have publicly stated the need for measures to increase OAT or Safe supply in general, and in the context of COVID-19. Receipt of research or program funding support from non-profit agencies or institutions was not considered a direct conflict of interest. On review, none of the disclosed direct conflicts of interest were deemed to be of sufficient weight or relevance to warrant exclusion from the Guidance review committee. Additional details regarding the conflict of interest policy can be found in Appendix 1. 1.0 Key points of the guidance document
• This guidance document does not supersede a provider's clinical experience and decisionmaking skills.
• Healthcare providers should use the same high-quality standards as in-person clinical care when using telemedicine for addiction services. They should aim to provide assessment and treatment of physical and mental health conditions and other drug use-related concerns, provide prevention, harm reduction and other health information and counseling, as appropriate.
• Patient consent must be obtained and documented during the telemedicine consultation, and healthcare providers must provide the limitations of telemedicine (ex. limited physical examination, limits in sound, image, and security breaches).
• Healthcare providers utilizing telemedicine should follow the same documentation guidelines as a regular consultation.
The following points pertain more specifically to opioid agonist therapy (OAT)
• Prescribers should assess and document safety concerns and measures to address them when prescribing any psychoactive substance, and in particular for methadone and sustained released oral morphine, as per Opioid Agonist Treatment Guidelines.
• Prescribers must use clinical judgment to determine patient suitability for carries. Exceptional carries (beyond maximum carries allowed in guidelines) may be provided during the current pandemic due to specific circumstances and should be well justified and reassessed regularly.
• Prescribers should explore alternative measures for witness dosing including virtual communication and observational methods.
• Safe storage and risk of carries as per Opioid Agonist Treatment Guidelines should be discussed and documented, and prescribers and patients should remotely agree and document a Safe Carry Agreement.
# Purpose And Scope
On March 11, 2020, the World Health Organization declared COVID-19, caused by a novel coronavirus SARS-CoV-2, a pandemic, citing concern over alarming levels of spread and severity across the globe.
The novel coronavirus has caused a national outbreak of respiratory infections in Canada since its discovery in December 2019. For most, this coronavirus causes only mild to moderate symptoms including fever and cough. However, people who use drugs (PWUD) have particular vulnerabilities that place them at risk of acquiring and transmitting SARS-CoV-2, such as poor housing and active addiction (factors that may make physical distancing challenging), as well as comorbid health conditions (e.g. COPD, HIV+) that may predispose to severe infection resulting in increased morbidity, mortality and healthcare system utilization.
The COVID-19 pandemic spurred professional bodies and provincial/territorial jurisdictions to recognize and clarify the growing role of telemedicine for healthcare access in times of confinement.
In reviewing existing telemedicine guidelines, it was found that they were somewhat restrictive and lacked specific information on how to effectively support and provide access to care for patients requiring addiction-related healthcare services.
The purpose of this guidance document is to support healthcare providers to deliver telemedicine for addiction services during the COVID-19 pandemic. This document is intended to provide general guidance related to telemedicine focused on covering OAT and other addiction-related pharmacological treatments. It does not cover the use of telemedicine for non-pharmacological approaches. Furthermore, it does not provide guidance for specific populations or specific conditions, such as the comorbidity of mental health, pregnancy, or use in other populations.
# INTENDED AUDIENCE
The target audience for this guidance document includes healthcare providers and pharmacists. The guidance contained in this document may also be relevant for policymakers, public health authorities, advocates, and other people working to support addiction services.
# DEVELOPMENT
The content and recommendations of this guidance document are based on a review of the literature focused on consensus practice regarding access to telemedicine for OAT, and was reviewed by the authorship committee members and external reviewers, some of whom are OAT prescribers who have been involved with the development and incorporation of telemedicine in their respective institutions. Search terms (see Appendix 2) were used to identify relevant research evidence within jurisdictions where telemedicine for addiction and/or OAT is known to be in place (see Appendix 3). These jurisdictions are: Ontario, Quebec, Australia, United Kingdom (UK), France, and the telemedicine services supported by the World Health Organization (WHO).
Recommendations were selected based on the general consensus for best practices found across the reviewed guideline and literature (referred to as 'best practice' in Table 1). A list of key points is also provided, based on common principles outlined in various guidance documents and expert opinions (referred to as 'consensus practice' in Table 1).
An independent CRISM committee of authorship committee members and external reviewers, made up of experts and people with lived and living experience from each regional CRISM node (n= 19), was assembled to participate and review this guidance document. The consensus of committee members was sought and secured through email and telephone communication, and tracked document review and revision. The draft guidance document and supporting materials were circulated to the committee for 2 rounds of review (May 4-12th, 2020), as well as a reviewer teleconference (May 8th, 2020).
Feedback was collated and incorporated into a revised Version 1 Guidance Document.
# DEFINITION OF TELEMEDICINE
We recognize that there are a number of terms used when referring to the use of information and communication technology to deliver healthcare. For the purposes of the following recommendations, the term "telemedicine" will be used as it is deemed to be the most relevant within the context of this report. We are basing this decision, using the definition for "telemedicine" set by the Federation of Medical Regulatory Authorities of Canada: "medical service provided remotely via information and communication technology." 2 While this guidance document does not distinguish between the type of telemedicine that exists (teleconsultation, tele-expertise, telemonitoring, or teleassistance), 3 healthcare providers must be consistent with their specific jurisdiction's regulations and guidelines. Best Practice 11
# 3.0
2. The tools (telephone and video conferencing), platforms, and data used during telemedicine must be secured and respect the confidentiality of the consultation. Patient consent can be obtained verbally, unless written consent is required at the sign-up of the tool/ platform being used. 3,4,6,7,[11][12][13]15 Best Practice 8
3. Patient identification must be provided at each telemedicine consultation, including name and at least one of the following: date of birth, address, health card number, or other valid form of identification (which can also be displayed on the screen). The healthcare provider's documentation should include the same elements as a regular note, while also indicating the reason and method for providing telemedicine. 3,4,7,10,12 Best Practice 5
Use of Telemedicine during a Pandemic 4. During a pandemic, it is recommended that healthcare providers always consider using telemedicine to provide care, whenever possible. Each patient's eligibility for telemedicine should be reviewed individually. [4][5][6][7][9][10][11][12][13]16 Prescriptions should be transmitted verbally, electronically, by fax, or via secured electronic medical record (EMR) to protect pharmacists, patients, and pharmacy employees from the transmission of COVID-19 by reducing visits to the pharmacy. [4][5][6][7][9][10][11][12][13]16 Consensus Practice
# 10
Utilizing Telemedicine to Provide OAT during COVID-19
5. The renewal/ re-induction of OAT is allowed by telemedicine, when indicated as per standard of care guidelines. OAT can be initiated by telemedicine in situations where the prescriber judges that a delay in the start of OAT would entail a risk for the patient, and if conditions are appropriate. All patients are encouraged to obtain a take-home naloxone kit. Information on how to use the take-home naloxone kit and training, along with other harm reduction strategies, should be made available to patients and their support systems. [4][5][6][7]17,18 Consensus Practice 6 6. Healthcare providers should provide increased support to patients via remote methods and maintain ongoing and open communication. Online resources should be offered to patients, and increased counselling services by phone or other platforms should be offered. 4,5,7,17,19 Consensus Practice 5 7. Pharmacy delivery should be used if available, and authorized/ designated agents can be used to pick up or receive carries. Patients must have safe housing or safe storage for carries (i.e., a locked box). Virtual communication and other safe observation methods for supervised dosing should be utilized where available. [5][6][7][8]17 Consensus Practice
# Telemedicine
Recent developments in information and communications technologies (ICT) have made it possible for healthcare providers to practice medicine virtually and deliver medical services to areas where otherwise unavailable. As the delivery of telemedicine lends itself to potential violation of ethical obligations, such as professional secrecy, it is vital that telemedicine be used in ways that comply with current guidelines set out within each jurisdiction across Canada to protect the patients and clients that it seeks to serve.
# TELEMEDICINE PROVIDERS
The healthcare provider using telemedicine must comply with their jurisdiction's standard or policy.
In some Canadian provinces, a license to practice telemedicine must be obtained.
Healthcare providers using telemedicine services with patients outside their jurisdiction must comply with the laws and regulations of the territory in which the patients are located, in addition to the guidelines and policies of the providers' jurisdictions. The practice of telemedicine should be avoided where healthcare providers are likely to compromise the quality of their practice.
# ASSESSING THE APPROPRIATE USE OF TELEMEDICINE
Healthcare providers should use discretion in deciding which patients are appropriate for care by telemedicine. Providers must assess the risks and benefits of care given by telemedicine compared to care given in-person. Both the provider and the patient must have the appropriate technological means for telemedicine to occur.
During a pandemic, the healthcare provider must also be cognizant of infection control considerations and consider the risk of contamination during a patient's visit to the clinic, hospital, and/or pharmacy. Given this risk, a new patient, who is not known to the provider, can be evaluated via telemedicine, if deemed appropriate.
During the COVID-19 pandemic, it is not necessary that a telemedicine consultation be done by the patient's treating healthcare provider, although this is preferable. 4
# TOOLS, PLATFORMS, PRIVACY, AND SECURITY
All tools (telephone and videoconferencing) and platforms used for telemedicine must be secured and must also respect confidentiality and privacy of all medical interviews and discussions with the patient. The healthcare provider is responsible for weighing the risks and benefits of using information and communication technology to carry out telemedicine.
Examples of platforms that may be used during telemedicine include:
• Those already included in properly secured electronic medical records (EMR);
• Those used by network establishments that have a telemedicine program; and,
• Secured telephone lines and/or direct dial toll-free (e.g. 1-800 number) and secured text messaging.
To maintain privacy and confidentiality, the physical environment of both the healthcare provider and the patient during the telemedicine session must be taken into account. Providers should conduct telemedicine in a quiet and enclosed room, whether in a home-office, or in a healthcare setting. Likewise, patients should be able to confirm that confidential information can be shared during the telemedicine session. Providers working from home should ensure that the storage and handling of patients' information is secured.
# PROVIDER AND PATIENT IDENTIFICATION
Healthcare providers should identify themselves at the beginning of each new consultation, by providing their name, title, professional licensing body and medical license number, and any relevant contact information if needed. The provider must then ask the patient to identify themselves, by providing their name, date of birth, address, and the province of the consultation. The provider may request the patient's health card to be displayed on the screen for further identification.
# PATIENT CONSENT
Patient consent must be obtained at the beginning of the telemedicine session. The patient must understand the limitations of telemedicine and confirm that their setting is appropriate for exchanging confidential information. The healthcare provider must provide information regarding all possible technological limits, such as limits in sound, image, and security breaches, and the limits of medical practice (ex. no physical examination). 4 All verbal and written consent should be documented in the patient's medical file. 20
# DOCUMENTATION
Healthcare providers should enter notes in the patient's medical file as soon as possible and should follow the same documentation guidelines as a regular consultation. The following details should also be included in the note:
• Technological means that have been used;
• The way in which the identification was made; and,
• The location of the patient during the telemedicine session (province and country).
Healthcare providers offering telemedicine services should have access to their EMR and should enter their notes there at the end of each meeting.
During a pandemic, if a healthcare provider does not have access to their EMR, or if they are still using paper files, they must add their note to the medical file as soon as possible, while protecting the confidentiality of the data. The healthcare provider is responsible for keeping notes secure and confidential. Once the notes have been placed in a patient's medical file, all other copies should be destroyed in a secure manner.
# Telemedicine and COVID-19
When possible, use of telemedicine services is highly encouraged during the COVID-19 pandemic, except where a physical examination or in-person test is required.
Healthcare providers should assess the feasibility of providing telemedicine services according to each patient's needs and the risks of contamination due to clinic, hospital and/or pharmacy visits.
Assessments can be an important source of support to patients who no longer have access to meetings, groups or counselling. Clinical judgment should apply when determining frequency of clinic visits. 5 Although not specifically covered in the current version of this guidance document, telemedicine consultations should aim for the high standard assessment and treatment of physical and mental health conditions and other drug use-related concerns, provide prevention, harm reduction, and other health information and counseling, as appropriate. Telemedicine should also be utilized as a method to check on mental health status as comorbidity is high and mental health issues are often exacerbated during pandemic times.
The following sections cover telemedicine in relation to pharmacotherapy.
# Relaxation of Prescription Rules during COVID-19
Patients requiring addiction services often require medication in treating their addiction-related condition. This includes psychoactive medications that can be prescribed by telemedicine.
# BENZODIAZEPINES AND PSYCHOSTIMULANTS
Provided that local licensing bodies do not object, the healthcare provider may prescribe benzodiazepines or psychostimulants to a previously known patient by telemedicine, as long as the provider ensures appropriate and timely follow-up, either in-person or by telemedicine (e.g. monitoring of weight and blood pressure in the case of a psychostimulant). 4 In the case of a new patient, the healthcare provider is permitted to prescribe benzodiazepines or psychostimulants by telemedicine, if they judge and document in the medical file that it is medically indicated, following provincial guidelines and standards, and that a delay in initiating treatment will entail a risk to the patient. Appropriate and timely follow-up must be carried out, either in-person or by telemedicine.
For all patients, the prescribed quantity must be safe and take into account the patient's condition and the associated risks. Prescribers should document safety concerns and measures to address them when prescribing any psychoactive substance.
If the patient has a usual prescriber or primary care provider, ensure proper communication is provided to the usual prescriber or primary care provider regarding what was prescribed, and reasoning for it.
# OPIOIDS
Opioid prescriptions may be renewed following a telemedicine consultation, according to the professional judgment of the prescriber, if the prescribing provider:
• Is the patient's treating provider;
• Is not the patient's treating provider, but has access to the patient's medical file kept by their treating provider; or,
• Is not the patient's treating provider, but has access to the patient's medical records and can trace their previous prescriptions. 4 The prescribed quantity of opioids must be safe (to an individual and the public) and documented, and be accompanied by appropriate and timely follow-up, either in-person or by telemedicine.
For opioid renewal of a prescription or a new prescription, in the absence of a patient's medical file or records, the prescriber can prescribe only if the clinical situation warrants it and following provincial college guidelines. Opioid prescription in the context of opioid use disorder is covered in more details in the next section. If applicable, effort must be made to communicate a renewal or change in prescription to the patient's usual prescriber or primary care provider.
# Opioid Agonist Treatment and Telemedicine during COVID-19
During the COVID-19 pandemic, it is essential that patients have continued and safe access to opioid agonist treatment (OAT) for their opioid use disorder. It is important to note that the following guideline should not supersede a provider's clinical experience and decision-making skills.
Healthcare providers should consider using telemedicine to provide continuous care for patients with opioid use disorder, taking into account each patient's needs, the fundamental concerns of stability, safety, storage, overdose risk, diversion risk, lapse or relapse, the new dangers associated with COVID-19, and current public health advice around physical distancing. 5 Providers should assume open, ongoing communication with patients. If it is not possible to provide care remotely, it may be more appropriate to continue in-person care. If performing a clinic in-person, then the clinic should follow the pandemic instructions given by their association, college, or Department of Health.
All decision-making processes should be recorded, including any deviations from these or standard guidelines, and clinical justifications should be made in the patient's record.
# RENEWAL OF PRESCRIPTION/ RE-INDUCTION
The renewal of a prescription or the re-induction of OAT can be provided via telemedicine consultation if the healthcare provider can confirm the patient's medication history on the medical file or record, and if the provider judges that this is justified by the patient's condition and that previous therapy was well-tolerated (based on consultation with pharmacists).
# INITIATION OF OAT
The initiation of OAT is authorized by telemedicine consultation only when the healthcare provider judges that a delay in the start of the treatment would entail a risk for the patient.
Conditions necessary to initiate OAT by telemedicine:
• The provider has the necessary elements to make a relevant diagnosis or differential diagnosis, following the College's guideline and standards.
• The provider obtains all relevant medical history, and a mental examination adapted to the situation occurs in a timely manner.
• The provider considers that a physical examination is not necessary or that it can be done later, in due time. An examination by a nurse can be done instead if the provider believes that all the tests performed by the nurse are sufficient for the moment. However, if a physical examination by a healthcare provider is deemed necessary in order to initiate and prescribe OAT, the provider will have to see the patient in-person to complete their assessment.
• The provider chooses the safest treatment under the circumstances and assesses the risks of toxicity, overdose and diversion of opioids, in relation to the treatment itself. When the provider does not have access to the patient's medical history or to information from a referent practitioner, OAT should be initiated at a low dose to begin and titrate up as per prudent OAT guidelines.
• The provider ensures that the patient has the necessary follow-up for their condition, either by telemedicine or in-person, while collaborating with the multidisciplinary team in place. The provider ensures that the required laboratory examinations, and if necessary, an electrocardiogram (ECG), are performed in a timely and feasible manner.
• During this pandemic period, the provider must weigh the risk of COVID-19 transmission (e.g. to other patients in a clinical setting) versus potential risks of telemedicine (e.g. inability to undertake a physical examination or tests). 18
# CLINICAL ASSESSMENTS OF SUITABILITY FOR CARRIES
OAT carries (i.e. take home dosing rather than daily witnessed ingestion) would enable healthcare providers to provide continuous care while ensuring that patients are safe in light of the COVID-19 pandemic, by reducing their number of visits to the pharmacy and to the clinic. When conditions allow, and public safety concerns can be considered, patients may be provided with additional carries.
Assessment of carries can be conducted using telemedicine. While applicable to the assessment of carries in general during COVID-19, this section covers specific guidance during telemedicine consultations.
Prescribers should use clinical judgment to determine whether the patient is suitable for carries. Urine drug detection samples (UDS) are not required for allowing carries. Prescribers should use clinical judgment to determine the maximum doses allowed for carries, in keeping with provincial guidelines. OAT carries above the number allowed by guidelines to reduce risk for the patient during the COVID-19 pandemic should be justified and documented.
Given the inferior safety profile of methadone, patients with methadone carries are more likely to have respiratory depression and overdose than those with buprenorphine/ naloxone carries. Document that patient states they have the ability to safely store increased number of carries. Prescribers should continue their normal practice with respect to buprenorphine/ naloxone storage safety.
All healthcare providers should request that patients obtain naloxone overdose kits and become educated and trained on the use of naloxone. Lost or diverted methadone carries should be managed as per MMTG. Lost or diverted buprenorphine/ naloxone carries should be managed according to usual standard of care.
Patients may be considered suitable for carries if they have safe housing or safe storage (i.e. locked box).
If available, pharmacists should deliver carries to the patient. If pharmacy delivery is not available, a reliable agent (e.g. a family member or friend) may be designated to pick up or receive the carries.
# OBSERVED DOSES
Authorized prescribers should explore alternative measures to support witnessed dosing, including virtual communication and observation methods. Verification can be completed by asking the patient to speak after taking the dose. 5,6 Witnessing the ingestion of carries may be difficult if the patient is isolating due to COVID-19 and the person delivering the carry dose does not have expert experience. Decisions regarding these cases should be taken on a case by case basis weighing risks and benefits.
Extra precautions should be considered while managing observed doses in-person, such as handling and disposal of dosing cups, and reduced contact by not requiring signatures for dosing. 17 Unless specified and required by the prescriber, the complete dissolution of the sublingual buprenorphine/ naloxone tablet does not need to be verified.
# BUPRENORPHINE/ NALOXONE
The choice of the OAT pharmacotherapy for patients newly assessed should follow best practices and evidence-based recommendations, with buprenorphine/ naloxone being suggested as the preferred option when appropriate. 7 Generally, doses of buprenorphine/ naloxone do not need to be witnessed, unless to address some specific clinical issue. Prescribers may prescribe up to four weeks of buprenorphine/ naloxone, in keeping with provincial guidelines. Prescribers should use clinical judgment to determine whether to be progressive with carries (e.g. advancing from one to four weeks).
Patients who are very stable may be assessed less frequently and be given carries for longer periods (e.g. every six to twelve weeks). 5 It may be possible and helpful to move appropriate patients from tablet sub/supra-lingual buprenorphine to depot buprenorphine. 7 Whenever possible, maintain patients on Buvidal® Monthly or Sublocade® to reduce attendance. 6
# METHADONE
Given the inferior safety profile of methadone, patients with methadone carries are more likely to have respiratory depression and overdose than those with buprenorphine/ naloxone carries. It is therefore imperative to weigh the risks of community transmissions of COVID-19 against the risks of patient overdose death and the public health risk if methadone is used by someone other than whom the medication was prescribed. 5 For those without carries, prescribers can introduce non-consecutive carries to reduce the frequency of pharmacy visits while reducing the risks of misuse/ diversion of larger amounts of methadone to patients without carries. Methadone safety should be assessed and documented, as per treatment guidelines. The suitability for consecutive carries should be considered based on risks, with, typically, up to a maximum of three consecutive doses treatment, and a maximum of six consecutive doses if the patient demonstrates stability.
Methadone carries above the number allowed by guidelines to reduce risk for the patient during the COVID-19 pandemic should be assessed on a case by case basis, justified and documented.
Advise patient that exceptional carries are being given due to current public health emergency. Discuss and document issues related to safe storage and risks of carries, including overdose and death, as per treatment guidelines.
A carry agreement should be remotely agreed to and documented in the chart.
At their observed doses, patients are seen by a pharmacist and assessed for sedation/ intoxication.
UDS are not required for low-risk patients but are required for higher-risk patients only if it will change clinical management.
Patients should not return used carry bottles at this time and should be advised and provided direction to ensure the used carry bottles are rinsed prior to disposal. 8
# New methadone starts
The initiation of methadone in methadone-naive patients requires a comprehensive assessment (virtual or in-person), and UDS should be done whenever possible.
Decision to prescribe methadone without UDS can only be made on a case by case basis and given that: i) the provider has the necessary elements to make a relevant diagnosis or differential diagnosis; and, ii) the provider assesses the safety of initiating methadone, the risks of toxicity, overdose and diversion of opioids, in relation to the treatment itself and provider communicates these risks to the patient.
Methadone initiation warrants more frequent clinical assessments, whether in-person or remotely. As a general rule, prescribers should consider waiting one month before initiating carries. 5 If not possible, patients should at least collect or have delivered their medicine daily from the pharmacy in the first week, followed by carries that are documented and justified. 6
# Methadone restarts
Patients restarting treatment must complete a virtual or in-person assessment.
# SUSTAINED RELEASE ORAL MORPHINE
Sustained Release Oral Morphine is an approved agonist treatment for opioid use disorder in Canada, and telemedicine can be used as for the other OAT medications.
Sustained Release Oral Morphine is considered a high-risk substance for diversion. Providers should follow established guidelines within their jurisdiction when initiating or following up patients on Sustained Release Oral Morphine while using telemedicine.
Providers should use clinical judgment on a case by case basis and weigh benefits (e.g. reduced interactions in healthcare settings) and potential harms (e.g. risk of diversion) to adapt their practice, and before attributing additional carries during the COVID-19 pandemic. Patients should be followed and decisions should be reassessed regularly based on client response to care.
# PATIENTS WHO HAVE MISSED DOSES
Patients who have missed doses considered as an interruption of treatment (according to provincial guidelines) should restart after a virtual assessment, without a UDS, but usually starting at a lower dose. 5,9
# SAFETY AND DOCUMENTATION
The safety of using carries and issues related to safe storage should be assessed, documented, and discussed with patients. Prescribers should consider possible misuse or diversion and overdose risk and discuss harm reduction strategies with patients. All healthcare providers should discuss obtaining naloxone overdose kits and educate the patients in the use of naloxone.
# COMMUNICATION
Healthcare providers should provide increased support to patients via remote methods. Ongoing and close communication with prescribers is critical. Assessments can be an important source of support to patients who no longer have access to meetings, groups, or counselling. When a UDS is not required for carries, consider using technology to allow patients to connect with their provider without coming to the clinic.
Healthcare providers should utilize this as an opportunity to educate and inform patients that unless necessary, in-person visits to the clinic or to pharmacies should be avoided.
# Expanded Roles of Pharmacists
As a result of the pandemic, the roles and scope of practice of pharmacists have expanded. Health Canada has, under Section 56(1) of the Controlled Drugs and Substances Act (CDSA), issued temporary exemptions for prescriptions of controlled substances. This permits pharmacists to extend prescriptions, transfer prescriptions to other pharmacists, permit prescribers to issue verbal orders, and allow pharmacy employees to deliver prescriptions of controlled substances. Prescribers, pharmacists, and other healthcare providers are encouraged to work closely together to identify the best possible solution and outcome for patients.
# NON-PHARMACOLOGICAL PRESCRIPTIONS/ CONSULTATION REQUESTS
Documents related to non-pharmacological prescriptions/ requests for consultation must be transmitted securely to patients, for example via secured internet-type platforms, by fax, or directly by verbal order to designated professionals.
# PHARMACOLOGICAL PRESCRIPTION
Healthcare providers should respect standards relating to individual prescriptions. When refilling prescriptions, especially for a patient that the provider does not know, the provider must ensure that the medication is still required, that it is well-tolerated, and that the dosage is appropriate for the patient's condition.
During a pandemic, it is recommended to send prescriptions by one of the following methods:
• Verbal transmission from doctor or authorized healthcare provider to pharmacist;
• Fax transmission, including directly via EMR; or,
• Transmission by electronic means (e.g. secured platforms).
# PHARMACY DELIVERY
For patients who are COVID-19 positive under isolation, or are at high-risk, symptomatic, and/or quarantined, or are presumed or confirmed COVID-19, pharmacists should deliver prescriptions to patients, if such service is available. If it is not available, appropriate precautions must be taken in order for the patient, the pharmacist, pharmacy employees, and pharmacy clients to maintain social distancing and avoid the dangers associated with COVID-19.
# Resources for Providers and Patients
See Appendix 4 for further online resources on substance use
• Use health messages and materials developed by credible public health sources (e.g. public health, CDC).
• Post signs at entrances and strategic places providing instruction on handwashing and coughing, use of cloth face coverings, and social distancing. For further guidance, please refer to other CRISM documents in this series, including: Harm Reduction Worker Safety, and Supporting People Who Use Substances in Emergency Shelter Settings.
• Provide educational materials about COVID-19 for non-French and non-English speakers or hearing impaired individuals.
-Identify and address potential language, cultural, and disability barriers associated with communicating COVID-19 information to staff and patients.
• Ensure communication with clients and key partners about changes in program policies and/ or changes in physical location.
• Identify communication platforms (e.g. hotline, automated text messaging, and websites) to help disseminate information inside and outside your organization.
# COUNSELLING FOR PATIENTS
Offer increased counselling services by phone or other platforms, with the intent of providing up-to-date medical information, reassurance, and mindfulness de-stressing where appropriate (see Appendix 4 for more resources). Disclosure of Interests and Management of Conflicts. 1 For this Guidance document, authorship committee members and external reviewers were required to disclose all sources and amounts of direct and indirect remuneration received in the past five years from industry, for-profit enterprises, and other entities (e.g. direct financial conflicts) that could introduce real, potential, or perceived risk of bias. In addition, authorship committee members and external reviewers were asked to disclose possible indirect conflicts of interest, such as academic advancement, clinical revenue, and professional or public standing that could potentially influence interpretation of evidence and formulation of recommendations.
Before the draft guidance document was circulated for review, two CRISM staff members independently reviewed the disclosure forms to screen potential authorship committee members and external reviewers who should be precluded from participation due to ongoing or current financial relationships (e.g. employment, paid consultancy or advisory board membership, stock ownership, intellectual property) with industry or commercial entities that could theoretically benefit from the guidance document recommendations. Consistent with the Institute of Medicine Standards for Developing Trustworthy Clinical Practice Guidelines, 24 any individual with a current, ongoing relationship with industry, who had received any remuneration or non-monetary support from industry within the past 12 months, or with a history of significant remuneration or non-monetary support from industry (defined for our purposes as cumulative receipt of more than $10,000 or equivalent value within the past five years), was excluded from participation on the guidance document prior to the review process. No authors nor contributors were excluded during initial screening as none met these criteria for exclusion.
# Summary of disclosures
No current or ongoing direct conflicts of interest were disclosed by the nineteen authorship committee members and external reviewers. Of the nineteen authorship committee members and external reviewers, three are CRISM staff.
Of the nineteen authorship committee members and external reviewers, one disclosed receipt of funds prior to Guidance document involvement from a commercial entity (Indivior Inc.) that could theoretically benefit from Guidance document recommendations. Six authorship committee members and external reviewers acknowledged that their employment involved the delivery of OAT to patients.
Eight authorship committee members and external reviewers acknowledged their employment involved the support of delivery the OAT programs. Seven authorship committee members and external reviewers acknowledged their employment involved engagement in developing OAT practice within their respective organization. Two authorship committee members and external reviewers acknowledged that their employment involved engagement in developing telemedicine practice within their respective organizations. Two authorship committee members and external reviewers acknowledged that they have publicly stated the need for measures to increase OAT or Safe supply in general, and in the context of COVID-19. Receipt of research or program funding support from non-profit agencies or institutions was not considered a direct conflict of interest. On review, none of the disclosed direct conflicts of interest were deemed to be of sufficient weight or relevance to warrant exclusion from the Guidance document.
Approximately 60% (n=11) of authorship committee members and external reviewers disclosed potential indirect sources of bias (e.g. specialization in addiction medicine, advisory board and committee membership, involvement with telemedicine programs, provincial OAT programs, previous guideline development, research interests).
To mitigate the risk of bias while maximizing the contributions of members in their respective areas of expertise, authorship committee members and external reviewers were reminded to consider any influential factors or sources of bias during the review process. Authorship committee members and external reviewers with indirect potential sources of conflict contributed to review of sections related to their areas of expertise as well as the overarching guidance document content to ensure that a broad range of clinical and academic specializations was adequately represented. 24 • Newly assessed: should usually be offered buprenorphine as first choice and will be able to take away unsupervised titration doses for up to 2 weeks. Those opting for methadone should collect their medicine daily from the pharmacy in the first week, followed by take-home doses.
# ONTARIO
• If only remote assessments are possible and drug testing is not possible, it may be possible to proceed with buprenorphine titration in known opioiddependent patients, based on an adequate history. This approach is unlikely to be suitable for methadone, where drug testing will usually be needed unless there is a clear history of opioid use and tolerance, in a known patient with evidence that opioids have been used in the last 24 hours. New methadone starts: should generally collect their medicine daily from the pharmacy in the first week, followed by take-home doses.
Methadone restart: People restarting treatment who were taking methadone no more than 7 days ago may be able to return to methadone after careful assessment but usually starting at a lower dose, titrated up again and with only 2 to 3 days pick-up to start.
# Appendix 1: Conflict of Interest Policy
Conflicts of interest were assessed using the Guidelines International Network's Principles for Appendix 2: Search Terms
• "COVID-19 Telemedicine Drug Users"
• "Telemedicine for People Who Use Drugs"
• "Opioid agonist therapy/ OAT COVID-19"
• "COVID-19 substance use"
• "COVID-19 Telemedicine OAT"
• "COVID-19 Telemedicine"
• "COVID-19 Telehealth"
• "COVID-19 Virtual Care"
• "COVID-19 Teleconsultation"
• "Virtual Care OAT"
• "Telemedicine OAT"
# Appendix 3: Finding Tables
See on next page (p. 33 -39).
# Appendix 4: Online Substance Use Resources Listing
Below is a list of online resources on substance use. Please note that this is not an exhaustive list of resources.
# Clinical Support Resources for Patients and Healthcare Providers
# Health Canada Subsection 56(1) Class Exemption for Patients, Practitioners and Pharmacists Prescribing and Providing Controlled Substances in Canada during the Coronavirus Pandemic
In response to the evolving health risk due to COVID-19, to maintain Canadians' access to controlled substances for medical treatments (e.g. treatment of substance use disorders and chronic pain), while they adhere to social distancing guidance from public health officials or if they need to self-isolate, Health Canada has issued exemptions for prescriptions of controlled substances under the Controlled Drugs and Substances Act (CDSA) and its Regulations.
# Mental Health First Aid Canada
Resource hub which provides credible information and resources for mental health for the Healthcare professionals "Resources for Healthcare Sector"
# Appendix 5: Health Canada Tool Kit
Health Canada has compiled a number of resources in an effort to provide clarity regarding the rules that apply for substance use disorder treatment or providing a pharmaceutical grade alternative to the toxic street supply in Canada, in the context of COVID-19. This includes:
• A regulatory pathways graphic;
• Frequently asked questions and answers related to the legislative and regulatory requirements for substance use disorder treatment/safer supply;
• A list of all relevant exemptions that have been issued under the Controlled Drugs and Substances Act;
• Formulary coverage under drug plans of medications used in substance use disorder treatment and as pharmaceutical grade alternatives to the illegal supply; and,
• Resources related to substance use disorder treatment and providing safer supply, both in general and during the COVID-19 pandemic.
https://www.dropbox.com/sh/x622qndzvmydsvm/AABi888G_Ase6T0-N1Pd3uboa?dl=0 | None | None |
9a9569b31ad23680fb2b9fa576b36bfd9ec30011 | cma | None | There is an urgent need for Canadian rehabilitation and exercise professionals to identify a new illness called Long COVID and guide safe rehabilitation interventions including therapeutic exercise prescription. Informed by the World Physio Briefing Paper, 1 key references 2,3,4 and consultation with the clinical community and stakeholders this living document consolidates resources to inform clinical decision making. Current as of August 2021, visit (LINK) for updates.#
Screen all clients for a past medical history of a COVID-19 infection (confirmed or suspected) before assessment and management in a rehabilitation or exercise setting.
# Why?
Evidence is still emerging, and it is not known when physical activity (including exercise) is safe/beneficial in people living with Long COVID, and it may be harmful. A cautious approach is required to prevent clients from experiencing worsening symptom and/or worsening of function due to physical activity. 1 World Physio Rehab and Long COVID Infographic Exercise testing and intervention should be closely supervised. Monitor, and teach clients to self-monitor for symptoms suggestive of cardiac involvement: disproportionate breathlessness, tachycardia, palpitations, chest pressure or pain at rest or exercise. Medical clearance may be necessary. Utilize readiness questionnaires. 6 Stop exercise if client is in distress.
# Oxygen Desaturation
Dysfunction of the respiratory or pulmonary system can be present following COVID-19.
Exercise testing and intervention should be closely supervised. Monitor, and teach clients to self-monitor for symptoms suggestive of respiratory distress: rate > 20 breaths/min, shortness of breath, accessory muscle use, chest pain, fatigue, dizziness, tachycardia or syncope. 7 If available, monitoring using pulse oximetry may be helpful (noting limitations in accuracy and racial bias). 8 Medical clearance may be necessary. Stop exercise if client is in distress.
# Dysautonomia
Some clients present with the inability to regulate the autonomic nervous system. This presents as variable heart rate, blood pressure, digestive issues, and temperature dysregulation. 10 Clients may self-report lightheadedness, fainting, unstable blood pressure, abnormal heart rate in response to activity. 9 Clinicians can assess orthostatic intolerance (in adults, sustained increase of HR more than 30 bpm with normal BP from lying to standing within 10 min) using the Canadian Guidelines. 10 Medical evaluation may be necessary. In clients with dysautonomia, recumbent, semi recumbent or horizontal exercise therapy is recommended. 9,10 Functional Cognition & Cognitive Communication Some clients experience "brain fog" or difficulties with thinking, attention and/or memory. These difficulties can cause cognitive-communication disorders, which may affect talking, understanding conversations, reading, written expression and social interaction. 11,12,13 Cognition and communication may be affected by many factors such as medical conditions, psychological status, fatigue, medication, and social/productive roles. Cognitive screens can identify need for neuropsychological, occupational therapy or speech-language pathology 14 assessment.
# Voice & Swallowing
Some clients may experience hoarse voice or difficulty swallowing. 13 Clients complaining of, presenting with, a hoarse voice or difficulty swallowing food or liquid need referral to a speech-language pathologist. Clients with voice problems also need referral to an Ear, Nose, Throat Specialist.
# What to Screen
# How to Screen and Action Necessary
Hearing & Tinnitus Some clients may experience a change in hearing or tinnitus (perception of ringing or other types of noise in the ear) in one or both ears. 15 Clients complaining of new onset of impaired hearing or tinnitus need referral to an audiologist.
# Psychological, Social & Spiritual Considerations
The onset of a new illness, loss of social roles or lack of social connection are stressful events which can cause anxiety and/ or low mood.
Clinicians making assessments should take a holistic, person-centred, and empathic approach. Assessment and treatment should encompass physical, cognitive, communication, psychological, and psychiatric symptoms, as well as functional abilities. 1 Ask questions about how Long COVID affects work, education, and physical or social wellbeing. Utilize Questionnaires. Offer resources from Wellness Together Canada, or the Canadian Psychological Association.
General Considerations for Management of Patients with Long COVID 1,2 - Due to the risk of worsening symptoms listed above on exertion and in the days following exertion, physical activity including exercise, needs to be prescribed with caution and clinical decision making.
- Educate clients with Long COVID on conservative activity and energy maximization.
- Ensure patients begin with monitoring activities of daily living, and only progress through gentle low intensity physical activity including exercise, once it is known how much is tolerated.
- Consider whether the selected management approach will contribute to function & recovery or result in an exacerbation or decline in function (including cognitive, communication, emotional and social function).
- Recognition, validation, and inclusion of patient experiences can help facilitate a therapeutic relationship.
- Some clients will require integrated, interprofessional rehabilitation, consider referrals to publicly-funded programs and services available at some hospitals, rehabilitation facilities, primary health care settings or use the tools for "Find a Physio", "Find an OT" , "Find a SLP/ Audiologists", or "Find a Registered Dietician".
- Detailed considerations can be found in guidelines developed by Alberta Health Services 4 or the Chartered Society of Physiotherapists (Version 2). 16
# Specific Consideration for Strength & Conditioning and Return to Sport
- Canadian Olympic and Paralympic Sport Institute Network have detailed Return to Health and Performance following COVID-19 Infection for those asymptomatic, with a course of illness > 10 days and for a graduated return to sport. 17 - All athletes need to progress symptom-free (including fatigue) through a Graduated Return to Play Protocol. 18 - Follow strength and conditioning principles in those without post exertional symptom exacerbation (see above) with a slow, progressive increase in intensity and volume. 19 - Ongoing monitoring of symptoms and vitals may be necessary due the unpredictable and relapsing nature of Long COVID.
# Link to Resources
Long COVID Physio: / | There is an urgent need for Canadian rehabilitation and exercise professionals to identify a new illness called Long COVID and guide safe rehabilitation interventions including therapeutic exercise prescription. Informed by the World Physio Briefing Paper, 1 key references 2,3,4 and consultation with the clinical community and stakeholders this living document consolidates resources to inform clinical decision making. Current as of August 2021, visit (LINK) for updates.#
Screen all clients for a past medical history of a COVID-19 infection (confirmed or suspected) before assessment and management in a rehabilitation or exercise setting.
# Why?
Evidence is still emerging, and it is not known when physical activity (including exercise) is safe/beneficial in people living with Long COVID, and it may be harmful. A cautious approach is required to prevent clients from experiencing worsening symptom and/or worsening of function due to physical activity. 1 World Physio Rehab and Long COVID Infographic Exercise testing and intervention should be closely supervised. Monitor, and teach clients to self-monitor for symptoms suggestive of cardiac involvement: disproportionate breathlessness, tachycardia, palpitations, chest pressure or pain at rest or exercise. Medical clearance may be necessary. Utilize readiness questionnaires. 6 Stop exercise if client is in distress.
# Oxygen Desaturation
Dysfunction of the respiratory or pulmonary system can be present following COVID-19.
Exercise testing and intervention should be closely supervised. Monitor, and teach clients to self-monitor for symptoms suggestive of respiratory distress: rate > 20 breaths/min, shortness of breath, accessory muscle use, chest pain, fatigue, dizziness, tachycardia or syncope. 7 If available, monitoring using pulse oximetry may be helpful (noting limitations in accuracy and racial bias). 8 Medical clearance may be necessary. Stop exercise if client is in distress.
# Dysautonomia
Some clients present with the inability to regulate the autonomic nervous system. This presents as variable heart rate, blood pressure, digestive issues, and temperature dysregulation. 10 Clients may self-report lightheadedness, fainting, unstable blood pressure, abnormal heart rate in response to activity. 9 Clinicians can assess orthostatic intolerance (in adults, sustained increase of HR more than 30 bpm with normal BP from lying to standing within 10 min) using the Canadian Guidelines. 10 Medical evaluation may be necessary. In clients with dysautonomia, recumbent, semi recumbent or horizontal exercise therapy is recommended. 9,10 Functional Cognition & Cognitive Communication Some clients experience "brain fog" or difficulties with thinking, attention and/or memory. These difficulties can cause cognitive-communication disorders, which may affect talking, understanding conversations, reading, written expression and social interaction. 11,12,13 Cognition and communication may be affected by many factors such as medical conditions, psychological status, fatigue, medication, and social/productive roles. Cognitive screens can identify need for neuropsychological, occupational therapy or speech-language pathology 14 assessment.
# Voice & Swallowing
Some clients may experience hoarse voice or difficulty swallowing. 13 Clients complaining of, presenting with, a hoarse voice or difficulty swallowing food or liquid need referral to a speech-language pathologist. Clients with voice problems also need referral to an Ear, Nose, Throat Specialist.
# What to Screen
# How to Screen and Action Necessary
Hearing & Tinnitus Some clients may experience a change in hearing or tinnitus (perception of ringing or other types of noise in the ear) in one or both ears. 15 Clients complaining of new onset of impaired hearing or tinnitus need referral to an audiologist.
# Psychological, Social & Spiritual Considerations
The onset of a new illness, loss of social roles or lack of social connection are stressful events which can cause anxiety and/ or low mood.
Clinicians making assessments should take a holistic, person-centred, and empathic approach. Assessment and treatment should encompass physical, cognitive, communication, psychological, and psychiatric symptoms, as well as functional abilities. 1 Ask questions about how Long COVID affects work, education, and physical or social wellbeing. Utilize Questionnaires. Offer resources from Wellness Together Canada, or the Canadian Psychological Association.
General Considerations for Management of Patients with Long COVID 1,2 • Due to the risk of worsening symptoms listed above on exertion and in the days following exertion, physical activity including exercise, needs to be prescribed with caution and clinical decision making.
• Educate clients with Long COVID on conservative activity and energy maximization.
• Ensure patients begin with monitoring activities of daily living, and only progress through gentle low intensity physical activity including exercise, once it is known how much is tolerated.
• Consider whether the selected management approach will contribute to function & recovery or result in an exacerbation or decline in function (including cognitive, communication, emotional and social function).
• Recognition, validation, and inclusion of patient experiences can help facilitate a therapeutic relationship.
• Some clients will require integrated, interprofessional rehabilitation, consider referrals to publicly-funded programs and services available at some hospitals, rehabilitation facilities, primary health care settings or use the tools for "Find a Physio", "Find an OT" , "Find a SLP/ Audiologists", or "Find a Registered Dietician".
• Detailed considerations can be found in guidelines developed by Alberta Health Services 4 or the Chartered Society of Physiotherapists (Version 2). 16
# Specific Consideration for Strength & Conditioning and Return to Sport
• Canadian Olympic and Paralympic Sport Institute Network have detailed Return to Health and Performance following COVID-19 Infection for those asymptomatic, with a course of illness > 10 days and for a graduated return to sport. 17 • All athletes need to progress symptom-free (including fatigue) through a Graduated Return to Play Protocol. 18 • Follow strength and conditioning principles in those without post exertional symptom exacerbation (see above) with a slow, progressive increase in intensity and volume. 19 • Ongoing monitoring of symptoms and vitals may be necessary due the unpredictable and relapsing nature of Long COVID.
# Link to Resources
Long COVID Physio: https://longcovid.physio/ | None | None |
a9c437a7ce92bddf56005d01a08f43851f4b5d29 | cma | None | To provide an overview of the mechanism of action, licensed indications, dosing regimens, and side-effect profile of apixaban.# INDICATIONS:
Apixaban is currently licensed in Canada for:
- Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation - Treatment of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE - Prevention of DVT and PE after elective hip or knee replacement surgery.
# DOSING:
- Prevention of stroke and systemic embolism in atrial fibrillation: 5 mg BID. No dose adjustment is generally necessary in patients with mild or moderate renal impairment or in those with CrCl 25-30 mL/min. However, a reduced dose of 2.5 mg BID is advised in patients with at least two of the following: (1) serum creatinine ≥ 133 µmol/L, (2) age ≥80 years, or (3) body weight ≤60 kg. Data are limited in patients with a CrCl of 15-24 mL/min and no dosing recommendation is provided by the manufacturer. Apixaban is not recommended in patients with CrCl <15mL/min or for those undergoing dialysis.
- Acute treatment of DVT or PE: 10 mg BID for 7 days, followed by 5 mg BID. No dose adjustment is necessary in patients with mild or moderate renal impairment (CrCl ≥30 mL/min). There are limited clinical data in patients with severe renal impairment (CrCl 15-29 mL/min) and apixaban should be used with caution in these patients because of a potentially higher bleeding risk. Apixaban is not recommended in patients with CrCl <15 mL/min or for those undergoing dialysis.
- Continued prevention of recurrent DVT and PE: After at least 6 months of treatment, consideration can be given to reducing the dose to 2.5 mg PO BID for long-term prevention of recurrent VTE.
- Thromboprophylaxis after hip/knee arthroplasty: 2.5 mg BID starting 12-24 hours after surgery and continuing for 14 or 35 days after knee or hip replacement, respectively.
# MONITORING:
Routine laboratory coagulation monitoring is not necessary. The prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT) are often normal in patients taking apixaban and do not provide reliable measures of the anticoagulant activity. Specific anti-factor Xa assays using apixaban calibrators are available in some laboratories to determine the plasma concentration but are not validated across centres and "safe" or therapeutic levels have not been established. For more details about specific testing, see the Clinical Guide: DOACs: Coagulation Tests.
Although routine laboratory coagulation monitoring is not required for long-term apixaban use, periodic clinical assessment is important to determine and reinforce compliance, review comorbidity and medication changes, including an assessment for possible interacting agents, and provide education. Furthermore, for most patients, at least yearly assessment of creatinine clearance is recommended. The creatinine should be measured more frequently in patients with an abnormal value at baseline or at risk of worsening renal function. The major adverse effect of apixaban is bleeding; concomitant use of antiplatelet drugs or other anticoagulants increases the bleeding risk. Apixaban should be avoided in patients with indwelling epidural catheters or with a history of recent spinal puncture in order to reduce the risk of epidural or spinal hematomas. Drug levels can also be increased or decreased by the use of concomitant medications (see Drug interactions). Approaches to the management of bleeding can be found in the Clinical Guide: DOACs: Management of Bleeding and the Tool: Bleed Management.
# PERI-PROCEDURAL MANAGEMENT:
See the Clinical Guide: NOACs/DOACs: Peri-operative Management and the Tool: Perioperative Anticoagulant Management.
# SPECIAL CONSIDERATIONS:
Administration: Apixaban may be taken with or without food.
# Pregnancy and breast feeding:
Apixaban crosses the placenta and should not be used in pregnancy. It should also be avoided in nursing mothers because it is uncertain whether apixaban appears in the breast milk.
Renal and hepatic dysfunction: Apixaban is not recommended in patients with CrCl <15 mL/min and those undergoing dialysis. Dosing recommendations by clinical indication for patients with less severe renal dysfunction are described above under Dosing. Apixaban should be used with caution in those with mild or moderate or hepatic impairment (Child-Pugh class A or B); however, no dosing modification is recommended in these patients. Apixaban is not recommended in patients with severe hepatic impairment (Child-Pugh class C) and is contraindicated in patients with coagulopathy associated with hepatic disease.
# Drug interactions:
The concomitant use of apixaban and drugs and/or herbal products that inhibit or induce both P-glycoprotein (P-gp) and CYP3A4 should be avoided. Patients taking strong inhibitors of both CYP3A4 and P-gp are at an increased risk of bleeding. Examples of inhibitors include azole antifungals (e.g. itraconazole, ketoconazole, voriconazole, and posaconazole), macrolide antibiotics (e.g. clarithromycin, erythromycin) and HIV protease inhibitors (e.g. ritanovir). Alternatively, concomitant use of strong inducers (e.g. rifampin, carbamazepine, phenytoin, St. John's Wort) can reduce apixaban levels.
Reversal: Andexanet alfa, a recombinant modified human factor Xa decoy protein, has been shown to reverse inhibition of factor Xa by apixaban and rivaroxaban in healthy volunteers and in those with major bleeding. In the latter group, effective hemostasis was noted at 12 hours in 79% of patients; however, thrombotic events occurred in 18% (12/67) of patients during 30-day follow-up. This agent is not yet available for use in Canada, although it has acquired FDA approval. Clinicians should consult their local institutional protocols for use of indirect reversal agents such as prothrombin complex concentrates (PCC) when reversal of apixaban is indicated for major or life-threatening bleeding. Approaches to the management of bleeding can be found in the Clinical Guide: DOACs: Management of Bleeding and the Tool: Bleed Management.
Pediatrics: Apixaban is not recommended for use in children until ongoing studies establish the pharmacokinetics, pharmacodynamics, safety, and efficacy of apixaban in these patients.
Treatment of cancer-associated thrombosis: Apixaban does not currently have a licensed indication in Canada specifically for use in this patient population but a randomized trial comparing apixaban (10 mg twice daily for 7 days then 5 mg twice daily) and subcutaneous dalteparin (at a dose of 200 IU/kg once daily for the first month, followed by 150 IU/kg once daily) for 6 months showed that, in this study population, apixaban was non-inferior to low molecular weight heparin (LMWH) in terms of both recurrent venous thromboembolism and major bleeding. The latter contrasts with other studies, which reported a higher incidence of major bleeding with other direct oral anticoagulants than with dalteparin in a similar population. Episodes of nonmajor bleeding were numerically higher in the apixaban group, a similar finding to that in studies of other direct oral anticoagulants. See the Clinical Guide: Cancer and Thrombosis.
Primary thrombosis prophylaxis in ambulatory cancer patients: When given in doses of 2.5 mg orally twice daily in ambulatory cancer patients judged to be at intermediate or high risk for venous thromboembolism according to their Khorana score, apixaban was associated with a reduction in overall (symptomatic and incidental) thrombosis risk from 10.2% to 4.2% (Hazard ratio of 0.41; 95% confidence interval (CI) 0.26-0.65); however, this came at a cost of increased major bleeding risk from 1.8% to 3.5% (HR 2.95; 95% CI, 1.01-3.95). As a result, decisions regarding the use of apixaban for primary prophylaxis in ambulatory cancer patients will need to be individualized and take into account estimated venous thromboembolism risk, cancer site (major bleeds were more likely to be gastrointestinal, genitourinary, or gynecologic in nature), patient values and preferences, and impact of drug cost. Apixaban is not currently licensed for this indication in Canada. See the Clinical Guide: Cancer and Thrombosis.
Atrial fibrillation patients receiving P2Y12 inhibitor for recent acute coronary artery syndrome (ACS) or percutaneous coronary intervention (PCI): The AUGUSTUS trial suggested that in atrial fibrillation patients with recent ACS or PCI taking a P2Y12 inhibitor, apixaban (at stroke prevention doses) without Aspirin resulted in less bleeding and fewer hospitalizations (without significant differences in the incidence of ischemic events) as regimens that included a vitamin K antagonist, Aspirin, or both.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES, RESOURCES AND TOOLS:
- Cancer and Thrombosis
# Date of Version: 02December2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide an overview of the mechanism of action, licensed indications, dosing regimens, and side-effect profile of apixaban.# INDICATIONS:
Apixaban is currently licensed in Canada for:
• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation • Treatment of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE • Prevention of DVT and PE after elective hip or knee replacement surgery.
# DOSING:
• Prevention of stroke and systemic embolism in atrial fibrillation: 5 mg BID. No dose adjustment is generally necessary in patients with mild or moderate renal impairment or in those with CrCl 25-30 mL/min. However, a reduced dose of 2.5 mg BID is advised in patients with at least two of the following: (1) serum creatinine ≥ 133 µmol/L, (2) age ≥80 years, or (3) body weight ≤60 kg. Data are limited in patients with a CrCl of 15-24 mL/min and no dosing recommendation is provided by the manufacturer. Apixaban is not recommended in patients with CrCl <15mL/min or for those undergoing dialysis.
• Acute treatment of DVT or PE: 10 mg BID for 7 days, followed by 5 mg BID. No dose adjustment is necessary in patients with mild or moderate renal impairment (CrCl ≥30 mL/min). There are limited clinical data in patients with severe renal impairment (CrCl 15-29 mL/min) and apixaban should be used with caution in these patients because of a potentially higher bleeding risk. Apixaban is not recommended in patients with CrCl <15 mL/min or for those undergoing dialysis.
• Continued prevention of recurrent DVT and PE: After at least 6 months of treatment, consideration can be given to reducing the dose to 2.5 mg PO BID for long-term prevention of recurrent VTE.
• Thromboprophylaxis after hip/knee arthroplasty: 2.5 mg BID starting 12-24 hours after surgery and continuing for 14 or 35 days after knee or hip replacement, respectively.
# MONITORING:
Routine laboratory coagulation monitoring is not necessary. The prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT) are often normal in patients taking apixaban and do not provide reliable measures of the anticoagulant activity. Specific anti-factor Xa assays using apixaban calibrators are available in some laboratories to determine the plasma concentration but are not validated across centres and "safe" or therapeutic levels have not been established. For more details about specific testing, see the Clinical Guide: DOACs: Coagulation Tests.
Although routine laboratory coagulation monitoring is not required for long-term apixaban use, periodic clinical assessment is important to determine and reinforce compliance, review comorbidity and medication changes, including an assessment for possible interacting agents, and provide education. Furthermore, for most patients, at least yearly assessment of creatinine clearance is recommended. The creatinine should be measured more frequently in patients with an abnormal value at baseline or at risk of worsening renal function. The major adverse effect of apixaban is bleeding; concomitant use of antiplatelet drugs or other anticoagulants increases the bleeding risk. Apixaban should be avoided in patients with indwelling epidural catheters or with a history of recent spinal puncture in order to reduce the risk of epidural or spinal hematomas. Drug levels can also be increased or decreased by the use of concomitant medications (see Drug interactions). Approaches to the management of bleeding can be found in the Clinical Guide: DOACs: Management of Bleeding and the Tool: Bleed Management.
# PERI-PROCEDURAL MANAGEMENT:
See the Clinical Guide: NOACs/DOACs: Peri-operative Management and the Tool: Perioperative Anticoagulant Management.
# SPECIAL CONSIDERATIONS:
Administration: Apixaban may be taken with or without food.
# Pregnancy and breast feeding:
Apixaban crosses the placenta and should not be used in pregnancy. It should also be avoided in nursing mothers because it is uncertain whether apixaban appears in the breast milk.
Renal and hepatic dysfunction: Apixaban is not recommended in patients with CrCl <15 mL/min and those undergoing dialysis. Dosing recommendations by clinical indication for patients with less severe renal dysfunction are described above under Dosing. Apixaban should be used with caution in those with mild or moderate or hepatic impairment (Child-Pugh class A or B); however, no dosing modification is recommended in these patients. Apixaban is not recommended in patients with severe hepatic impairment (Child-Pugh class C) and is contraindicated in patients with coagulopathy associated with hepatic disease.
# Drug interactions:
The concomitant use of apixaban and drugs and/or herbal products that inhibit or induce both P-glycoprotein (P-gp) and CYP3A4 should be avoided. Patients taking strong inhibitors of both CYP3A4 and P-gp are at an increased risk of bleeding. Examples of inhibitors include azole antifungals (e.g. itraconazole, ketoconazole, voriconazole, and posaconazole), macrolide antibiotics (e.g. clarithromycin, erythromycin) and HIV protease inhibitors (e.g. ritanovir). Alternatively, concomitant use of strong inducers (e.g. rifampin, carbamazepine, phenytoin, St. John's Wort) can reduce apixaban levels.
Reversal: Andexanet alfa, a recombinant modified human factor Xa decoy protein, has been shown to reverse inhibition of factor Xa by apixaban and rivaroxaban in healthy volunteers and in those with major bleeding. In the latter group, effective hemostasis was noted at 12 hours in 79% of patients; however, thrombotic events occurred in 18% (12/67) of patients during 30-day follow-up. This agent is not yet available for use in Canada, although it has acquired FDA approval. Clinicians should consult their local institutional protocols for use of indirect reversal agents such as prothrombin complex concentrates (PCC) when reversal of apixaban is indicated for major or life-threatening bleeding. Approaches to the management of bleeding can be found in the Clinical Guide: DOACs: Management of Bleeding and the Tool: Bleed Management.
Pediatrics: Apixaban is not recommended for use in children until ongoing studies establish the pharmacokinetics, pharmacodynamics, safety, and efficacy of apixaban in these patients.
Treatment of cancer-associated thrombosis: Apixaban does not currently have a licensed indication in Canada specifically for use in this patient population but a randomized trial comparing apixaban (10 mg twice daily for 7 days then 5 mg twice daily) and subcutaneous dalteparin (at a dose of 200 IU/kg once daily for the first month, followed by 150 IU/kg once daily) for 6 months showed that, in this study population, apixaban was non-inferior to low molecular weight heparin (LMWH) in terms of both recurrent venous thromboembolism and major bleeding. The latter contrasts with other studies, which reported a higher incidence of major bleeding with other direct oral anticoagulants than with dalteparin in a similar population. Episodes of nonmajor bleeding were numerically higher in the apixaban group, a similar finding to that in studies of other direct oral anticoagulants. See the Clinical Guide: Cancer and Thrombosis.
Primary thrombosis prophylaxis in ambulatory cancer patients: When given in doses of 2.5 mg orally twice daily in ambulatory cancer patients judged to be at intermediate or high risk for venous thromboembolism according to their Khorana score, apixaban was associated with a reduction in overall (symptomatic and incidental) thrombosis risk from 10.2% to 4.2% (Hazard ratio [HR] of 0.41; 95% confidence interval (CI) 0.26-0.65); however, this came at a cost of increased major bleeding risk from 1.8% to 3.5% (HR 2.95; 95% CI, 1.01-3.95). As a result, decisions regarding the use of apixaban for primary prophylaxis in ambulatory cancer patients will need to be individualized and take into account estimated venous thromboembolism risk, cancer site (major bleeds were more likely to be gastrointestinal, genitourinary, or gynecologic in nature), patient values and preferences, and impact of drug cost. Apixaban is not currently licensed for this indication in Canada. See the Clinical Guide: Cancer and Thrombosis.
Atrial fibrillation patients receiving P2Y12 inhibitor for recent acute coronary artery syndrome (ACS) or percutaneous coronary intervention (PCI): The AUGUSTUS trial suggested that in atrial fibrillation patients with recent ACS or PCI taking a P2Y12 inhibitor, apixaban (at stroke prevention doses) without Aspirin resulted in less bleeding and fewer hospitalizations (without significant differences in the incidence of ischemic events) as regimens that included a vitamin K antagonist, Aspirin, or both.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES, RESOURCES AND TOOLS:
• Cancer and Thrombosis
# Date of Version: 02December2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
a96cf8f22e7f193f4dfd24e76b63df1c0fb10daa | cma | None | These guidelines are not binding for nurses, other health providers or the organizations that employ them. The use of these guidelines should be flexible and based on individual needs and local circumstances. They constitute neither a liability nor discharge from liability. While every effort has been made to ensure the accuracy of the contents at the time of publication, neither the authors nor the Registered Nurses' Association of Ontario (RNAO) gives any guarantee as to the accuracy of the information contained in them or accepts any liability with respect to loss, damage, injury or expense arising from any such errors or omission in the contents of this work.With the exception of those portions of this document for which a specific prohibition or limitation against copying appears, the balance of this document may be produced, reproduced and published in its entirety, without modification, in any form, including in electronic form, for educational or non-commercial purposes. Should any adaptation of the material be required for any reason, written permission must be obtained from RNAO. Appropriate credit or citation must appear on all copied materials as follows: Registered Nurses' Association of Ontario (RNAO). Vascular access. 2nd ed. Toronto (ON): RNAO; 2021.This work is funded by the Government of Ontario. All work produced by RNAO is editorially independent from its funding source.In the context of RNAO best practice guideline development, the term "conflict of interest" (COI) refers to situations in which a RNAO staff member or expert panel member's financial, professional, intellectual, personal, organizational or other relationships may compromise their ability to conduct panel work independently. Declarations of COI that might be construed as constituting a perceived and/or actual conflict were made by all members of the expert panel prior to their participation in guideline development work using a standard form. Expert panel members also updated their COI at the beginning of each expert panel meeting. Any COI declared by an expert panel member was reviewed by the RNAO Best Practice Guideline Development and Research Team and expert panel co-chairs. No limiting conflicts were identified. See "Declarations of Conflicts of Interest Summary" at / guidelines/vascular-access-second-edition.# Vascular Access
# Second Edition
Vascular Access -Second Edition
# Greetings from Doris Grinspun, Chief Executive Officer, Registered Nurses' Association of Ontario
The Registered Nurses' Association of Ontario (RNAO) is delighted to present the second edition of the clinical best practice guideline (BPG) Vascular Access, Second Edition. Evidence-based practice supports the excellence in service that health providers are committed to delivering every day.
We offer our heartfelt thanks to the many stakeholders who make our vision for BPGs a reality. First, and most important, we thank the Government of Ontario that recognized in 1999 RNAO's capacity to lead a program that has gained worldwide recognition and is committed to funding it. We also thank the co-chairs of the RNAO expert panel, Nancy Moureau, RN, PhD (chief executive officer, PICC Excellence) and Darlene Murray, RN, MSN (interprofessional education specialist, The Hospital for Sick Children), for their invaluable expertise and stewardship of this BPG. Thanks to RNAO staff Amy Burt (guideline development lead), Christine Buchanan (guideline development methodologist), Verity Scott (guideline development project coordinator), Glynis Gittens (guideline development project coordinator), Nafsin Nizum (senior manager, guideline development and research) and the rest of the RNAO best practice guideline development and research team for their intense and expert work in the production of this BPG. Special thanks to the expert panel for generously providing their time, knowledge and perspectives, especially during these challenging times of the COVID-19 pandemic, to deliver a rigorous and robust evidence-based resource that will guide the education and practice of health providers. We couldn't have done it without you! Successful uptake of BPGs requires a concerted effort from educators, clinicians, employers, policy-makers, researchers and funders. The nursing and health communities, with their unwavering commitment and passion for excellence in patient care, provide the expertise and countless hours of volunteer work essential to the development of new and next edition BPGs. Employers have responded enthusiastically by becoming Best Practice Spotlight Organizations (BPSO ® ) -with over a 1,000 service and academic institutions in Canada and abroad. BPSO® have sponsored best practice champions, implemented BPGs, and evaluated their impact on patient and organizational outcomes. Governments at home and abroad have also joined in this awesome journey. Together, we are building a culture of evidence-based practice that benefits everyone.
We invite you to share this BPG with your colleagues from nursing and other professions, with the patient advisors who are partnering within organizations, and with the government agencies with which you work. We have so much to learn from one another. Together, we must ensure that the public receives the best possible care every time they come in contact with us-making them the real winners of this great effort!
# Table of Contents
Vascular Access -Second Edition
# Table of Contents
Vascular Access -Second Edition
# How to Use This Document
This best practice guideline G - (BPG) is a comprehensive document that provides guidance and resources for evidence-based nursing practice G . It is not intended to be a manual or "how-to" guide; rather, it is a tool to guide best practices and enhance decision making for nurses G , the interprofessional team G , educators, health-service organizations G , academic institutions, and persons G and their families G or caregivers G This BPG should be reviewed and applied in accordance with the needs of individual health-service organizations, academic institutions or other practice settings, and with the preferences of persons with a vascular access device G (VAD). This document provides evidence-based recommendation G statements and descriptions of: (a) practice, education and organizational policy; (b) benefits and harms; (c) values and preferences; and (d) health equity considerations.
Nurses, other members of the interprofessional team, educators and administrators who lead and facilitate practice changes will find this document invaluable for developing policies, procedures, protocols and educational programs to support service delivery. Nurses and other members of the interprofessional team in direct care will benefit from reviewing the recommendations and supporting evidence.
The RNAO convened an expert panel to determine the scope of the second edition of this BPG and to develop recommendation questions G to inform the systematic reviews G . The expert panel was interprofessional in composition. It was composed of individuals with knowledge and experience in clinical practice, education, research and policy across a range of health-service organizations, academic institutions, practice areas and sectors. These experts shared their insights on supporting and caring for persons with a VAD across the continuum of care (see page 24 for the list of RNAO best practice guideline expert panel members).
A comprehensive review and analysis was completed by the RNAO best practice guideline development and research team and the expert panel to determine the scope and priority recommendation questions for this BPG (see Appendix C).
# Scope
To determine the scope of this BPG, the RNAO best practice guideline development and research team conducted the following steps:
reviewed the previously published RNAO BPGs: Care and Maintenance to Reduce Vascular Access Complications (1) and Assessment and Device Selection for Vascular Access (2);
conducted an environmental scan of existing guidelines;
led 11 telephone key informant interviews with health providers G , administrators, educators and researchers;
held three telephone discussion groups with nursing students, health providers, managers, administrators and educators; and
consulted with the expert panel.
As with all procedures, health providers must be aware of scope of practice and follow regulatory body guidelines. Health providers should only be caring for or inserting VADs for which they have the necessary knowledge, skill and judgement. Health providers should also follow organizational policies and procedures related to VAD insertion and maintenance. This BPG addresses recommendations requiring advanced skill.
# CAUTION BAC K G R O U N D
Vascular Access -Second Edition Recommendation Question #6: Should the use of visualization technologies (e.g., ultrasound and vein finders) for the insertion of peripheral vascular access devices be recommended?
Outcomes: Success rate on the first attempt/number of failed attempts, patient satisfaction and complications.
Recommendation Question #7: Should pain management strategies (including pharmacological and nonpharmacological strategies) during the insertion of a vascular access device be recommended?
Outcomes: Patient's rating of pain, patient comfort, fear/anxiety (related to poke/needle phobia) and patient satisfaction.
Note: These priority recommendation questions are condensed versions of the more comprehensive PICO research questions developed by the expert panel to guide the systematic reviews and development of this BPG. For the PICO research questions and the detailed process of how the expert panel determined the priority recommendation questions and outcomes, see Appendix C.
# Good Practice Statement and Recommendations
The recommendations and resources in this BPG address topics such as the insertion, assessment, maintenance and management of VADs. Specifically, the guideline focuses on the following areas:
person and family education about VADs;
specialized training requirements for health providers;
daily review of PVADs;
the use of visualization technologies to insert PVADs and peripheral arterial catheters;
the use of VADs for obtaining blood samples; and
pain management strategies during the insertion of a VAD.
The evidence-based recommendations in this BPG are applicable to all practice settings where persons with a VAD are accessing services (e.g., acute care, long-term care, rehabilitation, primary care and community settings).
In this BPG, no recommendation questions were identified that addressed the need for conducting an assessment of persons prior to initiating vascular access. Please refer to the good practice statement on assessment that nurses and other members of the interprofessional team can use in their practice. The good practice statement is believed to be so beneficial that conducting a systematic review to prove its efficacy would be unreasonable. The resulting statement is not based on a systematic review, and it does not receive a rating of the certainty or confidence in the evidence or strength (i.e., a rating of conditional or strong) (7).
# RNAO BPGs and Other Resources That Align with This BPG
Other RNAO BPGs and evidence-based resources may support implementation of this BPG. See Appendix B for RNAO BPGs and other evidence-based resources on the following related topics:
client-centred learning;
pain management;
strategies to support self-management in chronic conditions;
implementation science, implementation frameworks and resources;
interprofessional collaboration; and
person-and family-centred care G .
# BAC K G R O U N D
Vascular Access -Second Edition
# Interpretation of Evidence and Recommendation Statements
RNAO BPGs are developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) G methods. For more information about the guideline development process, including the use of GRADE methods, refer to Appendix C.
# Certainty of Evidence
The certainty of evidence (i.e., the level of confidence we have that an estimate of effect is true) for quantitative research is determined using GRADE methods (8). After synthesizing the evidence for each prioritized outcome, the certainty of evidence is assessed. The overall certainty of evidence is determined by considering the certainty of evidence across all prioritized outcomes per recommendation. GRADE categorizes the overall certainty of evidence as high, moderate, low or very low (see Table 1 for the definition of these categories).
# Table 1: Certainty of Evidence
# CERTAINTY OF EVIDENCE DEFINITION High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
# Very Low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Source: Reprinted from: The GRADE Working Group. Quality of evidence. In: Schunemann H, Brozek J, Guyatt G, et al., editors. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach . ; 2013 . Table 5.1, Quality of evidence grades. Available from: #h.wsfivfhuxv4r. Reprinted with permission.
# Note:
The assigned certainty of evidence can be found directly below each recommendation statement. For more information on the process of determining the certainty of the evidence and the documented decisions made by RNAO guideline development methodologists, please see Appendix C.
# BAC K G R O U N D
Vascular Access -Second Edition
# Strength of Recommendations
Recommendations are formulated as strong or conditional by considering the certainty of evidence and the following key criteria (see Discussion of Evidence, below, for definitions):
balance of benefits and harms, values and preferences, and health equity.
According to Schunemann et al., "a strong recommendation reflects the expert panel's confidence that the desirable effects of an intervention outweigh its undesirable effects (strong recommendation for an intervention) or that the undesirable effects of an intervention outweigh its desirable effects (strong recommendation against an intervention)" (8). In contrast, "a conditional recommendation reflects the expert panel's confidence that the desirable effects probably outweigh the undesirable effects (conditional recommendation for an intervention) or undesirable effects probably outweigh desirable effects (conditional recommendation against an intervention), but some uncertainty exists" (8). Table 2 outlines the implications of strong and conditional recommendations. There is little variability in values and preferences among persons in this situation.
There is a need to consider the person's circumstances, preferences and values.
The benefits of a recommended course of action probably outweigh the harms. Therefore, some persons could receive the recommended course of action.
There is greater variability in values and preferences, or there is uncertainty about typical values and preferences among persons in this situation.
There is a need to consider the person's circumstances, preferences and values more carefully than usual.
# For persons receiving care
Most persons would want the recommended course of action, and a small portion would not.
The majority of persons in this situation would want the suggested course of action, but many would not.
For policy-makers The recommendation can be adapted as policy in most situations Policy-making will require substantial debate and involvement of many stakeholders. Policies are also more likely to vary between regions.
Source: Adapted from: The GRADE Working Group. Quality of evidence. In: Schunemann H, Brozek J, Guyatt G, et al., editors. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach . ; 2013 . Table 6.1, Implications of strong and weak recommendations for different users of guidelines. Available from: / handbook.html#h.wsfivfhuxv4r
# BAC K G R O U N D
Vascular Access -Second Edition Note: The strength of each recommendation statement is detailed directly below it and in the Summary of Recommendations (page 13). For more information on the process used by the expert panel to determine the strength of each recommendation, please see Appendix C.
# Discussion of Evidence
The Discussion of Evidence that follows each recommendation includes the following main sections:
- Benefits and Harms: Identifies the potential desirable and undesirable outcomes reported in the literature when the recommended practice is used. Content in this section solely includes research from the systematic review.
# Values and Preferences:
Denotes the relative importance or worth placed on health outcomes derived from following a particular clinical action from a person-centered perspective. Content for this section may include research from the systematic reviews and, when applicable, observations and/or considerations from the expert panel.
# Health Equity:
Identifies the potential impact that the recommended practice could have on health across different populations or settings and/or the barriers to implementing the recommended practice in particular settings. This section may include research from the systematic reviews and, when applicable, observations and/ or considerations from the expert panel.
# Expert Panel Justification of Recommendation:
Provides a rationale for why the expert panel made the decision to rate a recommendation as strong or conditional.
Practice Notes: Highlights pragmatic information for nurses and other members of the interprofessional team. This section may include supporting evidence from the systematic review and/or from other sources (e.g., the expert panel).
Supporting Resources: Includes a list of relevant resources (e.g., websites, books and organizations) that support the recommendations. Content listed in this section was assessed based on five criteria: relevancy, credibility, quality, accessibility and timeliness of publication (i.e., published within the last 10 years). Further details about this process and the five criteria are outlined in Appendix C. The list is not exhaustive and the inclusion of a resource in one of these lists does not imply an endorsement from RNAO. Some recommendations may not have any identified supporting resources. Note: all supporting resources are freely available or open access unless otherwise noted.
# BAC K G R O U N D
Vascular Access -Second Edition
# Summary of Recommendations
# GOOD PRACTICE STATEMENT
The expert panel recommends health providers complete a systematic assessment of the person prior to inserting a vascular access device .
As a good practice, this statement does not require application of the GRADE system . For more information on the good practice statement in this BPG, please see page 37 .
# RECOMMENDATIONS STRENGTH OF THE RECOMMENDATION Recommendation Question #1:
Should providing education to persons and their families about their vascular access device be recommended?
Outcomes: Hospital re-admission rate and complications .
# Recommendation 1.1:
The expert panel recommends that health providers provide comprehensive health teaching to persons and their families/caregivers about their vascular access device .
# Strong
Recommendation Question #2:
Should practical education for the insertion and management of vascular access devices for health providers be recommended?
Outcomes: Complications (including insertion-related complications), number of successful observed attempts and provider attitude/confidence .
# Recommendation 2.1:
The expert panel recommends health-service organizations implement practical education on the insertion and/or management of vascular access devices for health providers .
# Strong
Recommendation Question #3:
Should vascular access specialist teams be recommended?
Outcomes: Complications (including insertion-related complications) and number of successful observed attempts .
# Recommendation 3.1:
The expert panel suggests that acute care health-service organizations implement vascular access specialists or vascular access specialist teams to support the insertion and management of vascular access devices .
# Conditional BAC K G R O U N D
Vascular Access -Second Edition
# Recommendation Question #4:
Should blood draws from a vascular access device versus blood draws from venipuncture be recommended?
Outcomes: Specimen rejection, patient satisfaction, contamination rate (specific to blood cultures) and dwell time .
# Recommendation 4.1:
The expert panel suggests health providers perform venipuncture when drawing blood samples to maintain specimen integrity .
# Conditional
Recommendation Question #5:
Should the daily review of peripheral vascular access devices by health providers be recommended?
Outcomes: Complications .
# Recommendation 5.1:
The expert panel recommends that acute care health-service organizations implement a multi-component peripheral vascular access device care protocol . This protocol includes a minimum of a daily review by health providers, in collaboration with persons and their families .
# Strong
Recommendation Question #6:
Should the use of visualization technologies (e .g ., ultrasound and vein finders) for the insertion of peripheral vascular access devices be recommended?
Outcomes: Success rate on the first attempt/number of failed attempts, patient satisfaction and complications .
# Recommendation 6.1:
The expert panel recommends that health providers use ultrasound-guided technique for the insertion of peripheral arterial catheters .
# Strong
# Recommendation 6.2:
The expert panel suggests that health providers use ultrasound-guided technique for the insertion of peripheral vascular access devices in persons with difficult intravenous access .
# Conditional BAC K G R O U N D
Vascular Access -Second Edition Recommendation Question #7:
Should pain management strategies (including pharmacological and non-pharmacological strategies) during the insertion of a vascular access device be recommended?
Outcomes: Patient's rating of pain, patient comfort, fear/anxiety (related to poke/needle phobia) and patient satisfaction .
# Recommendation 7.1:
The expert panel recommends that health providers offer adults nonpharmacological and pharmacological pain management strategies during the insertion of a vascular access device .
# Strong
# Recommendation 7.2:
The expert panel recommends that health providers offer non-pharmacological and pharmacological pain management strategies during the insertion of a vascular access device to infants and children, tailored to their age and developmental stage .
Strong BAC K G R O U N D Vascular Access -Second Edition
# Best Practice Guideline Evaluation
As you implement the recommendations in this BPG, we ask you to consider how you will monitor and evaluate its implementation and impact.
The Donabedian model, which informs the development of indicators for evaluating quality health care, includes three categories: structure, process and outcome (9).
Structure describes the required attributes of the health system or health-service organization to ensure quality care. It includes physical resources, human resources, and information and financial resources.
Process examines the health-care activities being provided to, for and with persons or populations as part of the provision of quality care.
Outcome analyzes the effect of quality care on the health status of persons and populations, health workforce, health-service organizations or health systems (9).
For additional information, please refer to the RNAO, in partnership with Healthcare Excellence Canada (HEC), Leading Change Toolkit™ (10).
The following indicators have been developed to support evaluation and quality improvement. Consider Tables 3, 4 and 5, which provide a list of structure, process and outcome indicators to assess the impact of BPG implementation and are derived from BPG recommendations. Each table also identifies if the indicator aligns with other indicators in local, provincial, national and/or international data repositories and/or instruments. Alignment with data repositories/instruments is determined by comparing the following criteria with the developed indicators: the operational definition; if the indicator is nursing sensitive; and the inclusion/exclusion criteria. Depending upon the level of alignment, an indicator may be described to have full, partial or no alignment with external data repositories/ instruments.
The following indicators will support quality improvement and evaluation. Select the indicators most relevant to the changes being made in practice, education and/or policy based on BPG recommendations that are prioritized for implementation.
# BAC K G R O U N D
Vascular Access -Second Edition Table 3 provides structure indicators associated with specific recommendation statements that are related to human resources, educational recommendations and/or other organizational factors.
BAC K G R O U N D Vascular Access -Second Edition
Table 5 provides outcome indicators to assess the impact of implementing evidence-based practice changes.
# Stakeholder Acknowledgment
As a component of the guideline development process, feedback was obtained from participants across a wide range of health-service organizations, academic institutions, practice areas and sectors. Participants include nurses and other members of the interprofessional team, educators, students, individuals with lived experience and knowledgeable administrators. Stakeholders G representing diverse perspectives were also solicited for their feedback (see Appendix C). RNAO wishes to acknowledge the following individuals for their contribution in reviewing this BPG.
# BAC K G R O U N D
Vascular Access -Second Edition
# Background Context Vascular Access and Vascular Access Devices
Vascular access is the most common invasive procedure undergone by persons in the health system (12). Vascular access devices (VADs) are catheters inserted into central or peripheral veins or arteries that can be implanted or inserted under the skin (3). Catheters inserted into veins can be used to deliver fluids and medicines directly into the bloodstream of a person (3). Catheters inserted into arteries can be used to monitor therapy and patient status (i.e., hemodynamics) (3). There are different types of VADs that are used depending on the person's need. This includes devices such as:
peripheral vascular access devices (PVADs), such as short peripheral intravenous catheters (PIVs) and extended dwell, midline catheters;
central vascular access devices (CVADs), such as peripherally inserted central catheters (PICCs), tunneled catheters, non-tunneled catheters and implanted vascular access devices (IVADs); peripheral arterial catheters; and phlebotomy devices.
Appendix F provides an overview of the VADs listed above.
In the simplest sense, a VAD consists of a hub, a hollow tube divided into one or multiple sections (lumens) and a tip that may terminate within a peripheral or central blood vessel (13). VADs can be classified differently based on the insertion site and location of the device (13). PVADs remain in the periphery, with the terminal tip below the level of the axillary vein for upper extremity placement (14). CVADs are inserted with the terminal tip entering central circulation and advancing towards the heart. Except for haemodialysis catheters, terminal tip placement of all CVADs is in the vena cava (14).
Infusion therapy using VADs has historically been delivered in a hospital setting. However, infusion therapy and use of VADs increasingly is expanding into alternative health settings, including community care, infusion clinics and self-administration in the home (15). With wider use of VADs and a changing health landscape, it is important to recognize and support nurses, other members of the interprofessional team, and persons with vascular devices and their families with the administration of therapies involving VADs (15).
# Complications
Reliable vascular access is fundamental for safe and effective care (13). Ensuring safe insertion and management of VADs should be a priority for all health providers. Despite their important role, VADs are often the source of hospital-acquired infections and other types of complications G (13). In the United States, approximately 250,000 catheter-related blood stream infections occur each year, with an associated increase in length of stay and hospital costs (16).
Central line-associated blood stream infections (CLABSI) G are associated with particularly high morbidity and mortality: mortality is estimated to be between 4% and 20% (17). One CLABSI case prolongs hospitalization by an average of seven days and costs an estimated $3,700 USD to $29,000 USD (17). Other complications that can occur during the insertion or management of CVADs include catheter occlusion, catheter breakage/leakage, bleeding,
BAC K G R O U N D
Vascular Access -Second Edition thrombosis or thrombo-embolism, perforation of vessels, pneumothorax, cardiac arrhythmias, air embolisms and central venous stenosis (12). Safe vascular access and management is integral to ensure low risk and better outcomes for persons receiving care: care bundles or multi-component care protocols G have been widely used to address these complications in CVADs.
Common complications associated with PVADs include phlebitis G , infiltration G and extravasation G (18). Phlebitis is the most common complication of PVADs, occurring when there is acute inflammation of a vein in the presence of intravenous therapy (19). Infiltration occurs when infusing fluids leak into the surrounding tissue, caused by dislodgment of the VAD catheter, improper placement or damage to the vessel (18). Finally, extravasation occurs when there is infiltration of a vesicant G medication or other agent that can cause tissue damage, pain, inflammation, irritation, blistering or necrosis (18).
# Holistic and Person-and Family-centred Care
Person-and family-centred care means that the health provider is attentive to the emotional needs of the person with a VAD and their family or caregiver(s) (15). The nurse and other members of the interprofessional team play a large role in delivering care that is holistic and person-and family-centered. The selection, insertion and management of VADs by health providers have important implications for the person receiving care and their family. A person's preferences of VADs are unique and will depend on their diagnosis and intended treatment (12), their reasons for requiring a VAD, their health care context and their prior experience. As such, a person's preferences regarding infusion therapy may differ from those of health providers (15).
It is important to consider a variety of factors when choosing which VAD is most appropriate for a person. This consideration should be based on their condition as well as principles of person-and family-centred care. The use of only one device may not meet the vascular access needs of the person, necessitating the use of several devices throughout therapy (20). Considerations about preserving and minimizing vessel trauma, such as protocols that limit the number of VAD insertion attempts by a health provider, are also important (20).
VAD considerations are also likely to change across a person's lifespan. PVAD insertion can be more difficult in children due to their thin blood vessels, the deepness of the vessels, the cooperation level of the child (21), and because young children such as infants and toddlers have more subcutaneous tissue than older children and adults (22). Additionally, the type and frequency of complications in pediatric populations may differ from adults. These complications may be influenced by the smaller vessel size inherent in children and the length of therapy, and they most commonly include occlusion, migration, thrombosis and infection of CVADs (20).
Establishing and maintaining vascular access in older adults can also be challenging (23). Aging causes changes to the skin, vein walls and circulation; the skin loses tone and elasticity, and it becomes more fragile and prone to bruising (23). This can create problems when trying to establish VADs. In addition, older adults are more likely to have comorbidities and a weakened immune system, putting them at greater risk for infection (23). Finally, certain populations may require increased considerations when choosing and maintaining VADs. Some conditions associated with difficult intravenous access G (DiVA) include obesity, chronic illness, hypovolemia, substance use and vasculopathy (24).
# BAC K G R O U N D
Vascular Access -Second Edition
# Vascular Access Specialization
A vascular access specialist team (VAST) G refers to a grouping of health providers who have advanced knowledge and skills in the assessment, insertion, care and management of VADs, such as intravenous therapy teams and individual vascular access specialists (VAS) G (nurses, physicians, respiratory therapists, technicians and physician assistants) (3). Some organizations may implement VASTs or VAS to assist the interprofessional team in caring for persons with VADs. It is important that both nurses and the other members of the interprofessional team have the critical thinking skills to perform comprehensive vascular access assessments, and that they collaborate on necessary comprehensive assessments related to appropriate VAD selection. This includes prescribed therapy, person preference, language barriers and other variables (1). These specialist health providers or individual health providers can also be leaders of excellence and quality of care in vascular access within an organization (25).
# Conclusion
There is a need for up-to-date evidence to guide health provider practices regarding safe vascular access. This guideline aims to provide nurses (e.g., nurse practitioners, registered nurses, registered practical nurses and nursing students) and other members of the interprofessional team with evidence-based recommendations and resources related to the insertion, assessment and maintenance of VADs across the lifespan of individuals.
# Guiding Framework and Principles
# Guiding Frameworks
Acquisition of training and skills for VAD insertions and management is necessary to establish and maintain competence and ensure the safety of the person with a VAD. The supervisor or trainer is responsible for identifying the level of clinical competence of the learner as they guide them to higher levels of competence. Global rating scales are a helpful tool to document competence for certain procedures (such as ultrasound-guided peripheral catheter insertions). These scales are used as formal evaluation instruments to determine competence and may be used for annual assessment of competence (26). Benner's Stages of Clinical Competence may also be used to assess the learner or for education planning purposes. Benner (27) notes that health providers, specifically nurses, can advance through five levels of clinical competence during the acquisition and development of a new skill: novice, advanced beginner, competent, proficient and expert. This framework is foundational for recommendations and research questions on health provider education.
# Guiding Principles
The following principles provide fundamental prerequisite knowledge for each of the recommendations included in this BPG. It is expected that the recommendations are applied within the context of these guiding principles. It is recommended that nurses and other health providers receive adequate education and training with respect to these principles and apply them in their clinical practice.
# BAC K G R O U N D
Vascular Access -Second Edition
# Routine Practices and Additional Precautions
Routine practices and additional precautions are the expected processes and practices of care to be used in all health settings. Microorganisms have been transmitted from both symptomatic and asymptomatic people, so routine practices are expected in the care of all persons, at all times, across the continuum of care (28). Routine practices include the following:
point-of-care risk assessment;
hand hygiene;
source control (triage, early diagnosis and treatment, respiratory hygiene and spatial separation);
patient placement, accommodation and flow;
aseptic technique (e.g., Aseptic Non Touch Technique® G ) (29);
use of personal protective equipment (PPE);
sharps safety and prevention of blood-borne pathogen transmission;
management of the patient care environment (including cleaning and handling of waste and linen);
education of patients, families and visitors on infection prevention and control; and visitor management (28).
Similarly, as stated by Infection Prevention and Control (IPAC) Canada, health providers require IPAC core competencies (30). These competencies include, but are not limited to:
an understanding of point-of-care risk assessment;
an understanding that routine infection prevention and control practices are the key to preventing transmission of organisms among health-care providers, persons and visitors/family members;
an understanding and demonstrated use of appropriate PPE; and
an understanding of how to prevent and manage occupational exposures to sharps and blood/bodily fluids in an appropriate way (30).
For a full list of infection prevention and control competencies, please refer to IPAC Canada guidelines and standards available at (30).
Additional precautions should be used for patients with suspected or known infections or colonization G with microorganisms (28). Additional precautions are conventionally divided into the following categories (28):
Contact precautions for microorganisms of very low infective dose or situations where heavy contamination G of the person's environment is anticipated.
Droplet precautions for microorganisms primarily transmitted by the large droplet route.
Airborne precautions for microorganisms transmitted through the air over extended time and distance by small particles.
# Hand Hygiene
Hand hygiene is a comprehensive term that refers to handwashing, hand antisepsis and actions taken to maintain healthy hands and fingernails (31).
Hand hygiene plays a central role in infection prevention and control, especially in relation to hospital-acquired infections.
Public Health Ontario defines four key moments for hygiene (32). It recommends that health workers clean their hands at the following times:
- Before initial contact with patient environment.
- Before an aseptic procedure.
- After body fluid exposure.
- After patient/patient environment contact (32).
For details on supporting evidence, techniques (including choice of hand hygiene product) and other considerations, see the guidelines on hand hygiene from the World Health Organization (WHO) or PHAC (31)(32)(33), or the Canadian Vascular Access Association (CVAA) guideline for hand hygiene related to vascular access (25). Appendix M also provides further resources and details on infection control specifically for CVAD care.
# Aseptic Technique
Aseptic technique is the purposeful prevention of the transfer of microorganisms from the patient's body surface to a normally sterile body site, or from one person to another, by keeping the microbe count to an irreducible minimum (28). Aseptic techniques are used when performing procedures that expose the patient's normally sterile sites, such as the intravascular system, to keep them free from microorganisms.
One approach to standardizing aseptic practices is ANTT®. ANTT has been shown to support the reduction of health care-acquired infection (29,34). Given the high potential for patient harm from poorly applied aseptic technique, assurance that all staff are compliant with safe aseptic technique for all clinical procedures should be a priority for all health-care organizations (34).
# Use of Personal Protective Equipment
PPE is part of routine practices and additional precautions, and it is required to prevent exposure of infectious or harmful agents to patients, health-care workers and other staff (28). PPE may include gloves, gowns, masks and facial protection (face shields or eye protection) (28).
# Sharps Safety
VADs pose a risk to health providers through needlestick injuries and potential exposure to blood-borne pathogens (35). The United States Centers for Disease Control and Prevention (US CDC) estimates that 385,000 needlestick and other sharps-related injuries are sustained by hospital-based health workers each year (35). To prevent these injuries, PHAC recommends the following (28):
Safety engineered devices or needle-free systems be used wherever possible.
Needles should not be recapped. Used items should be placed immediately in a designated puncture-resistant container that is easily accessible at the point-of-care.
# BAC K G R O U N D
Vascular Access -Second Edition Health providers should cover open skin areas or lesions on hands and arms with a dry dressing at all times. Hand hygiene is still essential, so consultation is necessary if the dressing interferes with this procedure.
Eyes, nose and mouth should be protected if splashes with blood or body fluids are anticipated.
Immediately perform first aid if someone has been exposed to blood or body fluids. First aid should include:
thoroughly rinsing the injury site with running water, and gently cleaning with soap and water (if possible);
flushing the eyes, nose or mouth with running water if they have been exposed; and rinsing broken skin thoroughly.
Follow established organization policies and procedures for needlestick injuries, including reporting the incident and exposure immediately to your employer.
Follow instructions for further treatment and follow-up from medical professionals, where necessary.
# RECOMMENDATIONS
Vascular Access -Second Edition
# Recommendations
# GOOD PRACTICE STATEMENT:
The expert panel recommends health providers complete a systematic assessment of the person prior to inserting a vascular access device.
This is a good practice statement that does not require application of the GRADE system (7). Conducting an initial assessment of a person before developing a plan of care or any intervention is a standard of professional practice (36).
As such, completing a systematic assessment of persons prior to having a VAD inserted is good clinical practice and a pre-requisite for providing other clinical interventions.
The use of VADs, especially PVADs, is common throughout the health system. Any time a VAD is used as part of a care plan, it increases a person's risk for infection and other complications. Therefore, it is important that all persons requiring vascular access, regardless of duration of therapy, have a systematic assessment completed prior to the initiation of therapy (25,37). This systematic approach will include a vascular assessment, including determination of clinical indication, psychosocial assessment, site selection and device selection. See the "Practice Notes" below for the suggested components of a systematic assessment before initiating vascular access.
Assessment is necessary in all settings where a VAD may be inserted. It is especially important in home-care settings, where persons are sent home with a VAD. Furthermore, for persons in a hospital setting, assessing persons for the most appropriate device upon admission or early in their hospital stay leads to improved person-centred outcomes and is more cost-effective (20). Certain factors-such as age and diagnosis of the person-also need to be considered when choosing to initiate vascular access. For example, pediatric and elderly populations will have different VAD care considerations due to their smaller or more fragile veins; a systematic assessment and choosing the appropriate device are essential for optimizing person-centred outcomes in these specific populations. Health providers will need to consult with the interprofessional team when advocating for the best device for the person, based on a systematic assessment of the person.
# Practice Notes
# Considerations from the expert panel
It may not be possible to complete all components of a systematic assessment of persons needing vascular access in an emergency care situation. Health providers should not delay life-saving vascular access interventions.
# RECOMMENDATIONS
Vascular Access -Second Edition Vascular assessment is to include an assessment of current medications, including those that may increase complication risk, such as anticoagulants and immunosuppressant medications.
VAD assessment and planning is an ongoing process through the person's course of treatment (25).
Depending on the planned therapy and person receiving the VAD, the assessment may be more focused or more comprehensive.
# Psychosocial assessment
# RECOMMENDATIONS
Vascular Access -Second Edition
# COMPONENTS OF ASSESSMENT DETAILS OF ASSESSMENT
# Device selection and vesicant medications
Determine if the planned therapy poses an infusate risk or if the medication is a vesicant.
Do not use peripheral catheters for continuous vesicant therapy or infusates with an osmolarity greater than 900 mOsm/L (37). Use caution with parenteral nutrition.
Consultation with a pharmacist may be required for high risk or vesicant medications.
See Appendix H for a list of vesicant medications.
It is important to select the least invasive device for the duration and type of treatment, and one that promotes vessel preservation (25). When selecting a VAD (25):
Use a device with the minimum number of lumens.
Select the smallest gauge catheter that will accommodate the prescribed therapy.
See further details in Appendix F for considerations for different types of VADs and Appendix G for the right line decision tool (as included in the UK Vessel Health Preservation Framework) (38).
# Site selection
To select the site for VAD insertion, assess the person's vascular structure and integrity at and above the insertion site (25).
The following sites should be avoided for vascular access (25):
area of flexion ;
chest wall, digits or breast;
lower legs, except in a non-walking child;
insertion area that is painful on palpation;
vein that is obviously compromised (e.g., thrombosis, redness, cording, bruising, infiltration, phlebitis or engorgement);
extremity with a planned or actual arteriovenous fistula/graft site; and extremity affected by lymphedema, paralysis, extravasation, acute infection, tissue injury or acute trauma.
When selecting sites, health providers also must consider any previous history of breast cancer surgery and any potential sites for tissue donation.
If a short PVAD is deemed appropriate based on a comprehensive assessment of the person-and the health provider has the knowledge, skill and judgement to perform PVAD insertions-the health provider will select an insertion site appropriate for the required therapy that has the least risk of complication.
# RECOMMENDATIONS
Vascular Access -Second Edition
# Supporting Resources
# RESOURCE DESCRIPTION
Canadian Vascular Access Association. Canadian vascular access and infusion therapy guidelines. Pembroke (ON): Pappin Communications; 2019.
Canadian Vascular Access Association guideline.
Includes details on assessment and device selection.
Note: this is a resource for which there is a fee. The expert panel recommends that health providers provide comprehensive health teaching to persons and their families/caregivers about their vascular access device.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Very low
# Discussion of Evidence: Benefits and Harms
Comprehensive health teaching G involves a combination of learning experiences designed to help improve knowledge and skills related to self-management in persons and their families or caregivers (39-42). The evidence was focused on comprehensive health teaching for CVAD care in particular. Two studies focused on self-management education (39, 40), while seven studies focused on family or caregiver education (41)(42)(43)(44)(45)(46)(47), with the majority of these focused on parents or caregivers providing care for children.
Evidence suggests that comprehensive health teaching may reduce complications and hospital re-admission rate (39-49). However, the evidence is very uncertain.
Most studies reported a decrease in complications in persons who received health teaching when compared to either baseline or control groups (39, 40,. For instance, CLABSI rates decreased in three studies (43)(44)(45), and incidence of occlusion decreased in three studies (39,40,47). In one study, clotting was lower in the group that received education than in the control group (46). One study compared hospital readmission rates due to CLABSI before and after implementing a CVAD care class to family members: there were no hospital re-admissions related to CLABSI in one month of follow-up (42).
The studies did not report harms as a result of persons and families receiving health teaching about their VAD.
The certainty of the evidence was rated as very low due to serious limitations in how individual studies were conducted, serious imprecision related to the small number of total events or participants, and inconsistency in how outcomes were measured. For more detailed information on the impact of health teaching on the prioritized outcomes (hospital readmission rate and complications), refer to the evidence profiles available here: . ca/bpg/guidelines/vascular-access-second-edition.
Further details of the intervention noted in the literature are outlined below, under "Practice Notes. "
# RECOMMENDATIONS
Vascular Access -Second Edition
# Values and Preferences
Three studies gathered data on patient satisfaction (39, 41,46). Where this information was collected, persons and families reported improved satisfaction with the health teaching (39, 41), including feeling more comfortable with their care (46).
# Health Equity
No evidence was identified in the systematic review that directly assessed the impact of comprehensive health teaching on health equity. More research is required on this topic.
# Expert Panel Justification of Recommendation
This recommendation could have been a good practice statement however, the expert panel agreed that it was important to pose a recommendation question to examine the evidence on providing comprehensive health teaching to persons about their VAD. In addition, this evidence can support health providers by providing detailed information on the content and delivery of this education outlined in the evidence. There may be benefits to providing comprehensive health teaching to persons with a VAD and their families or caregivers. There were no harms reported. The expert panel felt that persons and their families or caregivers would value comprehensive health teaching, and that it would align with principles of informed consent, person-and family-centred care, self-management and autonomy. The expert panel also noted the potential for harms if health teaching was not completed. This included device failure or catheter-associated infection. Therefore, despite the very low certainty of the evidence, the expert panel determined the recommendation to be strong due to the potential for harms without health teaching. Although the literature was only on CVADs, the expert panel felt that health teaching on all types of VADs would be beneficial and determined the recommendation to be inclusive of all types of VADs.
# Practice Notes
Considerations from the expert panel At the very least, health teaching is to include signs and symptoms of complications. This should also include details about where, how and with whom to follow up and seek assistance if complications arise when discharged home with a VAD.
The amount of and formalization of health teaching will be dependent on the type of device and the discharge plan. For example, a person with a PVAD that is to be removed prior to discharge will have lower learning needs than a person discharged with a PICC line for a defined amount of time or a person with a long-term CVAD, who will require an in-depth understanding of the device.
Health teaching is to be tailored to the following (for further details, refer to "Supporting Resources, " below):
type of device;
type and duration of treatment (including type of infusion or medication);
discharge plan; person's age and developmental stage (including tailoring to children, adolescents and the needs of older adults);
person and family/caregiver's individual learning needs and preferences; and
person or family/caregiver capability for self-care.
# RECOMMENDATIONS
Vascular Access -Second Edition For more complex health teaching (if available and appropriate), consider referral to a VAS or VAST.
Health teaching is to be documented and included in the health record.
Comprehensive health teaching is to follow a teaching plan or checklist. See Appendix I for an example of a PICC health teaching guide. (44).
# Health provider providing the health teaching
In all but one study, health teaching was completed by a nurse (39, 40,. This was further described in the studies as one of the following:
nurse educator (44),
infusion nurse (39), or classes taught by specially trained registered nurses and reinforced by a bedside nurse (42).
In one study, health teaching was completing by the study investigator (41).
# Use of technology
Several studies used audiovisual demonstration through DVDs or videos to enhance education (39, 41,44,46,47).
One study used video calling technology to enhance coaching and accessibility of the education through one-on-one video chatting (39).
# Individualized or tailored approach
Most of the health teaching interventions tailored the teaching to the individual needs of the learner through various strategies (39-41, 43, 44). In the evidence these strategies included the following:
providing one-on-one health teaching (39, 41),
asking persons to express emotions and fears related to CVAD management and give opportunities to ask questions and receive feedback (40), and promoting family member autonomy in providing care (43). Models: Three education programs offered a chance to practise on mannequins or models (40,43).
# RECOMMENDATIONS
Evaluation or assessment:
In one study, the family member undergoing training was required to "room in" and provide total care for 24 hours to demonstrate their competency (44).
On the day before discharge, persons with a VAD were evaluated on how well they could perform the self-management tasks and were provided with feedback (40).
Another study assessed learner understanding through "teach back" strategies (42).
Finally, caregivers in one study were asked to demonstrate skills based on a checklist, and to re-demonstrate skills when the person they were caring for was re-admitted (45).
# Supporting Resources
# RESOURCE DESCRIPTION
Canadian Vascular Access Association. Canadian vascular access and infusion therapy guidelines. Pembroke (ON): Pappin Communications; 2019.
Canadian Vascular Access Association guideline.
Includes patient education as a core practice principle.
Note: this is a resource for which there is a fee. In particular, see Table 2 and Figure 1 within the document for self-management strategies.
# RECOMMENDATIONS
Vascular Access -Second Edition
# RECOMMENDATION QUESTION #2:
Should practical education for the insertion and management of vascular access devices for health providers be recommended?
Outcomes: Complications (including insertion-related complications), number of successful observed attempts and provider attitude/confidence.
# RECOMMENDATION 2.1:
The expert panel recommends health-service organizations implement practical education on the insertion and/or management of vascular access devices for health providers.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Low
# Discussion of Evidence: Benefits and Harms
For the purposes of this BPG, practical education G refers to skills practice, supervised insertion and management of VADs, hands-on training or one-on-one training for health providers. It also includes (but is not limited to) highfidelity simulation G training. Practical or skills lab training follows a structured teaching concept: it takes place under supervision and in consideration of foundational concepts, and it ideally creates an atmosphere that allows the repeated, risk-free practice of targeted clinical skills (50). The types of practical education provided varied across the evidence. Programs included a didactic theory session followed by simulation component (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70), an online or video component followed by in-class group simulation or a practical component (67,(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83), a simulation experience alone (84) or individualized mentoring or supervision (57,85).
The evidence suggests that practical education for health providers improves the number of successful attempts, probably reduces complications in persons with a VAD, and may improve provider attitude and confidence and insertion-related complications, although the evidence is uncertain . One systematic review reported higher success rates and marginally lower complications when practical education was compared to traditional education (51). Provider attitude and confidence was examined in 23 studies, with the majority reporting improvement in provider confidence from pre-to post-implementation of education or compared to a control group (55-60, 62, 63, 66, 67, 69-72, 74-76, 78, 79, 81, 82, 84). The majority of studies focused on practical education for CVAD insertion and management, but some studies also focused on PICC management (61), PVAD insertion (55,(67)(68)(69)(70)(71)(72)(73)85), and arterial catheter insertion (54,56,78,84). There was no evidence specifically examining PVAD maintenance.
There were no studies that reported harms as a result of health providers receiving practical education on the insertion and management of VADs.
# RECOMMENDATIONS
Vascular Access -Second Edition
The overall certainty of the evidence was rated as low due to serious concerns in how individual studies were conducted, inconsistency in the measurement of the outcomes, and imprecision related to the small number of total events or participants across the studies. For more detailed information on the impact of practical education on the prioritized outcomes (complications, insertion-related complications, number of successful observed attempts G and provider attitude/confidence), refer to the evidence profiles available here: .
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
Where reported, health providers in seven studies highly valued the practical education offered (60,62,66,67,76,81,82). In one study, in addition to the improved self-reported confidence, nurses described that the simulation environment was a safe place to learn, stating that they were able to concentrate on learning without being interrupted or disturbed (60). Medical residents that participated in a single 60-to 90-minute ultrasound-guided CVAD training session reported enjoying the practical training sessions because they were very realistic and rated higher perceived educational benefits (76).
# Health Equity
No evidence was identified in the systematic review that directly assessed the impact of practical education for health providers on health equity. More research is required on this topic.
# Expert Panel Justification of Recommendation
Conventionally based on GRADE, this recommendation could have been voted conditional since the certainty of the evidence of the effects was low. Based on the balance of benefits and harms, including the harms of not following the recommendation, as well as values and preferences, the expert panel came to consensus on a strong recommendation.
There are benefits to practical education for health providers on the insertion and management of VAD. The expert panel noted the risk of potential harms of health providers not receiving practical education on the insertion and management of VADs. Practical education was highly valued by health providers in the literature. Although the certainty of the evidence was rated as low, the expert panel voted the recommendation as strong as there were no harms noted in the studies, and they felt that all health providers would benefit from practical education.
# Practice Notes
# Considerations from the expert panel
Education is to be standardized within the health-service organization, with specific educational competencies outlined. See Appendix J for an example of a global rating scale for ultrasound-guided PVAD insertion. Additionally, organizations are to document competencies and review them on a regular basis through a formal process.
Due to loss of skills over time among health providers, refresher and ongoing education is to be offered.
Educators providing practical education need formal training, including skill development in debriefing.
High-fidelity simulation is preferable for complex cases and skills. However, it is recognized that high-fidelity simulation may not be feasible in all practice settings due to cost or accessibility issues.
# RECOMMENDATIONS
Vascular Access -Second Edition If simulation labs are used, simulation experts should be involved in their planning. It is important to note the consideration of the clinical experience levels of the learners when creating and conducting practical education sessions. Benner's Stages of Clinical Competence Framework may be used to tailor training to levels of expertise (see Guiding Framework and Principles on page 33). The expert panel suggests that acute care health-service organizations implement vascular access specialists or vascular access specialist teams to support the insertion and management of vascular access devices.
# Strength of the recommendation: Conditional
Certainty of the evidence of effects: Low
# Discussion of Evidence: Benefits and Harms
A VAST refers to a grouping of health providers who have advanced knowledge and skills in the assessment, insertion, care and management of VADs. This includes intravenous therapy teams and individual VAS (e.g., nurses, physicians, respiratory therapists, laboratory technicians, radiology technologists and physician assistants) (3).
The evidence suggests the implementation of VASTs and VAS may reduce complications, and that it probably improves successful attempts of VAD insertions (86)(87)(88)(89)(90)(91)(92)(93). Most studies focused on the insertion and management of CVADs, including PICCs (86)(87)(88)(89)93). The remaining studies focused on the insertion and management of PVADs (90)(91)(92).
In terms of complications, most studies reported an overall decrease in complications rates, catheter failure, catheterrelated blood stream infections and deep vein thrombosis rates when a VAST or VAS was involved in providing care (86-89, 91, 93). Three studies reported on the number of successful attempts and noted more successful insertions in persons who received care from VASTs compared to those who did not (90,92,93).
All studies except one reported no harms as a result of persons receiving care from a VAST. One study reported that the incidence of phlebitis was five per cent higher in VAS-inserted PVADs than for generalist insertions (90).
All studies took place in acute care settings. This recommendation therefore is specific to acute care.
# RECOMMENDATIONS
Vascular Access -Second Edition
The overall certainty of the evidence was rated as low due to serious concerns about imprecision related to the small number of total events or participants across studies, and due to some concerns about how individual studies were conducted. For more detailed information on the impact of VASTs and VAS on the prioritized outcomes (complications, number of successful attempts), refer to the evidence profiles available here: / guidelines/vascular-access-second-edition.
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
One study reported on patient satisfaction and found higher patient satisfaction rates among persons who received care from a VAS compared to those who did not (90). The median score of patient satisfaction with PVAD insertion was higher among those who received care from a VAS compared to those who received PVAD insertion from generalist health providers (9 versus 7, on a scale out of 10) (90).
# Health Equity
One study noted that persons with hematological malignancy may particularly benefit from VASTs and VAS compared to persons with other disorders (89). Of the persons who had a catheter-related bloodstream infection, 3 out of 4 of them also had a hematological malignant disorder (75%), and of the persons with a catheter-related deep venous thrombosis 3 out of 10 of them also had a hematological malignant disorder (30%) (89). The incidence of deep venous thrombosis in persons with hematological malignancy was 0.4/1000 catheter days, compared to 0.17/1000 catheter days in the overall cohort (89).
# Expert Panel Justification of Recommendation
There may be benefits to implementing VASTs and VAS in acute care health-service organizations. However, the certainty in the evidence was low. There also may be few harms of implementing VASTs and VAS. All people may not benefit equally from this intervention. Specific groups may benefit more from this intervention, such as older adults, children, persons with cancer and those with repeated need for device insertion. The expert panel recognized that there is limited evidence on the cost-effectiveness of VASTs or VAS. In addition, some health-service organizations may have challenges accessing VASTs or VAS due to cost or organization size. The expert panel felt the benefits of VASTs were important but that the evidence was not sufficient to make a strong recommendation.
# Practice Notes
Considerations from the expert panel The type of device needs to be considered when designing VASTs. For example, CVAD insertion and care are more likely to need VAST or VAS care than PVAD insertion and care. This recommendation excludes some health settings, such as home care and long-term care, but the expert panel feels that there are likely benefits to VASTs in these areas. However, there was no evidence from these health settings. See Table 15 on page 80 for research gaps and future implications.
# RECOMMENDATIONS
Vascular Access -Second Edition (88,(90)(91)(92).
Responsible for difficult PVAD insertions and difficult blood draws (87).
Responsible for all CVAD insertions (86) or all PICC insertions (88)(89)(90)94).
The VAS intervention in one study included individual assessment to identify the person's expected tolerance of the procedure (i.e., their sedation and pain management needs) (87).
# VAD management:
Responsible for CVAD dressing changes (87).
Education for persons and staff caring for persons with a short PVAD (87,88).
Responsible for all CVAD maintenance (including removal) (86).
Monitoring of VAD, including necessity (88,91).
Assessment and maintenance of CVAD and PVAD, as needed (92).
# VAS health provider in the evidence
Exclusively nurses (88)(89)(90)(91)(92)(93).
Nurse-led (87).
Nursing, medical and respiratory therapy (86). The expert panel suggests health providers perform venipuncture when drawing blood samples to maintain specimen integrity.
VAST
# Strength of the recommendation: Conditional
Certainty of the evidence of effects: Very low
# Discussion of Evidence: Benefits and Harms
The evidence suggests that venipuncture G for drawing blood samples may reduce specimen rejection and may reduce contamination of blood cultures compared with drawing blood from a VAD (94)(95)(96). However, one study also suggests that venipuncture for drawing blood samples may reduce patient satisfaction, when compared with drawing blood from a VAD (95). The certainty of the evidence was very low.
A systematic review concluded that blood sample collection through PVADs is associated with a higher risk of hemolysis G compared with blood drawn by venipuncture (94). Two additional non-randomized controlled trials were identified for the outcome of specimen rejection. One of the studies supported the findings of the systematic review (95). The other study reported lower rates of hemolysis in blood draws from a VAD compared with venipuncture, but it was blood drawn from a PICC (96).
The systematic review also reported on contamination of blood cultures based on two individual studies with mixed results (94). One study included in the review reported higher rates of blood culture contamination and false positives when blood was drawn from a PVAD compared with venipuncture (97). The other study included in the review reported no difference in blood culture contamination when blood was drawn from a PVAD within one hour of insertion when compared with venipuncture (98).
One study examined patient satisfaction, which was assessed on a scale from 0 to 10 (95). The study reported a mean difference of 1.27 in favour of blood draws from a PVAD (95). Finally, only one study reported on dwell time and concluded that blood draws from PVAD had little to no effect on dwell time (99). There were no additional harms reported in the studies.
# RECOMMENDATIONS
Vascular Access -Second Edition
The certainty of the evidence was rated as very low due to limitations in how individual studies were conducted, inconsistency across study results and a low number of total events and participants for some outcomes.
For more detailed information on the impact of the venipuncture compared to blood draws from a VAD on the prioritized outcomes (specimen rejection, patient satisfaction, contamination rate and dwell time), refer to the evidence profiles available here: .
# Values and Preferences
One study reported that 99 per cent of people preferred blood draw from a PVAD compared with venipuncture (95).
Additionally, one study reported lower pain when blood was drawn from a VAD (96).
# Health Equity
No evidence was identified in the systematic review that directly assessed the impact of venipuncture or blood draws from a VAD on health equity. More research is required on this topic. See Table 15 on page 80 for research gaps and future implications.
# Expert Panel Justification of Recommendation
There may be some benefits to using venipuncture compared to blood draws from a VAD, but the certainty of the evidence was very low. The evidence indicates that there are harms to performing blood draws from a VAD, such as specimen rejection of blood samples or contamination of blood cultures. Additionally, patient satisfaction may be lower when blood is drawn using venipuncture. The expert panel noted the potential for additional harms that were not captured in the body of evidence, including microclots in the samples and delayed treatment or misdiagnosis when blood draws are performed from a PVAD. Additionally, the expert panel felt that blood draws using venipuncture may not be appropriate at all times for all people. The examples of young children, people with cancer requiring repeated blood sampling or older adults with difficult intravenous access were given as potential populations where venipuncture may sometimes be more harmful than beneficial. Following an individualized riskbenefit assessment, other individuals also may not be appropriate candidates for venipuncture. Therefore, the expert panel determined the strength of the recommendation to be conditional.
Venipuncture is the preferred method of blood sampling. If this method is not feasible following an individualized risk-benefit assessment, then a blood draw from a VAD may be considered.
With any blood draw, health providers must adhere to a standardized blood sampling protocol or organizational policy. Health providers need adequate training and education on blood draws and VADs to support this recommendation. Specifically, the expert panel noted that health providers need to be educated on additional harms associated with blood draws from VADs (e.g., hemolysis and contamination of the specimen leading to false positive results and unnecessary treatment). Additionally, health-service organizations are to document competency of staff and review competencies on a regular basis through a formal process.
Health-service organizations are to develop policies based on their equipment and in collaboration with the VAD vendor specifications.
When developing policies, health-service organizations are to collaborate with laboratory guidelines and personnel.
Where an arterial blood sample is needed (e.g., for arterial blood gases), health providers are to follow established best practices for drawing blood from an artery or arterial catheter. See "Supporting Resources" (below) for guidance on arterial sampling procedure.
For persons with a CVAD in situ, see "Supporting Resources" (below) for guidance on sampling procedure. Decisions around blood draws from a CVAD also require an individualized risk-benefit assessment (see the factors listed above). The expert panel recommends that acute care health-service organizations implement a multicomponent PVAD care protocol. This protocol includes a minimum of a daily review by health providers, in collaboration with persons and their families.
# RECOMMENDATIONS
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Low
# Discussion of Evidence: Benefits and Harms
A multi-component care protocol G is a group of evidence-based interventions that can ensure the delivery of a standardized method of care (100). When these interventions are performed together, they can have a better outcome than if performed individually (this may be referred to as a "care bundle") (100). The evidence suggests that multicomponent PVAD care protocols may reduce complications (91,(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112).
The multi-component care protocol involved PVAD daily review and documentation (91,(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112) At a minimum, daily review involved an assessment of signs and symptoms of PVAD complications (91,(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112).
A majority of the studies also included assessment of device necessity as part of the PVAD daily review (91, 101-105, 108, 109, 111, 112).
Eleven out of 13 studies reported a decrease in complications when a multi-component PVAD care protocol with daily review was implemented (91,(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112). Steere et al. (2019) reported an overall decrease in complication rates and catheter failure rates (91). Infiltration was the most commonly assessed complication across studies, and its rate decreased in all the studies in which the outcome was reported (91,101,102,104,107,110,111). Phlebitis rate also decreased in the majority of the studies in which the outcome was reported (91,101,105,110). Furthermore, infection was assessed in three studies, and all studies reported a decrease in infection rate after implementation of a multi-component PVAD care protocol that included a daily review (103,106,109). There were no harms reported in the studies related to the use of a multi-component PVAD care protocol with daily review.
# RECOMMENDATIONS
Vascular Access -Second Edition
The certainty of the evidence was rated as low due to serious limitations in how individual studies were conducted.
For more detailed information on the impact of the multi-component PVAD care protocols, including a daily review on the prioritized outcomes (complications), refer to the evidence profiles available here: / guidelines/vascular-access-second-edition .
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
Another study conducted interviews with caregivers as part of intervention development (108). The following themes emerged related to PVAD care: the importance of communication, apprehension and fear around the device, an appreciation of skilled health providers and technology, and a recognition of the role of the caregiver (108).
# Health Equity
No evidence was identified in the systematic review that directly assessed the impact of multi-component PVAD care protocols on health equity. More research is required on this topic. See Table 15 on page 80 for research gaps and future implications.
# Expert Panel Justification of Recommendation
Conventionally based on GRADE, this recommendation could have been voted conditional since the certainty of the evidence of the effects was low. Based on the balance of benefits and harms, including the harms of not following the recommendation, as well as values and preferences, the expert panel came to consensus on a strong recommendation.
There may be benefits of implementing PVAD multi-component care protocols that include a daily review.
Additionally, there was some evidence to suggest that multi-component PVAD care protocols would be highly valued by persons and families or caregivers, particularly when caregivers were involved. The expert panel also noted that a daily review of a PVAD in particular would avoid additional harms not captured in the literature, as short PVAD complications can greatly impact a person's safety. A strong recommendation was selected by the panel to align with person's safety as well as values and preferences.
# Practice Notes
Considerations from the expert panel Daily reviews of PVADs are to be completed a minimum of once daily. More frequent assessment will be necessary for specific populations (such as neonatal or pediatric) and for infusing catheters.
PVAD care is not just the responsibility of an individual health provider; it also needs to be incorporated into health-service organization policies and procedures. Discussion of PVAD necessity, functionality and utilization is to include bedside and interprofessional team members.
Health-service organizations need to be responsible for education, training and monitoring related to multicomponent PVAD care policies and protocols. Additionally, organizations are to document competency of staff and review competencies on a regular basis through a formal process.
All studies took place in acute care settings. This recommendation therefore is specific to acute care.
# RECOMMENDATIONS
Vascular Access -Second Edition The assessment of a PVAD needs to follow an established protocol. See Appendix L for an example of a PVAD assessment protocol and Appendix G for daily evaluation included in the UK Vessel Health Preservation Framework.
Although this recommendation is for acute care settings, the expert panel felt that a multi-component PVAD care protocol would be beneficial in other settings, including long-term care and home care. More research is needed in these areas. See Table 15 on page 80 for research gaps and future implications.
This recommendation applies to PVADs. The expert panel did not feel that a recommendation on CVAD care was necessary, as there are many established multi-component care protocols (or "care bundles") currently in use. For more information on CVAD care, see Appendix M.
# PVAD daily review process
PVAD reviews were at minimum once per shift in some studies (107,109,110,112). They were once per day in others (91,101,102,109,110,112). Additionally, three protocols mandated hourly site assessment (104,108,111). One study required that assessment be completed whenever solutions changed or drugs were added to the intravenous therapy (105).
The acronym TLC (touch, look, compare) was used in one study (102), while ACT (assess, compare, touch) was used in another (104).
The acronym PIVCS formed the maintenance bundle in two studies: prompt removal, inspect hourly, vein patency by intermittent flush of 0.9% sodium chloride, clean hands, scrub the hub with 2%, chlorhexidine gluconate and 70% alcohol swab (108,111).
# PVAD dressings/ securement devices
Chlorhexidine antimicrobial bordered securement dressing (91).
Transparent dressing (91,101).
Semi-transparent polyurethane sterile dressing (106).
Sterile self-transparent adhesive gauze (105).
Bordered polyurethane dressing (108,111).
An additional elastic bandage was applied to reduce the risk of inadvertent withdrawal (105). The expert panel recommends that health providers use ultrasound-guided technique for the insertion of peripheral arterial catheters.
# RECOMMENDATIONS
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Moderate
# Discussion of Evidence: Benefits and Harms
Evidence suggests that the use of visualization technologies-specifically ultrasound-guided technique G -for the insertion of peripheral arterial catheters will increase the success rate on first attempts and will likely reduce complications (113)(114)(115)(116)(117)(118). Ultrasound-guided technique refers to ultrasound imaging (an image created by using sound waves within the body) that allows health providers to see surrounding anatomical structures such as arteries and veins (119). It is used to aid the health provider when inserting a PIV or peripheral arterial catheter. In particular, the use of ultrasound-guided technique was more effective when compared to the palpation technique in adult and pediatric populations (118).
Hematoma was the most frequently reported complication in the evidence. The systematic review reported fewer incidences of hematoma when using ultrasound-guided technique for arterial catheter insertion compared to palpation or traditional methods (118). Additional randomized controlled trials G that were included supported these findings (113)(114)(115)(116)(117).
Ultrasound-guided technique could provide greater value in the care of certain subpopulations. Based on subgroup analysis, one review noted that first attempt success rate of ultrasound-guided technique versus traditional palpation techniques for radial artery catheterization was particularly beneficial in children and persons undergoing emergent procedures (118).
There were no studies that reported on the outcome of patient satisfaction.
There were no harms reported in the studies.
The evidence was of moderate certainty due to some limitations in how individual studies were conducted. For more detailed information on the impact of the intervention (ultrasound-guided technique for arterial catheter insertion) on the prioritized outcomes (success rate on first attempt, patient satisfaction and complications), refer to the evidence profiles available here: .
# RECOMMENDATIONS
Vascular Access -Second Edition Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
There was no evidence identified in the systematic review that reported on the values and preferences of persons with a VAD related to the use of ultrasound-guided technique for the insertion of a peripheral arterial catheter.
# Health Equity
It is important to note that implementation barriers such as the cost of ultrasound devices may limit the feasibility and accessibility of ultrasound-guided technique in some health-service organizations.
# Expert Panel Justification of Recommendation
The benefits of using ultrasound-guided technique outweigh the harms, and there was moderate certainty of evidence for this. The expert panel agreed that the technique was feasible in most health-service organizations, and that it was acceptable to patients.
Overall, the expert panel noted that the potential harms of not using ultrasound-guided technique can be severe.
The expert panel noted the potential for additional harms that were not captured in the body of evidence, including ischemia, hemorrhage and thrombosis. Therefore, the expert panel determined the recommendation to be strong.
# Practice Notes
# Considerations from the expert panel
Training on the use of ultrasound needs to include a basic understanding of ultrasound technology, as well as ongoing maintenance of competencies (not a one-time certificate). Additionally, health-service organizations are to document competency of staff and review competencies through a formal process on a regular basis.
Training of health providers in ultrasound-guided techniques should involve practical education with the technology (see Recommendation 2.1 for details on practical education).
Two health providers may be required when using ultrasound, depending on the expertise and experience level of the health provider (i.e., one to hold the ultrasound probe and the other to insert the needle).
When using ultrasound-guided technique for the insertion of arterial catheters, it is important that health providers ensure correct positioning of the VAD prior to initiating treatment.
See Appendix K for an example of ultrasound-guided technique.
Appropriate scope of practice and level of training or expertise needs to be considered when applying this recommendation and determining the most appropriate health provider to insert the peripheral arterial catheter.
# CAUTION
# RECOMMENDATIONS
Vascular Access -Second Edition (119). In subgroup analysis, it was noted that those with ultrasound expertise had a higher first attempt success rate than those with no expertise (119).
Previous experience may improve the results and success of ultrasound-guided technique (120).
# Details of ultrasound technique
Short axis view, out-of-plane (113,(118)(119)(120).
One review noted that there was higher incidence of first attempt success in the subgroup analysis of pooled trials that used short axis out-of-plane ultrasound-guided approach (118).
Dynamic Needle Tip Positioning (DNTP) technique (a modified ultrasound technique that requires confirmation of the needle tip position in the vessel before advancing the catheter) (113,117).
Long axis view, in plane (115,118).
Seldinger technique (119,120) Single or double wall technique (120).
Vascular transducer used (120).
# Supporting Resources
# RESOURCE DESCRIPTION
Bardin-Spender A, Spencer TR. The expert panel suggests that health providers use ultrasound-guided technique for the insertion of PVADs for persons with difficult intravenous access.
# Strength of the recommendation: Conditional
Certainty of the evidence of effects: Very Low
# Discussion of Evidence: Benefits and Harms
Evidence suggests that the use of visualization technologies, specifically ultrasound-guided technique, for the insertion of PVADs in persons with difficult intravenous access may increase the success rate on first attempts and decrease complications, and that it likely will increase patient satisfaction (121)(122)(123)(124)(125)(126)(127)(128). However, the certainty of the evidence was very low.
Ultrasound-guided technique refers to ultrasound imaging (an image created by using sound waves within the body) that allows health providers to see surrounding anatomical structures, such as arteries and veins (119). It is used to aid the health provider when inserting a PVAD or peripheral arterial catheter.
Ultrasound-guided technique can be particularly useful for persons with DiVA, which is defined as a clinical situation where multiple attempts or special interventions are required to obtain and maintain peripheral venous access (129). How DiVA was determined varied across studies and included previous failed attempts (121,122), history of difficult access (121,122,127), health provider assessment (121,122,124,125,128), self-report (121,130) or certain comorbidities, such as sickle cell disease, obesity or intravenous drug use (121,124). Some studies focused on pediatric populations with different levels of venous access difficulty, or different ages and behaviours that may have influenced their cooperation with the procedure (22,123).
In adults and children with DiVA, ultrasound-guided PVAD insertion resulted in a higher success rate when compared to traditional techniques of palpation and direct visualization (22,(122)(123)(124)(125)(126)(127)(128). Furthermore, the evidence reported that adults and children with DiVA (or their parents/guardians) who received ultrasound-guided technique for the insertion of PVADs reported higher patient satisfaction than those who did not receive PVADs through ultrasound-guided technique (122,124,125).
Most studies reported fewer complications during the use of ultrasound-guided technique (121,125). There were no additional harms reported in the studies.
Of note were two systematic reviews that examined the effect that the use of near-infrared devices during PVAD insertion had on the success rate of first attempts (21, 130). Both systematic reviews found no difference in first attempt success rate when using near-infrared devices. Due to the limited evidence on this intervention, it was determined more research is needed in this area. As a result, the recommendation is solely focused on ultrasoundguided technique. See Table 15 on page 80 for research gaps and future implications.
# RECOMMENDATIONS
Vascular Access -Second Edition
The evidence was of very low certainty due to limitations in how individual studies were conducted and inconsistency in the reported results. For more detailed information on the impact of the intervention (ultrasound-guided technique) on the prioritized outcomes (success rate on first attempt, patient satisfaction and complications), refer to the evidence profiles available here: .
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
There was no evidence identified in the systematic review that reported on the values and preferences of persons with a VAD related to ultrasound-guided technique beyond the patient satisfaction outcome reported above.
# Health Equity
It is important to note that implementation barriers, such as the cost of ultrasound devices, may limit the feasibility and accessibility of ultrasound-guided technique in some health-service organizations. No evidence was identified in the systematic review that directly assessed the impact that visualization techniques for PVAD insertion had on health equity. More research is required on this topic. See Table 15 on page 80 for research gaps and future implications.
# Expert Panel Justification of Recommendation
There may be benefits to using ultrasound-guided technique in persons with DiVA in terms of insertion success rate and improvement of patient satisfaction. There was a reduction in the number of complications when using ultrasound-guided technique compared to traditional methods. The expert panel felt that the success of this recommendation would be dependent on individual considerations of the person receiving the PVAD and the expertise of the health provider. The certainty in the evidence was very low. Therefore, the expert panel determined the recommendation to be conditional.
# Practice Notes
# Considerations from the expert panel
Training on the use of ultrasound needs to include a basic understanding of ultrasound technology and ongoing maintenance of competencies (not a one-time certificate). Additionally, health-service organizations are to document and review competencies of staff on a regular basis through a formal process. See Appendix J for a validated scale on ultrasound-guided PVAD insertion and Appendix K for an example of ultrasound use during VAD insertion.
Health providers caring for persons in the community or home-care settings may need to refer persons with DiVA to an acute care setting to utilize ultrasound technology (if traditional methods of PVAD insertion are unsuccessful).
Appropriate scope of practice and level of training or expertise needs to be considered when applying this recommendation and determining the most appropriate health provider to insert the PVAD.
# CAUTION RECOMMENDATIONS
Vascular Access -Second Edition A validated scale can be used to determine DiVA. DiVA status should be assessed by an expert in PVAD insertion or a health provider who is appropriately trained to use the validated DiVA scale. Referral to VAS or VASTs may be needed to support the insertion of VADs in DiVA patients using ultrasound-guided technique (in organizations where available).
When using ultrasound-guided technique for the insertion of PVAD, it is important that health providers ensure correct positioning of the VAD prior to initiating treatment. It was noted that provider comfort and previous experience affected the success and implementation of the intervention (122,123,125).
One systematic review reported that provider expertise level and technique (e.g., one-person versus twoperson, and dynamic versus static) were associated with better results (122).
One study reported significant health provider effect on needle redirections, total time and needle manipulation time (123).
One study noted that attending physicians and nurses may have had higher success rates inserting PVADs than fellows because of more experience with placing ultrasound-guided VADs (125).
# Details of ultrasound technique
Dynamic Needle Tip Positioning (123,(125)(126)(127).
Short axis (121,123,125).
Long axis (121).
Single-operator technique (121,(125)(126)(127).
Two-provider technique (22,121,122).
One nurse operated the equipment and examined vessels in transverse and longitudinal directions with a 90-degree angle of the transducer, then chose the vein to be used. Another nurse performed skin antisepsis and the catheter insertion, analyzing the image on the screen (22).
# RECOMMENDATIONS
Vascular Access -Second Edition
# Should pain management strategies (including pharmacological and non-pharmacological strategies) during the insertion of a vascular access device be recommended?
Outcomes: Patient's rating of pain, patient comfort, fear/anxiety (related to poke/needle phobia) and patient satisfaction.
# RECOMMENDATION 7.1:
The expert panel recommends that health providers offer adults non-pharmacological and pharmacological pain management strategies during the insertion of a vascular access device.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Moderate
# Discussion of Evidence: Benefits and Harms
Evidence suggests that both pharmacological and non-pharmacological pain management interventions probably decrease pain, fear and anxiety, increase patient satisfaction during the insertion of a VAD for adults, and may increase patient comfort . Various needle procedures were examined across the studies, including CVAD insertion (131), arterial blood gas draw (147)(148)(149), intramuscular injections (141-143, 156), venipuncture (132,140,143,146), implanted port access (152), and PVAD insertion (132, 133, 136, 138, 143-145, 150, 151, 153-155).
Various types of pharmacological interventions were used in the studies, including fentanyl prior to CVAD insertion (131), a "needle-free powder lidocaine delivery system" given prior to venipuncture or PVAD insertion, and a variety of topical anesthetics (e.g., lidocaine-prilocaine cream, diclofenac patch, ketoprofen patch and tetracaine 4 per cent) (133-138, 148, 149). Specifically, the evidence reports that members of the "caine" family of drugs were estimated to be much more effective at reducing pain compared to no treatment (133).
Non-pharmacological interventions included both physical and psychological interventions (e.g., distraction techniques, acupressure, a vibrating cold device, vapocoolant spray, crushed ice, heat application, aromatherapy, a virtual reality device or hypnosis) (132,(140)(141)(142)(143)(144)(145)(146)(147)(148)(149)(150)(151)(152)(153)(154)(155)(156). The evidence reported that non-pharmacological techniques probably decrease pain and increase patient satisfaction (132,(140)(141)(142)(143)(144)(145)(146)(147)(149)(150)(151)(152)(153)(154)(155)(156).
The evidence demonstrated that overall, there was minimal or no difference in patient comfort levels when they were given pharmacological or non-pharmacological pain management interventions when compared to no pain management intervention (131,132,142,155). For the outcome of patient fear/anxiety, two systematic reviews demonstrated minimal to no difference when patients were given pharmacological or non-pharmacological pain management interventions when compared to no pain management intervention (132,143).
# RECOMMENDATIONS Vascular Access -Second Edition
The harms reported in the literature were due to side effects from pharmacological interventions. These included episodes of decreased oxygen saturation related to fentanyl use (131), nausea and pruritis related to fentanyl use (131), and mild skin reactions related to topical medications (e.g., skin blanching, rashes, petechiae, erythema and edema) (132,134,136,137).
The evidence was of moderate certainty due to how individual studies were conducted and inconsistency in the measurement of the outcomes. For more detailed information on the impact of the intervention (pharmacological and non-pharmacological pain management strategies) on the prioritized outcomes (patient's rating of pain, patient comfort, fear/anxiety related to poke or needle phobia, and patient satisfaction), refer to the evidence profiles available here: .
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
Several studies reported on patient satisfaction. Persons reported they were satisfied with the experience of topical anesthetic application, and more than 76 per cent were willing to use the cream again (134). Persons given lidocaine by injection for their procedure were more likely to want it next time than those who had never had lidocaine (133). Many persons also had a preference for lidocaine when asked to choose between lidocaine, guided imagery or nothing prior to PVAD insertion (133). All of those who chose lidocaine said they were satisfied with the PVAD insertion compared to those who chose no pain relief (133).
For non-pharmacological pain management, it was noted that individual differences-such as the desire to attend a medical procedure-may impact an individual's ability to engage with a distraction intervention (143). In one study that used heat and cold application prior to PVAD insertion, 93.3 per cent of those in the hot application group stated that they were satisfied with the application, whereas 80.0 per cent stated that they wanted the application again (150). Conversely, 50 per cent of those in the cold application group stated that they were not satisfied with the application, and 56.7 per cent expressed that they did not want the application again (150).
# Health Equity
Minimal considerations related to health equity were reported in the evidence. There were some studies that discussed accessibility issues. Non-pharmacological pain management devices such as the "needle-free powder lidocaine delivery system" and vibrating cold devices are currently unavailable in Canada (as of May 2021) (157).
In addition, not all settings may have access to lidocaine-prilocaine cream (134), particularly in some developing countries that restrict its use as a routine medication for PVAD insertion (136). One study recommended using diclofenac gel instead of lidocaine-prilocaine cream because of increased accessibility and domestic production in general (135).
# Expert Panel Justification of Recommendation
There are likely benefits to offering non-pharmacological and pharmacological pain management strategies. Although there were some harms in the form of side effects associated with pharmacological pain management strategies, the expert panel felt that the benefits greatly outweighed the harms. The interventions were also highly valued by persons, and the expert panel felt that the recommendation aligned with person-and family-centred care principles. It is important to note that the expert panel chose the action word "offer" for this recommendation to highlight that pain
# RECOMMENDATIONS
Vascular Access -Second Edition management strategies need to be person-and family-centred and that ultimately the person with a VAD will make the decision whether or not to receive pain management. The certainty in the evidence was moderate. Therefore, the expert panel determined the recommendation to be strong.
# Practice Notes
Considerations from the expert panel Aseptic technique needs to be maintained during VAD insertion, regardless of the type of pain management strategy used.
The expert panel recognized that time constraints experienced by health providers may be a barrier to providing pain management strategies. In these situations, pain management strategies should still be offered. Health providers may consider faster acting strategies, such as thermotherapy or cryotherapy, while keeping in mind the preferences of persons and their families/caregivers.
The expert panel noted that some individuals may not prefer topical anesthetic due to the increase in overall procedure time (i.e., topical anesthetic can take longer to take effect).
A physician order may be required prior to administration of pharmacological pain management interventions.
Decisions around pharmacological pain management interventions may require an individualized risk-benefit assessment, including (but not limited to) factors such as the following:
person preference;
presence of needle phobia, or fear/anxiety about the procedure;
DiVA score/history of DiVA; and type of pharmacological intervention and potential side effects, such as vasoconstriction associated with some topical medications.
# RECOMMENDATIONS
Vascular Access -Second Edition Arterial catheter insertion: There were three studies that examined using ice or topical anesthetics for arterial blood gas draws, and these were found to be effective pain management strategies (147)(148)(149).
CVAD insertion: One study examined the use of fentanyl for CVAD insertion (131). This type of intervention may not be necessary for less invasive procedures, such as venipuncture or PVAD insertion.
# Local anesthetic administration
Choice of drug: One systematic review and network meta-analysis found that drug members of the "caine" family (e.g., lidocaine and iontocaine) were most effective in reducing patient pain when undergoing needle procedures (133).
Timing: Three studies reported that topical anesthetic cream should be applied 60 minutes prior to the procedure in order to be most effective (134)(135)(136).
# RECOMMENDATIONS
Vascular Access -Second Edition
# KEY INTERVENTION DETAILS FROM THE EVIDENCE Distraction
The evidence examined various types of distraction techniques (143,144,(152)(153)(154)(155).
Verbal cues were found to have a mixed effect in reducing a person's pain. These interventions included giving a verbal signal to the person to warn them of the impending needle poke (e.g., "sting" or "sharp scratch") (143).
Visual distraction techniques may include having people look through a kaleidoscope (143), distraction cards containing optical illusion pictures (154) or virtual reality devices (154).
Hypnosis was used in one study, involving classical non-verbal hypnotic tools adapted to the subject and indirect suggestion of comfort by body language (155).
Aromatherapy, including lavender, eucalyptus or peppermint essential oils inhaled by persons prior to needle insertion, was used in two studies (152,153). For aromatherapy interventions, health providers should be aware of any allergies prior to administering the aromatherapy oils.
Breathing techniques may include things such as the "cough trick" or Valsalva maneuver G (143) or spirometry (144). The Valsalva maneuver is a breathing technique that can be used as a pain management strategy during VAD insertion. It involves a deep inhale, followed by a forceful holding of the breath during which the venous cannulation insertion occurs (143).
For breathing techniques, health providers should be aware of the person's health history and status and related contraindications to the Valsalva maneuver or coughing, including respiratory conditions such as COPD and asthma.
# Scope of practice considerations
Acupressure: If considering acupressure as a pain management intervention, it is important to recognize that health providers would need additional education and training in order to utilize this pain management strategy.
Opioids: One study found that the use of intravenous fentanyl given prior to CVAD placement procedure was effective in reducing person's pain (131). Health providers need to be aware of scope of practice surrounding prescribing or administering opioids. They should consult with the interprofessional team about opioid administration in circumstances where it would be beneficial to advocate for this pain management strategy for the person with a VAD.
Hypnosis: One study examined the impact of hypnosis on PVAD insertion, but it is important to note that the health providers received additional certifications in hypnosis prior to delivering the intervention (155). Pain toolkit for older adults.
# RECOMMENDATIONS
Includes pain scales and pain management strategies.
# RECOMMENDATIONS
Vascular Access -Second Edition
# RECOMMENDATION 7.2:
The expert panel recommends that health providers offer non-pharmacological and pharmacological pain management strategies during the insertion of a vascular access device to infants and children, tailored to their age and developmental stage.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Low
# Discussion of Evidence: Benefits and Harms
Research evidence suggests that both pharmacological and non-pharmacological pain management interventions may decrease pain (139,156,(158)(159)(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175) fear and anxiety (162,164,166,171,173,174), and increase comfort (176), and that they probably increase patient or parent/guardian satisfaction ( 139) during the insertion of a VAD for infants and children.
The majority of studies examined non-pharmacological interventions. These included psychological interventions (e.g., distraction techniques, virtual reality devices, cartoons, aromatherapy and informational materials about the procedure) (164,165,168,(171)(172)(173)(174)(175) and physical interventions (e.g., breastfeeding and other feeding interventions, a vibrating cold device, ice, heat therapy, acupressure and holding/positioning techniques) (139, 156, 160-163, 166-168, 170, 176, 177, 179, 180, 182, 197-220). One systematic review showed that interactive distraction interventions-such as virtual reality, a toy accompanied by a reading activity and video games-were most effective in reducing fear/anxiety prior to the needle procedure (164). Furthermore, a meta-analysis reported a positive effect on the outcome of fear/anxiety among children who received distraction during the insertion of a VAD compared to those who did not receive distraction (164). Types of non-pharmacological interventions used in the studies varied with child and infant age and developmental stage. Further details of effective non-pharmacological pain management strategies are outlined below, under "Practice Notes. "
Various pharmacological interventions were used in the studies, including oral melatonin 30 minutes before venipuncture (221), and lidocaine-prilocaine cream (169), 5 per cent lidocaine cream (169), vapocoolant spray (156), amethocaine, paracetamol and ibuprofen before needle procedures (158,159). Lidocaine-prilocaine cream and oral melatonin were found to reduce pain scores, and it was noted that lidocaine-prilocaine cream had the highest probability of being most effective in reducing pain (158,159). In addition, children who received melatonin had lower anxiety than those treated with placebo (221). Paracetamol and ibuprofen were not shown to reduce pain scores (158).
The harms reported in the literature were due to side effects from pharmacological interventions or adverse events associated with non-pharmacological interventions. In one review, two studies reported skin blanching as an adverse effect of lidocaine-prilocaine cream application (159). Feeding-related adverse events included choking while drinking formula milk during vaccination (not leading to additional interventions or complications) (212), or infants coughing, gagging and vomiting following sucrose administration (116,160,199,207). One study reported that when using non-nutritive sucking, some infants may refuse to suck and should not be forced to do so, as it may increase distress (162). Mild to moderate nausea was noted in some children when participating in a virtual reality intervention (187), and in another study examining virtual reality as an intervention two children took off the headset
# RECOMMENDATIONS
Vascular Access -Second Edition during the procedure stating that they felt distressed (175). Finally, one study on breathing techniques reported adverse events: three of 50 children reported respiratory difficulties when asked to engage in a specialized form of deep breathing (164).
The evidence was of low certainty due to some concerns over how individual studies were conducted, inconsistency in the measurement of the outcomes, and variability in the types of needle procedures examined. For more detailed information on the impact of the intervention (pharmacological and non-pharmacological pain management strategies) on the prioritized outcomes (patient's rating of pain, patient comfort, fear/anxiety related to poke or needle phobia, and patient satisfaction), refer to the evidence profiles available here: / vascular-access-second-edition.
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
An important consideration reported in the literature was recognizing the developmental stage of the child and how it may influence their preferred pain management intervention. In addition, children in a study using a virtual reality intervention reported positive satisfaction: one child explained that he was "nervous at the idea of blood draw, the virtual reality game truly helped distract from the feeling of the needle being inserted" (187). Another study that used virtual reality as an intervention reported that users of the virtual reality headsets stated that the device was effective in reducing pain and anxiety and offered a pleasant experience (190).
The evidence also reported infant feeding/positioning preferences. Not all mothers may want to breastfeed (or formula feed) their child, especially during immunization, if they are anxious themselves (208). One study stated it is important to consider the parental wishes for infant procedures (e.g., they could stay in the room or leave during the procedure, or they could offer comfort measures to the child) (200). In one study, parents preferred to have their children sitting up for the injections (162).
# Health Equity
Multiple studies examined breastfeeding as an intervention and noted it to be inexpensive, readily available and convenient (182,209). However, it is important to recognize person-and family-centred care principles: not all persons have the ability to breastfeed, or they simply may prefer not to do so.
No additional considerations for health equity were reported in the studies.
# Expert Panel Justification of Recommendation
Conventionally based on GRADE, this recommendation could have been voted conditional since the certainty of the evidence of the effects was low. Based on the balance of benefits and harms, including the harms of not following the recommendation, as well as values and preferences, the expert panel came to consensus on a strong recommendation. There are likely benefits to offering non-pharmacological and pharmacological pain management strategies. Although there were some harms in the form of side effects associated with pharmacological pain management strategies and feeding, the expert panel felt that the benefits greatly outweighed the harms. The interventions were also highly valued by children, infants and parents/guardians, and the expert panel felt that they aligned with person-and family-centred care principles. It is important to note that the expert panel chose the action word "offer" for this
# RECOMMENDATIONS
Vascular Access -Second Edition recommendation to highlight that pain management strategies need to be person-and family-centred and that ultimately the decision whether or not to receive pain management is up to the child and/or parents/guardians.
The certainty of the evidence was low, but due to the reasons stated above, the expert panel determined the recommendation to be strong.
# Practice Notes
Considerations from the expert panel Aseptic technique needs to be maintained during VAD insertion, regardless of the type of pain management strategy used.
The expert panel emphasized the importance of offering children, infants and parents/guardians the choice of a variety of pain management interventions. The expert panel noted that some children do not prefer topical anesthetic due to the increase in overall procedure time (i.e., topical anesthetic can take longer to take effect). An additional example was given of some children disliking the feeling associated with cryotherapy (such as aerosol vapocoolant sprays).
A physician order may be required prior to administration of pharmacological pain management interventions.
# RECOMMENDATIONS
Vascular Access -Second Edition One study reported that "the receptivity of infants to distraction is hypothesized to vary due to developing motor and cognitive capacities. On the basis of developmental milestones, a two-month old would seem less likely to benefit from distraction. However, a child older than 12 months would seem to have greater ability to benefit from distraction" (165).
Another study reported that distraction methods such as toys or books are generally preferred for children aged 7-12 years (190).
Information and preparation materials should be tailored to the age of the child. Storybooks that include age-appropriate health education messages and pictures enable children to better understand their treatment regimen (189).
# Psychological techniques
Various distraction interventions may be used by health providers. These include movies, cartoons, video games, storybooks, toys, cards, blowing bubbles, chewing gum, balloon inflation, virtual reality, music, parent distraction, a medical clown or squeezing a rubber ball.
Interactive or directed distraction may confer a larger benefit than non-directed distraction interventions. For example, one study stated that passive distraction by watching a cartoon may be less effective in reducing procedural pain than virtual reality motion videos, such as riding a roller coaster (190).
One systematic review that examined combined cognitive behavioural therapy and breathing interventions for reducing children's needle-related pain or distress found that combining multiple psychological strategies can be beneficial (164).
Positioning and touch Positioning of infants for the vascular access procedure may be different than it is for children.
Children: Parents may want to hold their older child sitting upright during the procedure (162,214). Holding the child in a parent's lap in a gentle hug, with the child's legs on either side of the parent, may be one way to deliver this intervention (162).
Infants: Skin-to-skin, swaddling, hugging, caressing, or facilitated tucking may be appropriate interventions (161,162,219).
# Infant feeding
Breastfeeding was shown to confer the greatest benefit as a nonpharmacological pain management intervention, since it combines the therapeutic effects of feeding, skin-to-skin care and infant positioning (161).
Formula feeding, non-nutritive sucking and sucrose were also found to be effective interventions if breastfeeding is not an option based on person-and family-centred care principles (162,212).
One study noted that non-nutritive sucking may be particularly beneficial for infants with latching difficulties or those who are unable to breastfeed (173).
# RECOMMENDATIONS
Vascular Access -Second Edition
# KEY INTERVENTION DETAILS FROM THE EVIDENCE
Acupressure/massage Three studies examined acupressure or massage therapy (216,220,222).
One study reported that "acupressure is a safe, inexpensive and easy-tolearn technique. Therefore, nurses can teach this technique to patients and involve them in their own treatment, and thereby enhance their self-confidence" (222).
However, it is important to note that health providers need additional training to perform acupressure.
The study that used this intervention noted that the acupressure intervention was implemented in two steps, with a 30-minute interval in between, and that it was performed by someone who had received the necessary acupressure training from an acupressure specialist (222).
Another study also noted that the researcher performing acupressure received certification prior to performing the intervention (220).
# Aromatherapy
One study demonstrated that aromatherapy using inhaled lavender essential oil for infants prior to heel lance reduced pain (197).
A systematic review demonstrated that inhaled maternal milk odor prior to heel lance was also effective in reducing pain in infants (167).
For aromatherapy interventions, health providers should be aware of any known allergies prior to administering the aromatherapy oils.
# Heat therapy
Two studies examined forms of heat therapy prior to heel lance or PVAD insertion in infants and children (176,218).
Electric heating pad: In one study of children aged 5-18 years, an electric heating pad (40°C) was applied at the site of the identified PVAD insertion for 10 minutes before PVAD insertion (218). The child was asked to inform the health provider if the heating device caused discomfort when applied to the chosen site (218).
In another study, infants in the experimental group received a heating pad ("thermophore") application for five minutes before a heel lance procedure (176). The warmth of the pad was kept between 34-37˚C. To prevent the heating pad from directly contacting the sole of the infant's foot, it was wrapped in a cloth and placed on the sole from which the heel lance would be taken (176).
Health providers should be aware of the potential for burns, irritation and skin discomfort when using heat therapy interventions.
# RECOMMENDATIONS
Vascular Access -Second Edition
# Supporting Resources
# RESOURCE DESCRIPTION
# Research Gaps and Future Implications
In reviewing the evidence for this BPG, the RNAO best practice guideline development and research team and expert panel identified priority areas for future research (outlined in Table 15). Studies conducted in these areas would provide further evidence to support high-quality and equitable support for persons with VAD. The list is not exhaustive; other areas of research may be required. Studies that explore blood draws from a VAD and their impact on device dwell time.
The impact of blood draws from a VAD versus blood draw from venipuncture on person and family values and preferences.
Qualitative studies examining the impact of blood draw technique on person and family experience (including a range of ages and cognitive needs).
Studies that explore blood draws from CVADs and their impact on infection and specimen integrity.
# RECOMMENDATION QUESTION #5:
Should the daily review of peripheral vascular access devices by health providers be recommended?
Outcomes: Complications.
Randomized controlled trials exploring the effectiveness of multi-component care protocols or daily PVAD reviews.
Long-term follow-up studies exploring the effect of PVAD care on rare complications.
Qualitative studies examining the role of PVAD care in person and family experience. Studies exploring pain management strategies for CVAD insertion and arterial catheter insertion.
Studies exploring the impact of routine use of topical anesthesia for PVAD insertion or venipuncture in adults.
Studies exploring person and family satisfaction and experience with pain management strategies (including people of various ages and cognitive needs).
Qualitative studies exploring pain management strategies for VAD insertion in adults and children.
# Applicable to all recommendation questions
Studies exploring the health equity implications of VAD insertion and management.
# RECOMMENDATIONS
Vascular Access -Second Edition
# Implementation Strategies
Implementing guidelines at the point of care is multi-faceted and challenging. It takes more than awareness and distribution of BPGs for practice to change must be adapted for each practice setting in a systematic and participatory way to ensure that recommendations fit the local context (223). The RNAO Leading Change Toolkit™ (2021), available online at provides evidence-informed processes for this (see Appendix Q).
The Leading Change Toolkit™ uses two complementary frameworks to guide evidence uptake and sustainability (see Figure 1). They can be used together to maximize and accelerate change.
# Figure 1: Leading Change Toolkit™ Two Complementary Frameworks to Accelerate your Success
The Social Movement Action Framework ( 224) is descriptive and identifies the defining elements of a social movement for knowledge (e.g., BPGs) uptake and sustainability. It integrates a 'bottom-up' , people-led approach to change for a shared concern (or common cause) in which change agents and change teams mobilize individual and collective action to achieve goals. The framework's elements, categorized as preconditions, key characteristics and outcomes, are dynamic, inter-related and develop spontaneously as the social movement evolves.
The Knowledge-to-Action Framework uses a process model of action cycle phases to systematically guide the adaptation of the new knowledge (e.g., BPG) to the local context and implementation. This framework suggests identifying and using knowledge tools/products, such as guidelines, to determine gaps and begin the process of tailoring the new knowledge to local settings.
# RECOMMENDATIONS
Vascular Access -Second Edition
The Leading Change Toolkit™ is based on emerging evidence in health and social sciences that successful uptake and sustainability of best practice in health care is more likely when:
BPGs are selected for implementation through a participatory process led by change agents and change teams;
The selected BPGs reflect priority areas for a shared concern that is credible, valued and meaningful, or an urgency for action;
Stakeholders are identified and engaged throughout implementation to engage in individual and collective action;
Receptivity for implementing BPGs, including environmental readiness, is assessed;
Implementation strategies are tailored to the local context and designed to address barriers;
Use of the BPG is monitored and sustained;
Evaluation of the BPG's impact is embedded in the process to determine if the goals and outcomes have been met;
There are adequate resources to complete all aspects of the uptake and sustainability of the BPG; and, The BPG is scaled up, out, or deep, where possible, to widen its influence and create lasting health improvements.
RNAO is committed to widespread deployment and implementation of our BPGs. We use a coordinated approach to dissemination, incorporating a variety of strategies, including the following:
- The Nursing Best Practice Champion Network®, which develops the capacity of individual nurses to foster awareness, engagement, and adoption of BPGs.
- The BPG Order Sets TM provide clear, concise and actionable intervention statements derived from practice recommendations. BPG Order Sets TM can be readily embedded within electronic records, but they can also be used in paper-based or hybrid environments.
- The BPSO® designation supports implementation at the organization and system levels. BPSOs focus on developing evidence-based cultures with the specific mandate to implement, evaluate and sustain multiple RNAO BPGs.
In addition, we offer annual capacity-building learning institutes on specific BPGs and their implementation.
Information about our implementation strategies can be found at:
RNAO
# R E F E R E N C E S
Vascular Access -Second Edition
# A P P E N D I C E S
Vascular Access -Second Edition Good practice statement: A good practice statement is directed primarily to nurses and the interprofessional teams who provide care to persons and their families across the spectrum of care, including (but not limited to): primary care, acute care, home care and long-term care. It refers to a practice already accepted as beneficial or to practical advice.
In the case of this BPG, the good practice statement is believed to be so beneficial that conducting a systematic review to prove its efficacy would be unreasonable. These statements are not based on a systematic review and do not receive a rating of the certainty or confidence in the evidence or strength (i.e., conditional or strong) (7).
# Grading of Recommendations Assessment, Development and Evaluation (GRADE):
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) is a methodological approach to assess the certainty of a body of evidence in a consistent and transparent way, and to develop recommendations in a systematic way. The body of evidence across identified important and/or critical outcomes is evaluated based on risk of bias, consistency of results, relevance of studies, precision of estimates, publication bias, large effect, dose-response and opposing confounding (8).
When using GRADE, five components contribute to the assessment of confidence in the evidence for each outcome. These components are as follows:
- Risk of bias, which focuses on the flaws in the design of a study or problems in its execution. 2. Inconsistency, which looks at a body of evidence and assesses whether the results point in the same direction, or if they are different. 3. Imprecision, which refers to the accuracy of results based on the number of participants and/or events included, and the width of the confidence intervals across a body of evidence. 4. Indirectness, whereby each primary study that supports an outcome is assessed and a decision is made regarding the applicability of the findings to the population, intervention and outcome outlined in the research question. 5. Publication bias, where a decision is made about whether the body of published literature for an outcome potentially includes only positive or statistically significant results (237).
Health provider: Refers to both regulated workers (e.g., nurses, physicians, and respiratory therapists) and unregulated workers (e.g., physician's assistants and paramedics) who are part of the interprofessional team.
# Regulated health provider:
In Ontario, the Regulated Health Professional Act, 1991 (RHPA) provides a framework for regulating 23 health professions, outlining the scope of practice and the profession-specific controlled or authorized acts that each regulated professional is authorized to perform when providing health services (5).
Unregulated health provider: These providers fulfill a variety of roles in areas that are not subject to the RHPA. They are accountable to their employers but not to an external regulating professional body (e.g., the College of Nurses of Ontario). Unregulated health providers fulfill a variety of roles and perform tasks that are determined by their employer and employment setting. Unregulated health providers only have the authority to perform a controlled act as set out in the RHPA if the procedure falls under one of the exemptions set out in the Act (6).
# A P P E N D I C E S
Vascular Access -Second Edition Health-service organization: In this BPG, health-service organization refers to any health setting or workplace in which persons and/or families receive care from a health provider related to a VAD. . Hemolysis: "Destruction of the membrane of the red blood cells, resulting in the liberation of hemoglobin, which diffuses into the surrounding fluid" (228) . Blood samples that are hemolyzed due to improper handling or drawing of blood samples cannot be processed. This is the leading cause of samples being rejected by clinical laboratories.
# Implanted vascular access device (IVAD):
Permanent catheters that are characterized by a subcutaneous reservoir with a diaphragm that acts as a receptacle for infusion. The reservoir is connected to a central vein in the chest with a catheter (229). Port-a-caths (single or double) and broviacs (single or double) are examples of IVADs.
Implementation science: Defined as "the scientific study of methods to promote the systematic uptake of research findings and other evidence-based practices into routine practice, and, hence, to improve the quality and effectiveness of health services and care" (page 1) (270).
Infiltration: "The inadvertent administration of medication or solution into the surrounding subcutaneous or subdermal tissue instead of into the intended vascular pathway" (238). This has been reported to be the most frequent complication that is associated with short PVADs, specifically when located in the hand (102).
Interprofessional team: team comprising multiple health providers (regulated and unregulated) who work collaboratively to deliver comprehensive and quality health services to people within, between and across health settings (4). Key interprofessional team members supporting persons with vascular devices may include: nurses, nurse practitioners, physicians, respiratory therapists, physician's assistants, paramedics and child life specialists. It is important to emphasize that persons with a VAD and their chosen family are at the centre as active participants of the team.
Meta-analysis: systematic review that uses statistical methods to analyze and summarize the results of the included studies (239).
# See systematic review
Multi-component care protocol: A group of evidence-based interventions that can ensure the delivery of a standardized method of care; when these interventions are performed together, they can have a better outcome than if performed individually (also sometimes called a "care bundle") (adapted from (100).
Nurse: "Refers to registered nurses, licensed practical nurses (referred to as registered practical nurses in Ontario), registered psychiatric nurses and nurses in advanced practice roles, such as nurse practitioners and clinical nurse specialists" (5).
# A P P E N D I C E S
Vascular Access -Second Edition Osmolarity: The number of osmotically active particles in a solution (228).
Outcomes: A dependent variable, or the clinical and/or functional status of a patient or population, that is used to assess if an intervention is successful. In GRADE, outcomes are prioritized based on if they are critical for decision making, important but not critical for decision making, or not important. In so doing, the literature search and systematic reviews are more focused (8).
# See Grading of Recommendations Assessment, Development and Evaluation (GRADE)
Peripherally inserted central catheter (PICC): "A catheter inserted through veins of the upper extremity or neck in adults and children. For infants, the PICC may be inserted through veins of the scalp or a lower extremity. The catheter tip is located in the superior or inferior vena cava, preferably at its junction with the right atrium, regardless of insertion site" (228).
Peripheral Vascular Access Device (PVAD): "VAD inserted in peripheral vein with its tip not extending into the central vasculature" (25).
Person: An individual with whom a health provider has established a therapeutic relationship for the purpose of partnering for health. Replaces the terms "patient, " "client, " and "resident, " which are used across healthservice organizations (235).
Person-and family-centred care: An "approach to care certain practices that put the person and their family members at the centre of health services. Person-and family-centred care respects and empowers individuals to be genuine partners with health providers for their health" (235).
Phlebitis: Redness, swelling, tenderness, pain, purulent discharge and/or induration (palpable cord) at the insertion site of a vascular device (240,241).
# PICO research question:
A framework to outline a focused question. It specifies four components: 1. The patient or population that is being studied.
- The intervention to be investigated.
- The alternative or comparison intervention. 4. The outcome that is of interest (8).
# Practical education:
For the purposes of this guideline, practical education refers to deliberate practice, supervised insertions of VADs, hands-on training or one-on-one training for health providers. Practical or skills lab training follows a structured teaching concept, takes place under supervision and in consideration of foundational concepts, and ideally creates an atmosphere that allows the repeated, risk-free practice of targeted clinical skills (50).
# A P P E N D I C E S
Vascular Access -Second Edition Quasi-experimental study: A study that estimates causal effects by observing the exposure of interest, but in which the experiments are not directly controlled by the researcher and lack randomization (e.g., before-andafter designs) (242).
Randomized controlled trial: An experiment in which the investigator assigns one or more interventions to participants who are randomly allocated to either the experimental group (receives intervention) and the comparison (conventional treatment) or control group (placebo or no intervention) (239).
Recommendation: A course of action(s) that directly answers a recommendation question (also known as a PICO research question). A recommendation is based on a systematic review of the literature and is made in consideration of its (a) benefit and harms, (b) values and preferences, and (c) health equity. All recommendations are given a strength-either strong or conditional-through panel consensus.
It is important to note that recommendations should not be viewed as dictates, because recommendations cannot take into account all of the unique features of individual, organizational and clinical circumstances (8).
# Recommendation question:
A priority research area of practice, policy or education identified by expert panel members that requires evidence to answer. The recommendation question may also aim to answer a topic area around which there is ambiguity or controversy. The recommendation question informs the research questions, which guides the systematic review (8).
Simulation (simulation learning): "Simulation is the imitation of some real thing, state of affairs or process.
In health professions education, simulation is a methodology to help achieve educational goals. Health-care simulation encompasses a range of activities that share a broad but common purpose: to improve the safety, effectiveness and efficiency of health-care services" (243). "Simulation activities can include computer-based simulation, e-learning, high-fidelity patient simulators, role playing and other blended approaches" (244).
Social movement in the context of knowledge uptake and sustainability: Individuals, groups and/or organizations who, as voluntary and intrinsically motivated change agents, mobilize to transform health outcomes (266).
Stakeholder: "An individual, group or organization that has a vested interest in the decisions and actions of organizations, and which may attempt to influence decisions and actions" (245). Stakeholders include all of the individuals and groups that will be directly or indirectly affected by the change or solution to the problem.
# Successful Observed Attempt (or Successful VAD insertion attempt):
A PVAD insertion attempt is deemed to be successful if there is evidence of blood flashback in the catheter upon insertion, and if the device flushes easily with no signs of infiltration, swelling or leakage upon flushing (adapted from ( 126), (127), and ( 128)).
Note: If ultrasound-guidance technique is used, it should be evident on ultrasound that the catheter is positioned properly in the vein. A CVAD insertion attempt should be confirmed with x-ray.
# A P P E N D I C E S
Vascular Access -Second Edition Systematic review: A comprehensive review of the literature that uses clearly formulated questions and systematic and explicit methods to identify, select and critically appraise relevant research. A systematic review collects and analyzes data from the included studies and presents them, sometimes using statistical methods (239).
# See meta-analysis
Ultrasound-guided Technique: Ultrasound imaging (an image created by sending sound waves through soft tissue) allows health providers to see surrounding anatomical structures (119). It can be used to aid the health provider when inserting a PVAD, CVAD or peripheral arterial catheter. Ultrasound guidance allows visualization of both the needle and the target vessel on the monitor, using either the short-axis or long-axis view (123).
Valsalva maneuver: A breathing technique that can be used as a pain management strategy during VAD insertion. It involves "a deep inhale, followed by a forceful holding of the breath, during which the venous cannulation insertion occurs" (143).
# Vascular access device (VAD):
Vascular access devices (VADs) are defined as a catheter (thin tube) inserted into veins that can be implanted or inserted under the skin, allowing fluids and medicines to be delivered into veins (adapted from ( 3)). Catheters inserted into arteries can be used to monitor therapy (adapted from ( 3)).
# Examples of VADs include:
peripheral vascular access devices (PVADs), such as short peripheral intravenous catheters (PIVs) and extended dwell, midline catheters;
central vascular access devices (CVADs), such as peripherally inserted central catheters (PICCs), tunneled catheters, non-tunneled catheters and implanted vascular access devices (IVADs); peripheral arterial catheters; and phlebotomy devices.
# Vascular access specialist team (VAST) or vascular access specialists (VAS)\
; "A grouping of health providers who have advanced knowledge and skills in the assessment, insertion, care and management of VADs" (3). This includes infusion/intravenous, intravenous therapy teams and individual vascular access specialists (nurses, physicians, respiratory therapists, laboratory technicians and physician assistants) (3).
Venipuncture: "A procedure in which a needle is used to take blood from a vein, usually for laboratory testing. Also called blood draw and phlebotomy" (246).
Vesicant: "An agent capable of causing tissue damage when it escapes from the intended vascular pathway into surrounding tissue" (228). Tissue damage can cause injury, blistering, necrosis and redness of the skin.
# A P P E N D I C E S
Vascular Access -Second Edition *Note: An updated edition of the infusion therapy standards of practice published in early 2021, and this updated version was used as a supporting resource in this BPG, and to inform the good practice statement, glossary and appendices where applicable.
Canadian Vascular Access Association. Canadian vascular access and infusion therapy guidelines. Pembroke (ON): Pappin Communications; 2019.
Score: 5 out of 7.
This guideline was used as a supporting resource in this BPG, and to inform the background, good practice statement, glossary and appendices.
Telephone key informant interviews. Eleven interviews were conducted with experts in the field-including direct care health providers, researchers, educators and managers-to understand the needs of nurses, members of the interprofessional health team and persons with lived experience.
- Telephone discussion group sessions. Three sessions were convened to understand the needs of nurses, members of the interprofessional health team and persons with lived experience.
# Assembly of the Expert Panel
RNAO aims for diversity in membership of an expert panel; this is in alignment with its Organizational Statement on Diversity and Inclusivity, which is part of the RNAO Mission and Values (248).
RNAO identifies and selects members of an expert panel through numerous different avenues. This includes the following:
searching the literature for researchers in the topic area;
soliciting recommendations from key informant interviews;
drawing from established professional networks, such as RNAO Interest Groups, the Nursing Best Practice Champions Network® and BPSOs®; and
drawing from other nursing and health provider associations, topic-relevant technical associations or organizations, and advocacy bodies.
For this BPG, the RNAO best practice guideline development and research team assembled a panel of experts from nursing practice, research and education, as well as other members of the interprofessional team, to represent a range of sectors and practice areas (see members of the RNAO Best Practice Guideline Expert Panel on page 24).
The expert panel engaged in the following activities:
approved the purpose and scope of this BPG, determined the recommendation questions and outcomes to be addressed in this BPG, participated in a consensus G development process to finalize recommendation statements, provided feedback on the drafts of this BPG, participated in the development of evaluation indicators, helped develop BPG Order Sets™, and identified appropriate stakeholders to review the draft guideline prior to publication.
# A P P E N D I C E S
Vascular Access -Second Edition
In addition to the above, the expert panel co-chairs engaged in the following activities:
participated in monthly meetings with the guideline development methodologists and guideline development project coordinator, facilitated expert panel meetings, provided in-depth guidance on clinical and/or research issues, and moderated voting processes. | These guidelines are not binding for nurses, other health providers or the organizations that employ them. The use of these guidelines should be flexible and based on individual needs and local circumstances. They constitute neither a liability nor discharge from liability. While every effort has been made to ensure the accuracy of the contents at the time of publication, neither the authors nor the Registered Nurses' Association of Ontario (RNAO) gives any guarantee as to the accuracy of the information contained in them or accepts any liability with respect to loss, damage, injury or expense arising from any such errors or omission in the contents of this work.With the exception of those portions of this document for which a specific prohibition or limitation against copying appears, the balance of this document may be produced, reproduced and published in its entirety, without modification, in any form, including in electronic form, for educational or non-commercial purposes. Should any adaptation of the material be required for any reason, written permission must be obtained from RNAO. Appropriate credit or citation must appear on all copied materials as follows: Registered Nurses' Association of Ontario (RNAO). Vascular access. 2nd ed. Toronto (ON): RNAO; 2021.This work is funded by the Government of Ontario. All work produced by RNAO is editorially independent from its funding source.In the context of RNAO best practice guideline development, the term "conflict of interest" (COI) refers to situations in which a RNAO staff member or expert panel member's financial, professional, intellectual, personal, organizational or other relationships may compromise their ability to conduct panel work independently. Declarations of COI that might be construed as constituting a perceived and/or actual conflict were made by all members of the expert panel prior to their participation in guideline development work using a standard form. Expert panel members also updated their COI at the beginning of each expert panel meeting. Any COI declared by an expert panel member was reviewed by the RNAO Best Practice Guideline Development and Research Team and expert panel co-chairs. No limiting conflicts were identified. See "Declarations of Conflicts of Interest Summary" at https://RNAO.ca/bpg/ guidelines/vascular-access-second-edition.# Vascular Access
# Second Edition
Vascular Access -Second Edition
# Greetings from Doris Grinspun, Chief Executive Officer, Registered Nurses' Association of Ontario
The Registered Nurses' Association of Ontario (RNAO) is delighted to present the second edition of the clinical best practice guideline (BPG) Vascular Access, Second Edition. Evidence-based practice supports the excellence in service that health providers are committed to delivering every day.
We offer our heartfelt thanks to the many stakeholders who make our vision for BPGs a reality. First, and most important, we thank the Government of Ontario that recognized in 1999 RNAO's capacity to lead a program that has gained worldwide recognition and is committed to funding it. We also thank the co-chairs of the RNAO expert panel, Nancy Moureau, RN, PhD (chief executive officer, PICC Excellence) and Darlene Murray, RN, MSN (interprofessional education specialist, The Hospital for Sick Children), for their invaluable expertise and stewardship of this BPG. Thanks to RNAO staff Amy Burt (guideline development lead), Christine Buchanan (guideline development methodologist), Verity Scott (guideline development project coordinator), Glynis Gittens (guideline development project coordinator), Nafsin Nizum (senior manager, guideline development and research) and the rest of the RNAO best practice guideline development and research team for their intense and expert work in the production of this BPG. Special thanks to the expert panel for generously providing their time, knowledge and perspectives, especially during these challenging times of the COVID-19 pandemic, to deliver a rigorous and robust evidence-based resource that will guide the education and practice of health providers. We couldn't have done it without you! Successful uptake of BPGs requires a concerted effort from educators, clinicians, employers, policy-makers, researchers and funders. The nursing and health communities, with their unwavering commitment and passion for excellence in patient care, provide the expertise and countless hours of volunteer work essential to the development of new and next edition BPGs. Employers have responded enthusiastically by becoming Best Practice Spotlight Organizations (BPSO ® ) -with over a 1,000 service and academic institutions in Canada and abroad. BPSO® have sponsored best practice champions, implemented BPGs, and evaluated their impact on patient and organizational outcomes. Governments at home and abroad have also joined in this awesome journey. Together, we are building a culture of evidence-based practice that benefits everyone.
We invite you to share this BPG with your colleagues from nursing and other professions, with the patient advisors who are partnering within organizations, and with the government agencies with which you work. We have so much to learn from one another. Together, we must ensure that the public receives the best possible care every time they come in contact with us-making them the real winners of this great effort!
# Table of Contents
Vascular Access -Second Edition
# Table of Contents
Vascular Access -Second Edition
# How to Use This Document
This best practice guideline G * (BPG) is a comprehensive document that provides guidance and resources for evidence-based nursing practice G . It is not intended to be a manual or "how-to" guide; rather, it is a tool to guide best practices and enhance decision making for nurses G , the interprofessional team G , educators, health-service organizations G , academic institutions, and persons G and their families G or caregivers G This BPG should be reviewed and applied in accordance with the needs of individual health-service organizations, academic institutions or other practice settings, and with the preferences of persons with a vascular access device G (VAD). This document provides evidence-based recommendation G statements and descriptions of: (a) practice, education and organizational policy; (b) benefits and harms; (c) values and preferences; and (d) health equity considerations.
Nurses, other members of the interprofessional team, educators and administrators who lead and facilitate practice changes will find this document invaluable for developing policies, procedures, protocols and educational programs to support service delivery. Nurses and other members of the interprofessional team in direct care will benefit from reviewing the recommendations and supporting evidence.
The RNAO convened an expert panel to determine the scope of the second edition of this BPG and to develop recommendation questions G to inform the systematic reviews G . The expert panel was interprofessional in composition. It was composed of individuals with knowledge and experience in clinical practice, education, research and policy across a range of health-service organizations, academic institutions, practice areas and sectors. These experts shared their insights on supporting and caring for persons with a VAD across the continuum of care (see page 24 for the list of RNAO best practice guideline expert panel members).
A comprehensive review and analysis was completed by the RNAO best practice guideline development and research team and the expert panel to determine the scope and priority recommendation questions for this BPG (see Appendix C).
# Scope
To determine the scope of this BPG, the RNAO best practice guideline development and research team conducted the following steps:
reviewed the previously published RNAO BPGs: Care and Maintenance to Reduce Vascular Access Complications (1) and Assessment and Device Selection for Vascular Access (2);
conducted an environmental scan of existing guidelines;
led 11 telephone key informant interviews with health providers G , administrators, educators and researchers;
held three telephone discussion groups with nursing students, health providers, managers, administrators and educators; and
consulted with the expert panel.
As with all procedures, health providers must be aware of scope of practice and follow regulatory body guidelines. Health providers should only be caring for or inserting VADs for which they have the necessary knowledge, skill and judgement. Health providers should also follow organizational policies and procedures related to VAD insertion and maintenance. This BPG addresses recommendations requiring advanced skill.
# CAUTION BAC K G R O U N D
Vascular Access -Second Edition Recommendation Question #6: Should the use of visualization technologies (e.g., ultrasound and vein finders) for the insertion of peripheral vascular access devices be recommended?
Outcomes: Success rate on the first attempt/number of failed attempts, patient satisfaction and complications.
Recommendation Question #7: Should pain management strategies (including pharmacological and nonpharmacological strategies) during the insertion of a vascular access device be recommended?
Outcomes: Patient's rating of pain, patient comfort, fear/anxiety (related to poke/needle phobia) and patient satisfaction.
Note: These priority recommendation questions are condensed versions of the more comprehensive PICO research questions developed by the expert panel to guide the systematic reviews and development of this BPG. For the PICO research questions and the detailed process of how the expert panel determined the priority recommendation questions and outcomes, see Appendix C.
# Good Practice Statement and Recommendations
The recommendations and resources in this BPG address topics such as the insertion, assessment, maintenance and management of VADs. Specifically, the guideline focuses on the following areas:
person and family education about VADs;
specialized training requirements for health providers;
daily review of PVADs;
the use of visualization technologies to insert PVADs and peripheral arterial catheters;
the use of VADs for obtaining blood samples; and
pain management strategies during the insertion of a VAD.
The evidence-based recommendations in this BPG are applicable to all practice settings where persons with a VAD are accessing services (e.g., acute care, long-term care, rehabilitation, primary care and community settings).
In this BPG, no recommendation questions were identified that addressed the need for conducting an assessment of persons prior to initiating vascular access. Please refer to the good practice statement on assessment that nurses and other members of the interprofessional team can use in their practice. The good practice statement is believed to be so beneficial that conducting a systematic review to prove its efficacy would be unreasonable. The resulting statement is not based on a systematic review, and it does not receive a rating of the certainty or confidence in the evidence or strength (i.e., a rating of conditional or strong) (7).
# RNAO BPGs and Other Resources That Align with This BPG
Other RNAO BPGs and evidence-based resources may support implementation of this BPG. See Appendix B for RNAO BPGs and other evidence-based resources on the following related topics:
client-centred learning;
pain management;
strategies to support self-management in chronic conditions;
implementation science, implementation frameworks and resources;
interprofessional collaboration; and
person-and family-centred care G .
# BAC K G R O U N D
Vascular Access -Second Edition
# Interpretation of Evidence and Recommendation Statements
RNAO BPGs are developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) G methods. For more information about the guideline development process, including the use of GRADE methods, refer to Appendix C.
# Certainty of Evidence
The certainty of evidence (i.e., the level of confidence we have that an estimate of effect is true) for quantitative research is determined using GRADE methods (8). After synthesizing the evidence for each prioritized outcome, the certainty of evidence is assessed. The overall certainty of evidence is determined by considering the certainty of evidence across all prioritized outcomes per recommendation. GRADE categorizes the overall certainty of evidence as high, moderate, low or very low (see Table 1 for the definition of these categories).
# Table 1: Certainty of Evidence
# CERTAINTY OF EVIDENCE DEFINITION High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
# Very Low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Source: Reprinted from: The GRADE Working Group. Quality of evidence. In: Schunemann H, Brozek J, Guyatt G, et al., editors. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach [Internet]. [place unknown: publisher unknown]; 2013 [cited 2018 Aug 31]. Table 5.1, Quality of evidence grades. Available from: https://gdt.gradepro.org/app/handbook/handbook.html#h.wsfivfhuxv4r. Reprinted with permission.
# Note:
The assigned certainty of evidence can be found directly below each recommendation statement. For more information on the process of determining the certainty of the evidence and the documented decisions made by RNAO guideline development methodologists, please see Appendix C.
# BAC K G R O U N D
Vascular Access -Second Edition
# Strength of Recommendations
Recommendations are formulated as strong or conditional by considering the certainty of evidence and the following key criteria (see Discussion of Evidence, below, for definitions):
balance of benefits and harms, values and preferences, and health equity.
According to Schunemann et al., "a strong recommendation reflects the expert panel's confidence that the desirable effects of an intervention outweigh its undesirable effects (strong recommendation for an intervention) or that the undesirable effects of an intervention outweigh its desirable effects (strong recommendation against an intervention)" (8). In contrast, "a conditional recommendation reflects the expert panel's confidence that the desirable effects probably outweigh the undesirable effects (conditional recommendation for an intervention) or undesirable effects probably outweigh desirable effects (conditional recommendation against an intervention), but some uncertainty exists" (8). Table 2 outlines the implications of strong and conditional recommendations. There is little variability in values and preferences among persons in this situation.
There is a need to consider the person's circumstances, preferences and values.
The benefits of a recommended course of action probably outweigh the harms. Therefore, some persons could receive the recommended course of action.
There is greater variability in values and preferences, or there is uncertainty about typical values and preferences among persons in this situation.
There is a need to consider the person's circumstances, preferences and values more carefully than usual.
# For persons receiving care
Most persons would want the recommended course of action, and a small portion would not.
The majority of persons in this situation would want the suggested course of action, but many would not.
For policy-makers The recommendation can be adapted as policy in most situations Policy-making will require substantial debate and involvement of many stakeholders. Policies are also more likely to vary between regions.
Source: Adapted from: The GRADE Working Group. Quality of evidence. In: Schunemann H, Brozek J, Guyatt G, et al., editors. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach [Internet]. [place unknown: publisher unknown]; 2013 [cited 2020 May 11]. Table 6.1, Implications of strong and weak recommendations for different users of guidelines. Available from: https://gdt.gradepro.org/app/handbook/ handbook.html#h.wsfivfhuxv4r
# BAC K G R O U N D
Vascular Access -Second Edition Note: The strength of each recommendation statement is detailed directly below it and in the Summary of Recommendations (page 13). For more information on the process used by the expert panel to determine the strength of each recommendation, please see Appendix C.
# Discussion of Evidence
The Discussion of Evidence that follows each recommendation includes the following main sections:
1. Benefits and Harms: Identifies the potential desirable and undesirable outcomes reported in the literature when the recommended practice is used. Content in this section solely includes research from the systematic review.
# Values and Preferences:
Denotes the relative importance or worth placed on health outcomes derived from following a particular clinical action from a person-centered perspective. Content for this section may include research from the systematic reviews and, when applicable, observations and/or considerations from the expert panel.
# Health Equity:
Identifies the potential impact that the recommended practice could have on health across different populations or settings and/or the barriers to implementing the recommended practice in particular settings. This section may include research from the systematic reviews and, when applicable, observations and/ or considerations from the expert panel.
# Expert Panel Justification of Recommendation:
Provides a rationale for why the expert panel made the decision to rate a recommendation as strong or conditional.
# 5.
Practice Notes: Highlights pragmatic information for nurses and other members of the interprofessional team. This section may include supporting evidence from the systematic review and/or from other sources (e.g., the expert panel).
Supporting Resources: Includes a list of relevant resources (e.g., websites, books and organizations) that support the recommendations. Content listed in this section was assessed based on five criteria: relevancy, credibility, quality, accessibility and timeliness of publication (i.e., published within the last 10 years). Further details about this process and the five criteria are outlined in Appendix C. The list is not exhaustive and the inclusion of a resource in one of these lists does not imply an endorsement from RNAO. Some recommendations may not have any identified supporting resources. Note: all supporting resources are freely available or open access unless otherwise noted.
# BAC K G R O U N D
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# Summary of Recommendations
# GOOD PRACTICE STATEMENT
The expert panel recommends health providers complete a systematic assessment of the person prior to inserting a vascular access device .
As a good practice, this statement does not require application of the GRADE system . For more information on the good practice statement in this BPG, please see page 37 .
# RECOMMENDATIONS STRENGTH OF THE RECOMMENDATION Recommendation Question #1:
Should providing education to persons and their families about their vascular access device be recommended?
Outcomes: Hospital re-admission rate and complications .
# Recommendation 1.1:
The expert panel recommends that health providers provide comprehensive health teaching to persons and their families/caregivers about their vascular access device .
# Strong
Recommendation Question #2:
Should practical education for the insertion and management of vascular access devices for health providers be recommended?
Outcomes: Complications (including insertion-related complications), number of successful observed attempts and provider attitude/confidence .
# Recommendation 2.1:
The expert panel recommends health-service organizations implement practical education on the insertion and/or management of vascular access devices for health providers .
# Strong
Recommendation Question #3:
Should vascular access specialist teams be recommended?
Outcomes: Complications (including insertion-related complications) and number of successful observed attempts .
# Recommendation 3.1:
The expert panel suggests that acute care health-service organizations implement vascular access specialists or vascular access specialist teams to support the insertion and management of vascular access devices .
# Conditional BAC K G R O U N D
Vascular Access -Second Edition
# Recommendation Question #4:
Should blood draws from a vascular access device versus blood draws from venipuncture be recommended?
Outcomes: Specimen rejection, patient satisfaction, contamination rate (specific to blood cultures) and dwell time .
# Recommendation 4.1:
The expert panel suggests health providers perform venipuncture when drawing blood samples to maintain specimen integrity .
# Conditional
Recommendation Question #5:
Should the daily review of peripheral vascular access devices by health providers be recommended?
Outcomes: Complications .
# Recommendation 5.1:
The expert panel recommends that acute care health-service organizations implement a multi-component peripheral vascular access device care protocol . This protocol includes a minimum of a daily review by health providers, in collaboration with persons and their families .
# Strong
Recommendation Question #6:
Should the use of visualization technologies (e .g ., ultrasound and vein finders) for the insertion of peripheral vascular access devices be recommended?
Outcomes: Success rate on the first attempt/number of failed attempts, patient satisfaction and complications .
# Recommendation 6.1:
The expert panel recommends that health providers use ultrasound-guided technique for the insertion of peripheral arterial catheters .
# Strong
# Recommendation 6.2:
The expert panel suggests that health providers use ultrasound-guided technique for the insertion of peripheral vascular access devices in persons with difficult intravenous access .
# Conditional BAC K G R O U N D
Vascular Access -Second Edition Recommendation Question #7:
Should pain management strategies (including pharmacological and non-pharmacological strategies) during the insertion of a vascular access device be recommended?
Outcomes: Patient's rating of pain, patient comfort, fear/anxiety (related to poke/needle phobia) and patient satisfaction .
# Recommendation 7.1:
The expert panel recommends that health providers offer adults nonpharmacological and pharmacological pain management strategies during the insertion of a vascular access device .
# Strong
# Recommendation 7.2:
The expert panel recommends that health providers offer non-pharmacological and pharmacological pain management strategies during the insertion of a vascular access device to infants and children, tailored to their age and developmental stage .
Strong BAC K G R O U N D Vascular Access -Second Edition
# Best Practice Guideline Evaluation
As you implement the recommendations in this BPG, we ask you to consider how you will monitor and evaluate its implementation and impact.
The Donabedian model, which informs the development of indicators for evaluating quality health care, includes three categories: structure, process and outcome (9).
Structure describes the required attributes of the health system or health-service organization to ensure quality care. It includes physical resources, human resources, and information and financial resources.
Process examines the health-care activities being provided to, for and with persons or populations as part of the provision of quality care.
Outcome analyzes the effect of quality care on the health status of persons and populations, health workforce, health-service organizations or health systems (9).
For additional information, please refer to the RNAO, in partnership with Healthcare Excellence Canada (HEC), Leading Change Toolkit™ (10).
The following indicators have been developed to support evaluation and quality improvement. Consider Tables 3, 4 and 5, which provide a list of structure, process and outcome indicators to assess the impact of BPG implementation and are derived from BPG recommendations. Each table also identifies if the indicator aligns with other indicators in local, provincial, national and/or international data repositories and/or instruments. Alignment with data repositories/instruments is determined by comparing the following criteria with the developed indicators: the operational definition; if the indicator is nursing sensitive; and the inclusion/exclusion criteria. Depending upon the level of alignment, an indicator may be described to have full, partial or no alignment with external data repositories/ instruments.
The following indicators will support quality improvement and evaluation. Select the indicators most relevant to the changes being made in practice, education and/or policy based on BPG recommendations that are prioritized for implementation.
# BAC K G R O U N D
Vascular Access -Second Edition Table 3 provides structure indicators associated with specific recommendation statements that are related to human resources, educational recommendations and/or other organizational factors.
BAC K G R O U N D Vascular Access -Second Edition
Table 5 provides outcome indicators to assess the impact of implementing evidence-based practice changes.
# Stakeholder Acknowledgment
As a component of the guideline development process, feedback was obtained from participants across a wide range of health-service organizations, academic institutions, practice areas and sectors. Participants include nurses and other members of the interprofessional team, educators, students, individuals with lived experience and knowledgeable administrators. Stakeholders G representing diverse perspectives were also solicited for their feedback (see Appendix C). RNAO wishes to acknowledge the following individuals for their contribution in reviewing this BPG.
# BAC K G R O U N D
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# Background Context Vascular Access and Vascular Access Devices
Vascular access is the most common invasive procedure undergone by persons in the health system (12). Vascular access devices (VADs) are catheters inserted into central or peripheral veins or arteries that can be implanted or inserted under the skin (3). Catheters inserted into veins can be used to deliver fluids and medicines directly into the bloodstream of a person (3). Catheters inserted into arteries can be used to monitor therapy and patient status (i.e., hemodynamics) (3). There are different types of VADs that are used depending on the person's need. This includes devices such as:
peripheral vascular access devices (PVADs), such as short peripheral intravenous catheters (PIVs) and extended dwell, midline catheters;
central vascular access devices (CVADs), such as peripherally inserted central catheters (PICCs), tunneled catheters, non-tunneled catheters and implanted vascular access devices (IVADs); peripheral arterial catheters; and phlebotomy devices.
Appendix F provides an overview of the VADs listed above.
In the simplest sense, a VAD consists of a hub, a hollow tube divided into one or multiple sections (lumens) and a tip that may terminate within a peripheral or central blood vessel (13). VADs can be classified differently based on the insertion site and location of the device (13). PVADs remain in the periphery, with the terminal tip below the level of the axillary vein for upper extremity placement (14). CVADs are inserted with the terminal tip entering central circulation and advancing towards the heart. Except for haemodialysis catheters, terminal tip placement of all CVADs is in the vena cava (14).
Infusion therapy using VADs has historically been delivered in a hospital setting. However, infusion therapy and use of VADs increasingly is expanding into alternative health settings, including community care, infusion clinics and self-administration in the home (15). With wider use of VADs and a changing health landscape, it is important to recognize and support nurses, other members of the interprofessional team, and persons with vascular devices and their families with the administration of therapies involving VADs (15).
# Complications
Reliable vascular access is fundamental for safe and effective care (13). Ensuring safe insertion and management of VADs should be a priority for all health providers. Despite their important role, VADs are often the source of hospital-acquired infections and other types of complications G (13). In the United States, approximately 250,000 catheter-related blood stream infections occur each year, with an associated increase in length of stay and hospital costs (16).
Central line-associated blood stream infections (CLABSI) G are associated with particularly high morbidity and mortality: mortality is estimated to be between 4% and 20% (17). One CLABSI case prolongs hospitalization by an average of seven days and costs an estimated $3,700 USD to $29,000 USD (17). Other complications that can occur during the insertion or management of CVADs include catheter occlusion, catheter breakage/leakage, bleeding,
BAC K G R O U N D
Vascular Access -Second Edition thrombosis or thrombo-embolism, perforation of vessels, pneumothorax, cardiac arrhythmias, air embolisms and central venous stenosis (12). Safe vascular access and management is integral to ensure low risk and better outcomes for persons receiving care: care bundles or multi-component care protocols G have been widely used to address these complications in CVADs.
Common complications associated with PVADs include phlebitis G , infiltration G and extravasation G (18). Phlebitis is the most common complication of PVADs, occurring when there is acute inflammation of a vein in the presence of intravenous therapy (19). Infiltration occurs when infusing fluids leak into the surrounding tissue, caused by dislodgment of the VAD catheter, improper placement or damage to the vessel (18). Finally, extravasation occurs when there is infiltration of a vesicant G medication or other agent that can cause tissue damage, pain, inflammation, irritation, blistering or necrosis (18).
# Holistic and Person-and Family-centred Care
Person-and family-centred care means that the health provider is attentive to the emotional needs of the person with a VAD and their family or caregiver(s) (15). The nurse and other members of the interprofessional team play a large role in delivering care that is holistic and person-and family-centered. The selection, insertion and management of VADs by health providers have important implications for the person receiving care and their family. A person's preferences of VADs are unique and will depend on their diagnosis and intended treatment (12), their reasons for requiring a VAD, their health care context and their prior experience. As such, a person's preferences regarding infusion therapy may differ from those of health providers (15).
It is important to consider a variety of factors when choosing which VAD is most appropriate for a person. This consideration should be based on their condition as well as principles of person-and family-centred care. The use of only one device may not meet the vascular access needs of the person, necessitating the use of several devices throughout therapy (20). Considerations about preserving and minimizing vessel trauma, such as protocols that limit the number of VAD insertion attempts by a health provider, are also important (20).
VAD considerations are also likely to change across a person's lifespan. PVAD insertion can be more difficult in children due to their thin blood vessels, the deepness of the vessels, the cooperation level of the child (21), and because young children such as infants and toddlers have more subcutaneous tissue than older children and adults (22). Additionally, the type and frequency of complications in pediatric populations may differ from adults. These complications may be influenced by the smaller vessel size inherent in children and the length of therapy, and they most commonly include occlusion, migration, thrombosis and infection of CVADs (20).
Establishing and maintaining vascular access in older adults can also be challenging (23). Aging causes changes to the skin, vein walls and circulation; the skin loses tone and elasticity, and it becomes more fragile and prone to bruising (23). This can create problems when trying to establish VADs. In addition, older adults are more likely to have comorbidities and a weakened immune system, putting them at greater risk for infection (23). Finally, certain populations may require increased considerations when choosing and maintaining VADs. Some conditions associated with difficult intravenous access G (DiVA) include obesity, chronic illness, hypovolemia, substance use and vasculopathy (24).
# BAC K G R O U N D
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# Vascular Access Specialization
A vascular access specialist team (VAST) G refers to a grouping of health providers who have advanced knowledge and skills in the assessment, insertion, care and management of VADs, such as intravenous therapy teams and individual vascular access specialists (VAS) G (nurses, physicians, respiratory therapists, technicians and physician assistants) (3). Some organizations may implement VASTs or VAS to assist the interprofessional team in caring for persons with VADs. It is important that both nurses and the other members of the interprofessional team have the critical thinking skills to perform comprehensive vascular access assessments, and that they collaborate on necessary comprehensive assessments related to appropriate VAD selection. This includes prescribed therapy, person preference, language barriers and other variables (1). These specialist health providers or individual health providers can also be leaders of excellence and quality of care in vascular access within an organization (25).
# Conclusion
There is a need for up-to-date evidence to guide health provider practices regarding safe vascular access. This guideline aims to provide nurses (e.g., nurse practitioners, registered nurses, registered practical nurses and nursing students) and other members of the interprofessional team with evidence-based recommendations and resources related to the insertion, assessment and maintenance of VADs across the lifespan of individuals.
# Guiding Framework and Principles
# Guiding Frameworks
Acquisition of training and skills for VAD insertions and management is necessary to establish and maintain competence and ensure the safety of the person with a VAD. The supervisor or trainer is responsible for identifying the level of clinical competence of the learner as they guide them to higher levels of competence. Global rating scales are a helpful tool to document competence for certain procedures (such as ultrasound-guided peripheral catheter insertions). These scales are used as formal evaluation instruments to determine competence and may be used for annual assessment of competence (26). Benner's Stages of Clinical Competence may also be used to assess the learner or for education planning purposes. Benner (27) notes that health providers, specifically nurses, can advance through five levels of clinical competence during the acquisition and development of a new skill: novice, advanced beginner, competent, proficient and expert. This framework is foundational for recommendations and research questions on health provider education.
# Guiding Principles
The following principles provide fundamental prerequisite knowledge for each of the recommendations included in this BPG. It is expected that the recommendations are applied within the context of these guiding principles. It is recommended that nurses and other health providers receive adequate education and training with respect to these principles and apply them in their clinical practice.
# BAC K G R O U N D
Vascular Access -Second Edition
# Routine Practices and Additional Precautions
Routine practices and additional precautions are the expected processes and practices of care to be used in all health settings. Microorganisms have been transmitted from both symptomatic and asymptomatic people, so routine practices are expected in the care of all persons, at all times, across the continuum of care (28). Routine practices include the following:
point-of-care risk assessment;
hand hygiene;
source control (triage, early diagnosis and treatment, respiratory hygiene and spatial separation);
patient placement, accommodation and flow;
aseptic technique (e.g., Aseptic Non Touch Technique® G [ANTT®]) (29);
use of personal protective equipment (PPE);
sharps safety and prevention of blood-borne pathogen transmission;
management of the patient care environment (including cleaning and handling of waste and linen);
education of patients, families and visitors on infection prevention and control; and visitor management (28).
Similarly, as stated by Infection Prevention and Control (IPAC) Canada, health providers require IPAC core competencies (30). These competencies include, but are not limited to:
an understanding of point-of-care risk assessment;
an understanding that routine infection prevention and control practices are the key to preventing transmission of organisms among health-care providers, persons and visitors/family members;
an understanding and demonstrated use of appropriate PPE; and
an understanding of how to prevent and manage occupational exposures to sharps and blood/bodily fluids in an appropriate way (30).
For a full list of infection prevention and control competencies, please refer to IPAC Canada guidelines and standards available at https://ipac-canada.org/evidence-based-guidelines.php (30).
Additional precautions should be used for patients with suspected or known infections or colonization G with microorganisms (28). Additional precautions are conventionally divided into the following categories (28):
Contact precautions for microorganisms of very low infective dose or situations where heavy contamination G of the person's environment is anticipated.
Droplet precautions for microorganisms primarily transmitted by the large droplet route.
Airborne precautions for microorganisms transmitted through the air over extended time and distance by small particles.
# Hand Hygiene
Hand hygiene is a comprehensive term that refers to handwashing, hand antisepsis and actions taken to maintain healthy hands and fingernails (31).
Hand hygiene plays a central role in infection prevention and control, especially in relation to hospital-acquired infections.
Public Health Ontario defines four key moments for hygiene (32). It recommends that health workers clean their hands at the following times:
1. Before initial contact with patient environment.
2. Before an aseptic procedure.
3. After body fluid exposure.
4. After patient/patient environment contact (32).
For details on supporting evidence, techniques (including choice of hand hygiene product) and other considerations, see the guidelines on hand hygiene from the World Health Organization (WHO) or PHAC (31)(32)(33), or the Canadian Vascular Access Association (CVAA) guideline for hand hygiene related to vascular access (25). Appendix M also provides further resources and details on infection control specifically for CVAD care.
# Aseptic Technique
Aseptic technique is the purposeful prevention of the transfer of microorganisms from the patient's body surface to a normally sterile body site, or from one person to another, by keeping the microbe count to an irreducible minimum (28). Aseptic techniques are used when performing procedures that expose the patient's normally sterile sites, such as the intravascular system, to keep them free from microorganisms.
One approach to standardizing aseptic practices is ANTT®. ANTT has been shown to support the reduction of health care-acquired infection (29,34). Given the high potential for patient harm from poorly applied aseptic technique, assurance that all staff are compliant with safe aseptic technique for all clinical procedures should be a priority for all health-care organizations (34).
# Use of Personal Protective Equipment
PPE is part of routine practices and additional precautions, and it is required to prevent exposure of infectious or harmful agents to patients, health-care workers and other staff (28). PPE may include gloves, gowns, masks and facial protection (face shields or eye protection) (28).
# Sharps Safety
VADs pose a risk to health providers through needlestick injuries and potential exposure to blood-borne pathogens (35). The United States Centers for Disease Control and Prevention (US CDC) estimates that 385,000 needlestick and other sharps-related injuries are sustained by hospital-based health workers each year (35). To prevent these injuries, PHAC recommends the following (28):
Safety engineered devices or needle-free systems be used wherever possible.
Needles should not be recapped. Used items should be placed immediately in a designated puncture-resistant container that is easily accessible at the point-of-care.
# BAC K G R O U N D
Vascular Access -Second Edition Health providers should cover open skin areas or lesions on hands and arms with a dry dressing at all times. Hand hygiene is still essential, so consultation is necessary if the dressing interferes with this procedure.
Eyes, nose and mouth should be protected if splashes with blood or body fluids are anticipated.
Immediately perform first aid if someone has been exposed to blood or body fluids. First aid should include:
thoroughly rinsing the injury site with running water, and gently cleaning with soap and water (if possible);
flushing the eyes, nose or mouth with running water if they have been exposed; and rinsing broken skin thoroughly.
Follow established organization policies and procedures for needlestick injuries, including reporting the incident and exposure immediately to your employer.
Follow instructions for further treatment and follow-up from medical professionals, where necessary.
# RECOMMENDATIONS
Vascular Access -Second Edition
# Recommendations
# GOOD PRACTICE STATEMENT:
The expert panel recommends health providers complete a systematic assessment of the person prior to inserting a vascular access device.
This is a good practice statement that does not require application of the GRADE system (7). Conducting an initial assessment of a person before developing a plan of care or any intervention is a standard of professional practice (36).
As such, completing a systematic assessment of persons prior to having a VAD inserted is good clinical practice and a pre-requisite for providing other clinical interventions.
The use of VADs, especially PVADs, is common throughout the health system. Any time a VAD is used as part of a care plan, it increases a person's risk for infection and other complications. Therefore, it is important that all persons requiring vascular access, regardless of duration of therapy, have a systematic assessment completed prior to the initiation of therapy (25,37). This systematic approach will include a vascular assessment, including determination of clinical indication, psychosocial assessment, site selection and device selection. See the "Practice Notes" below for the suggested components of a systematic assessment before initiating vascular access.
Assessment is necessary in all settings where a VAD may be inserted. It is especially important in home-care settings, where persons are sent home with a VAD. Furthermore, for persons in a hospital setting, assessing persons for the most appropriate device upon admission or early in their hospital stay leads to improved person-centred outcomes and is more cost-effective (20). Certain factors-such as age and diagnosis of the person-also need to be considered when choosing to initiate vascular access. For example, pediatric and elderly populations will have different VAD care considerations due to their smaller or more fragile veins; a systematic assessment and choosing the appropriate device are essential for optimizing person-centred outcomes in these specific populations. Health providers will need to consult with the interprofessional team when advocating for the best device for the person, based on a systematic assessment of the person.
# Practice Notes
# Considerations from the expert panel
It may not be possible to complete all components of a systematic assessment of persons needing vascular access in an emergency care situation. Health providers should not delay life-saving vascular access interventions.
# RECOMMENDATIONS
Vascular Access -Second Edition Vascular assessment is to include an assessment of current medications, including those that may increase complication risk, such as anticoagulants and immunosuppressant medications.
VAD assessment and planning is an ongoing process through the person's course of treatment (25).
Depending on the planned therapy and person receiving the VAD, the assessment may be more focused or more comprehensive.
# Psychosocial assessment
# RECOMMENDATIONS
Vascular Access -Second Edition
# COMPONENTS OF ASSESSMENT DETAILS OF ASSESSMENT
# Device selection and vesicant medications
Determine if the planned therapy poses an infusate risk or if the medication is a vesicant.
Do not use peripheral catheters for continuous vesicant therapy or infusates with an osmolarity greater than 900 mOsm/L (37). Use caution with parenteral nutrition.
Consultation with a pharmacist may be required for high risk or vesicant medications.
See Appendix H for a list of vesicant medications.
It is important to select the least invasive device for the duration and type of treatment, and one that promotes vessel preservation (25). When selecting a VAD (25):
Use a device with the minimum number of lumens.
Select the smallest gauge catheter that will accommodate the prescribed therapy.
See further details in Appendix F for considerations for different types of VADs and Appendix G for the right line decision tool (as included in the UK Vessel Health Preservation Framework) (38).
# Site selection
To select the site for VAD insertion, assess the person's vascular structure and integrity at and above the insertion site (25).
The following sites should be avoided for vascular access (25):
area of flexion [except where this is not possible in trauma or emergency cases];
chest wall, digits or breast;
lower legs, except in a non-walking child;
insertion area that is painful on palpation;
vein that is obviously compromised (e.g., thrombosis, redness, cording, bruising, infiltration, phlebitis or engorgement);
extremity with a planned or actual arteriovenous fistula/graft site; and extremity affected by lymphedema, paralysis, extravasation, acute infection, tissue injury or acute trauma.
When selecting sites, health providers also must consider any previous history of breast cancer surgery and any potential sites for tissue donation.
If a short PVAD is deemed appropriate based on a comprehensive assessment of the person-and the health provider has the knowledge, skill and judgement to perform PVAD insertions-the health provider will select an insertion site appropriate for the required therapy that has the least risk of complication.
# RECOMMENDATIONS
Vascular Access -Second Edition
# Supporting Resources
# RESOURCE DESCRIPTION
Canadian Vascular Access Association. Canadian vascular access and infusion therapy guidelines. Pembroke (ON): Pappin Communications; 2019.
Canadian Vascular Access Association guideline.
Includes details on assessment and device selection.
Note: this is a resource for which there is a fee. The expert panel recommends that health providers provide comprehensive health teaching to persons and their families/caregivers about their vascular access device.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Very low
# Discussion of Evidence: Benefits and Harms
Comprehensive health teaching G involves a combination of learning experiences designed to help improve knowledge and skills related to self-management in persons and their families or caregivers (39-42). The evidence was focused on comprehensive health teaching for CVAD care in particular. Two studies focused on self-management education (39, 40), while seven studies focused on family or caregiver education (41)(42)(43)(44)(45)(46)(47), with the majority of these focused on parents or caregivers providing care for children.
Evidence suggests that comprehensive health teaching may reduce complications and hospital re-admission rate (39-49). However, the evidence is very uncertain.
Most studies reported a decrease in complications in persons who received health teaching when compared to either baseline or control groups (39, 40,[42][43][44][45][46][47][48][49]. For instance, CLABSI rates decreased in three studies (43)(44)(45), and incidence of occlusion decreased in three studies (39,40,47). In one study, clotting was lower in the group that received education than in the control group (46). One study compared hospital readmission rates due to CLABSI before and after implementing a CVAD care class to family members: there were no hospital re-admissions related to CLABSI in one month of follow-up (42).
The studies did not report harms as a result of persons and families receiving health teaching about their VAD.
The certainty of the evidence was rated as very low due to serious limitations in how individual studies were conducted, serious imprecision related to the small number of total events or participants, and inconsistency in how outcomes were measured. For more detailed information on the impact of health teaching on the prioritized outcomes (hospital readmission rate and complications), refer to the evidence profiles available here: https://RNAO. ca/bpg/guidelines/vascular-access-second-edition.
Further details of the intervention noted in the literature are outlined below, under "Practice Notes. "
# RECOMMENDATIONS
Vascular Access -Second Edition
# Values and Preferences
Three studies gathered data on patient satisfaction (39, 41,46). Where this information was collected, persons and families reported improved satisfaction with the health teaching (39, 41), including feeling more comfortable with their care (46).
# Health Equity
No evidence was identified in the systematic review that directly assessed the impact of comprehensive health teaching on health equity. More research is required on this topic.
# Expert Panel Justification of Recommendation
This recommendation could have been a good practice statement however, the expert panel agreed that it was important to pose a recommendation question to examine the evidence on providing comprehensive health teaching to persons about their VAD. In addition, this evidence can support health providers by providing detailed information on the content and delivery of this education outlined in the evidence. There may be benefits to providing comprehensive health teaching to persons with a VAD and their families or caregivers. There were no harms reported. The expert panel felt that persons and their families or caregivers would value comprehensive health teaching, and that it would align with principles of informed consent, person-and family-centred care, self-management and autonomy. The expert panel also noted the potential for harms if health teaching was not completed. This included device failure or catheter-associated infection. Therefore, despite the very low certainty of the evidence, the expert panel determined the recommendation to be strong due to the potential for harms without health teaching. Although the literature was only on CVADs, the expert panel felt that health teaching on all types of VADs would be beneficial and determined the recommendation to be inclusive of all types of VADs.
# Practice Notes
Considerations from the expert panel At the very least, health teaching is to include signs and symptoms of complications. This should also include details about where, how and with whom to follow up and seek assistance if complications arise when discharged home with a VAD.
The amount of and formalization of health teaching will be dependent on the type of device and the discharge plan. For example, a person with a PVAD that is to be removed prior to discharge will have lower learning needs than a person discharged with a PICC line for a defined amount of time or a person with a long-term CVAD, who will require an in-depth understanding of the device.
Health teaching is to be tailored to the following (for further details, refer to "Supporting Resources, " below):
type of device;
type and duration of treatment (including type of infusion or medication);
discharge plan; person's age and developmental stage (including tailoring to children, adolescents and the needs of older adults);
person and family/caregiver's individual learning needs and preferences; and
person or family/caregiver capability for self-care.
# RECOMMENDATIONS
Vascular Access -Second Edition For more complex health teaching (if available and appropriate), consider referral to a VAS or VAST.
Health teaching is to be documented and included in the health record.
Comprehensive health teaching is to follow a teaching plan or checklist. See Appendix I for an example of a PICC health teaching guide. (44).
# Health provider providing the health teaching
In all but one study, health teaching was completed by a nurse (39, 40,[42][43][44][45][46]. This was further described in the studies as one of the following:
nurse educator (44),
infusion nurse (39), or classes taught by specially trained registered nurses and reinforced by a bedside nurse (42).
In one study, health teaching was completing by the study investigator (41).
# Use of technology
Several studies used audiovisual demonstration through DVDs or videos to enhance education (39, 41,44,46,47).
One study used video calling technology to enhance coaching and accessibility of the education through one-on-one video chatting (39).
# Individualized or tailored approach
Most of the health teaching interventions tailored the teaching to the individual needs of the learner through various strategies (39-41, 43, 44). In the evidence these strategies included the following:
providing one-on-one health teaching (39, 41),
asking persons to express emotions and fears related to CVAD management and give opportunities to ask questions and receive feedback (40), and promoting family member autonomy in providing care (43). Models: Three education programs offered a chance to practise on mannequins or models (40,43).
# RECOMMENDATIONS
Evaluation or assessment:
In one study, the family member undergoing training was required to "room in" and provide total care for 24 hours to demonstrate their competency (44).
On the day before discharge, persons with a VAD were evaluated on how well they could perform the self-management tasks and were provided with feedback (40).
Another study assessed learner understanding through "teach back" strategies (42).
Finally, caregivers in one study were asked to demonstrate skills based on a checklist, and to re-demonstrate skills when the person they were caring for was re-admitted (45).
# Supporting Resources
# RESOURCE DESCRIPTION
Canadian Vascular Access Association. Canadian vascular access and infusion therapy guidelines. Pembroke (ON): Pappin Communications; 2019.
Canadian Vascular Access Association guideline.
Includes patient education as a core practice principle.
Note: this is a resource for which there is a fee. In particular, see Table 2 and Figure 1 within the document for self-management strategies.
# RECOMMENDATIONS
Vascular Access -Second Edition
# RECOMMENDATION QUESTION #2:
Should practical education for the insertion and management of vascular access devices for health providers be recommended?
Outcomes: Complications (including insertion-related complications), number of successful observed attempts and provider attitude/confidence.
# RECOMMENDATION 2.1:
The expert panel recommends health-service organizations implement practical education on the insertion and/or management of vascular access devices for health providers.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Low
# Discussion of Evidence: Benefits and Harms
For the purposes of this BPG, practical education G refers to skills practice, supervised insertion and management of VADs, hands-on training or one-on-one training for health providers. It also includes (but is not limited to) highfidelity simulation G training. Practical or skills lab training follows a structured teaching concept: it takes place under supervision and in consideration of foundational concepts, and it ideally creates an atmosphere that allows the repeated, risk-free practice of targeted clinical skills (50). The types of practical education provided varied across the evidence. Programs included a didactic theory session followed by simulation component (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70), an online or video component followed by in-class group simulation or a practical component (67,(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83), a simulation experience alone (84) or individualized mentoring or supervision (57,85).
The evidence suggests that practical education for health providers improves the number of successful attempts, probably reduces complications in persons with a VAD, and may improve provider attitude and confidence and insertion-related complications, although the evidence is uncertain . One systematic review reported higher success rates and marginally lower complications when practical education was compared to traditional education (51). Provider attitude and confidence was examined in 23 studies, with the majority reporting improvement in provider confidence from pre-to post-implementation of education or compared to a control group (55-60, 62, 63, 66, 67, 69-72, 74-76, 78, 79, 81, 82, 84). The majority of studies focused on practical education for CVAD insertion and management, but some studies also focused on PICC management (61), PVAD insertion (55,(67)(68)(69)(70)(71)(72)(73)85), and arterial catheter insertion (54,56,78,84). There was no evidence specifically examining PVAD maintenance.
There were no studies that reported harms as a result of health providers receiving practical education on the insertion and management of VADs.
# RECOMMENDATIONS
Vascular Access -Second Edition
The overall certainty of the evidence was rated as low due to serious concerns in how individual studies were conducted, inconsistency in the measurement of the outcomes, and imprecision related to the small number of total events or participants across the studies. For more detailed information on the impact of practical education on the prioritized outcomes (complications, insertion-related complications, number of successful observed attempts G and provider attitude/confidence), refer to the evidence profiles available here: https://RNAO.ca/bpg/guidelines/vascularaccess-second-edition.
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
Where reported, health providers in seven studies highly valued the practical education offered (60,62,66,67,76,81,82). In one study, in addition to the improved self-reported confidence, nurses described that the simulation environment was a safe place to learn, stating that they were able to concentrate on learning without being interrupted or disturbed (60). Medical residents that participated in a single 60-to 90-minute ultrasound-guided CVAD training session reported enjoying the practical training sessions because they were very realistic and rated higher perceived educational benefits (76).
# Health Equity
No evidence was identified in the systematic review that directly assessed the impact of practical education for health providers on health equity. More research is required on this topic.
# Expert Panel Justification of Recommendation
Conventionally based on GRADE, this recommendation could have been voted conditional since the certainty of the evidence of the effects was low. Based on the balance of benefits and harms, including the harms of not following the recommendation, as well as values and preferences, the expert panel came to consensus on a strong recommendation.
There are benefits to practical education for health providers on the insertion and management of VAD. The expert panel noted the risk of potential harms of health providers not receiving practical education on the insertion and management of VADs. Practical education was highly valued by health providers in the literature. Although the certainty of the evidence was rated as low, the expert panel voted the recommendation as strong as there were no harms noted in the studies, and they felt that all health providers would benefit from practical education.
# Practice Notes
# Considerations from the expert panel
Education is to be standardized within the health-service organization, with specific educational competencies outlined. See Appendix J for an example of a global rating scale for ultrasound-guided PVAD insertion. Additionally, organizations are to document competencies and review them on a regular basis through a formal process.
Due to loss of skills over time among health providers, refresher and ongoing education is to be offered.
Educators providing practical education need formal training, including skill development in debriefing.
High-fidelity simulation is preferable for complex cases and skills. However, it is recognized that high-fidelity simulation may not be feasible in all practice settings due to cost or accessibility issues.
# RECOMMENDATIONS
Vascular Access -Second Edition If simulation labs are used, simulation experts should be involved in their planning. It is important to note the consideration of the clinical experience levels of the learners when creating and conducting practical education sessions. Benner's Stages of Clinical Competence Framework may be used to tailor training to levels of expertise (see Guiding Framework and Principles on page 33). The expert panel suggests that acute care health-service organizations implement vascular access specialists or vascular access specialist teams to support the insertion and management of vascular access devices.
# Strength of the recommendation: Conditional
Certainty of the evidence of effects: Low
# Discussion of Evidence: Benefits and Harms
A VAST refers to a grouping of health providers who have advanced knowledge and skills in the assessment, insertion, care and management of VADs. This includes intravenous therapy teams and individual VAS (e.g., nurses, physicians, respiratory therapists, laboratory technicians, radiology technologists and physician assistants) (3).
The evidence suggests the implementation of VASTs and VAS may reduce complications, and that it probably improves successful attempts of VAD insertions (86)(87)(88)(89)(90)(91)(92)(93). Most studies focused on the insertion and management of CVADs, including PICCs (86)(87)(88)(89)93). The remaining studies focused on the insertion and management of PVADs (90)(91)(92).
In terms of complications, most studies reported an overall decrease in complications rates, catheter failure, catheterrelated blood stream infections and deep vein thrombosis rates when a VAST or VAS was involved in providing care (86-89, 91, 93). Three studies reported on the number of successful attempts and noted more successful insertions in persons who received care from VASTs compared to those who did not (90,92,93).
All studies except one reported no harms as a result of persons receiving care from a VAST. One study reported that the incidence of phlebitis was five per cent higher in VAS-inserted PVADs than for generalist insertions (90).
All studies took place in acute care settings. This recommendation therefore is specific to acute care.
# RECOMMENDATIONS
Vascular Access -Second Edition
The overall certainty of the evidence was rated as low due to serious concerns about imprecision related to the small number of total events or participants across studies, and due to some concerns about how individual studies were conducted. For more detailed information on the impact of VASTs and VAS on the prioritized outcomes (complications, number of successful attempts), refer to the evidence profiles available here: https://RNAO.ca/bpg/ guidelines/vascular-access-second-edition.
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
One study reported on patient satisfaction and found higher patient satisfaction rates among persons who received care from a VAS compared to those who did not (90). The median score of patient satisfaction with PVAD insertion was higher among those who received care from a VAS compared to those who received PVAD insertion from generalist health providers (9 versus 7, on a scale out of 10) (90).
# Health Equity
One study noted that persons with hematological malignancy may particularly benefit from VASTs and VAS compared to persons with other disorders (89). Of the persons who had a catheter-related bloodstream infection, 3 out of 4 of them also had a hematological malignant disorder (75%), and of the persons with a catheter-related deep venous thrombosis 3 out of 10 of them also had a hematological malignant disorder (30%) (89). The incidence of deep venous thrombosis in persons with hematological malignancy was 0.4/1000 catheter days, compared to 0.17/1000 catheter days in the overall cohort (89).
# Expert Panel Justification of Recommendation
There may be benefits to implementing VASTs and VAS in acute care health-service organizations. However, the certainty in the evidence was low. There also may be few harms of implementing VASTs and VAS. All people may not benefit equally from this intervention. Specific groups may benefit more from this intervention, such as older adults, children, persons with cancer and those with repeated need for device insertion. The expert panel recognized that there is limited evidence on the cost-effectiveness of VASTs or VAS. In addition, some health-service organizations may have challenges accessing VASTs or VAS due to cost or organization size. The expert panel felt the benefits of VASTs were important but that the evidence was not sufficient to make a strong recommendation.
# Practice Notes
Considerations from the expert panel The type of device needs to be considered when designing VASTs. For example, CVAD insertion and care are more likely to need VAST or VAS care than PVAD insertion and care. This recommendation excludes some health settings, such as home care and long-term care, but the expert panel feels that there are likely benefits to VASTs in these areas. However, there was no evidence from these health settings. See Table 15 on page 80 for research gaps and future implications.
# RECOMMENDATIONS
Vascular Access -Second Edition (88,(90)(91)(92).
Responsible for difficult PVAD insertions and difficult blood draws (87).
Responsible for all CVAD insertions (86) or all PICC insertions (88)(89)(90)94).
The VAS intervention in one study included individual assessment to identify the person's expected tolerance of the procedure (i.e., their sedation and pain management needs) (87).
# VAD management:
Responsible for CVAD dressing changes (87).
Education for persons and staff caring for persons with a short PVAD (87,88).
Responsible for all CVAD maintenance (including removal) (86).
Monitoring of VAD, including necessity (88,91).
Assessment and maintenance of CVAD and PVAD, as needed (92).
# VAS health provider in the evidence
Exclusively nurses (88)(89)(90)(91)(92)(93).
Nurse-led (87).
Nursing, medical and respiratory therapy (86). The expert panel suggests health providers perform venipuncture when drawing blood samples to maintain specimen integrity.
VAST
# Strength of the recommendation: Conditional
Certainty of the evidence of effects: Very low
# Discussion of Evidence: Benefits and Harms
The evidence suggests that venipuncture G for drawing blood samples may reduce specimen rejection and may reduce contamination of blood cultures compared with drawing blood from a VAD (94)(95)(96). However, one study also suggests that venipuncture for drawing blood samples may reduce patient satisfaction, when compared with drawing blood from a VAD (95). The certainty of the evidence was very low.
A systematic review concluded that blood sample collection through PVADs is associated with a higher risk of hemolysis G compared with blood drawn by venipuncture (94). Two additional non-randomized controlled trials were identified for the outcome of specimen rejection. One of the studies supported the findings of the systematic review (95). The other study reported lower rates of hemolysis in blood draws from a VAD compared with venipuncture, but it was blood drawn from a PICC (96).
The systematic review also reported on contamination of blood cultures based on two individual studies with mixed results (94). One study included in the review reported higher rates of blood culture contamination and false positives when blood was drawn from a PVAD compared with venipuncture (97). The other study included in the review reported no difference in blood culture contamination when blood was drawn from a PVAD within one hour of insertion when compared with venipuncture (98).
One study examined patient satisfaction, which was assessed on a scale from 0 to 10 (95). The study reported a mean difference of 1.27 in favour of blood draws from a PVAD (95). Finally, only one study reported on dwell time and concluded that blood draws from PVAD had little to no effect on dwell time (99). There were no additional harms reported in the studies.
# RECOMMENDATIONS
Vascular Access -Second Edition
The certainty of the evidence was rated as very low due to limitations in how individual studies were conducted, inconsistency across study results and a low number of total events and participants for some outcomes.
For more detailed information on the impact of the venipuncture compared to blood draws from a VAD on the prioritized outcomes (specimen rejection, patient satisfaction, contamination rate and dwell time), refer to the evidence profiles available here: https://RNAO.ca/bpg/guidelines/vascular-access-second-edition .
# Values and Preferences
One study reported that 99 per cent of people preferred blood draw from a PVAD compared with venipuncture (95).
Additionally, one study reported lower pain when blood was drawn from a VAD (96).
# Health Equity
No evidence was identified in the systematic review that directly assessed the impact of venipuncture or blood draws from a VAD on health equity. More research is required on this topic. See Table 15 on page 80 for research gaps and future implications.
# Expert Panel Justification of Recommendation
There may be some benefits to using venipuncture compared to blood draws from a VAD, but the certainty of the evidence was very low. The evidence indicates that there are harms to performing blood draws from a VAD, such as specimen rejection of blood samples or contamination of blood cultures. Additionally, patient satisfaction may be lower when blood is drawn using venipuncture. The expert panel noted the potential for additional harms that were not captured in the body of evidence, including microclots in the samples and delayed treatment or misdiagnosis when blood draws are performed from a PVAD. Additionally, the expert panel felt that blood draws using venipuncture may not be appropriate at all times for all people. The examples of young children, people with cancer requiring repeated blood sampling or older adults with difficult intravenous access were given as potential populations where venipuncture may sometimes be more harmful than beneficial. Following an individualized riskbenefit assessment, other individuals also may not be appropriate candidates for venipuncture. Therefore, the expert panel determined the strength of the recommendation to be conditional.
Venipuncture is the preferred method of blood sampling. If this method is not feasible following an individualized risk-benefit assessment, then a blood draw from a VAD may be considered.
With any blood draw, health providers must adhere to a standardized blood sampling protocol or organizational policy. Health providers need adequate training and education on blood draws and VADs to support this recommendation. Specifically, the expert panel noted that health providers need to be educated on additional harms associated with blood draws from VADs (e.g., hemolysis and contamination of the specimen leading to false positive results and unnecessary treatment). Additionally, health-service organizations are to document competency of staff and review competencies on a regular basis through a formal process.
Health-service organizations are to develop policies based on their equipment and in collaboration with the VAD vendor specifications.
When developing policies, health-service organizations are to collaborate with laboratory guidelines and personnel.
Where an arterial blood sample is needed (e.g., for arterial blood gases), health providers are to follow established best practices for drawing blood from an artery or arterial catheter. See "Supporting Resources" (below) for guidance on arterial sampling procedure.
For persons with a CVAD in situ, see "Supporting Resources" (below) for guidance on sampling procedure. Decisions around blood draws from a CVAD also require an individualized risk-benefit assessment (see the factors listed above). The expert panel recommends that acute care health-service organizations implement a multicomponent PVAD care protocol. This protocol includes a minimum of a daily review by health providers, in collaboration with persons and their families.
# RECOMMENDATIONS
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Low
# Discussion of Evidence: Benefits and Harms
A multi-component care protocol G is a group of evidence-based interventions that can ensure the delivery of a standardized method of care (100). When these interventions are performed together, they can have a better outcome than if performed individually (this may be referred to as a "care bundle") (100). The evidence suggests that multicomponent PVAD care protocols may reduce complications (91,(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112).
The multi-component care protocol involved PVAD daily review and documentation (91,(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112) At a minimum, daily review involved an assessment of signs and symptoms of PVAD complications (91,(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112).
A majority of the studies also included assessment of device necessity as part of the PVAD daily review (91, 101-105, 108, 109, 111, 112).
Eleven out of 13 studies reported a decrease in complications when a multi-component PVAD care protocol with daily review was implemented (91,(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112). Steere et al. (2019) reported an overall decrease in complication rates and catheter failure rates (91). Infiltration was the most commonly assessed complication across studies, and its rate decreased in all the studies in which the outcome was reported (91,101,102,104,107,110,111). Phlebitis rate also decreased in the majority of the studies in which the outcome was reported (91,101,105,110). Furthermore, infection was assessed in three studies, and all studies reported a decrease in infection rate after implementation of a multi-component PVAD care protocol that included a daily review (103,106,109). There were no harms reported in the studies related to the use of a multi-component PVAD care protocol with daily review.
# RECOMMENDATIONS
Vascular Access -Second Edition
The certainty of the evidence was rated as low due to serious limitations in how individual studies were conducted.
For more detailed information on the impact of the multi-component PVAD care protocols, including a daily review on the prioritized outcomes (complications), refer to the evidence profiles available here: https://RNAO.ca/bpg/ guidelines/vascular-access-second-edition .
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
Another study conducted interviews with caregivers as part of intervention development (108). The following themes emerged related to PVAD care: the importance of communication, apprehension and fear around the device, an appreciation of skilled health providers and technology, and a recognition of the role of the caregiver (108).
# Health Equity
No evidence was identified in the systematic review that directly assessed the impact of multi-component PVAD care protocols on health equity. More research is required on this topic. See Table 15 on page 80 for research gaps and future implications.
# Expert Panel Justification of Recommendation
Conventionally based on GRADE, this recommendation could have been voted conditional since the certainty of the evidence of the effects was low. Based on the balance of benefits and harms, including the harms of not following the recommendation, as well as values and preferences, the expert panel came to consensus on a strong recommendation.
There may be benefits of implementing PVAD multi-component care protocols that include a daily review.
Additionally, there was some evidence to suggest that multi-component PVAD care protocols would be highly valued by persons and families or caregivers, particularly when caregivers were involved. The expert panel also noted that a daily review of a PVAD in particular would avoid additional harms not captured in the literature, as short PVAD complications can greatly impact a person's safety. A strong recommendation was selected by the panel to align with person's safety as well as values and preferences.
# Practice Notes
Considerations from the expert panel Daily reviews of PVADs are to be completed a minimum of once daily. More frequent assessment will be necessary for specific populations (such as neonatal or pediatric) and for infusing catheters.
PVAD care is not just the responsibility of an individual health provider; it also needs to be incorporated into health-service organization policies and procedures. Discussion of PVAD necessity, functionality and utilization is to include bedside and interprofessional team members.
Health-service organizations need to be responsible for education, training and monitoring related to multicomponent PVAD care policies and protocols. Additionally, organizations are to document competency of staff and review competencies on a regular basis through a formal process.
All studies took place in acute care settings. This recommendation therefore is specific to acute care.
# RECOMMENDATIONS
Vascular Access -Second Edition The assessment of a PVAD needs to follow an established protocol. See Appendix L for an example of a PVAD assessment protocol and Appendix G for daily evaluation included in the UK Vessel Health Preservation Framework.
Although this recommendation is for acute care settings, the expert panel felt that a multi-component PVAD care protocol would be beneficial in other settings, including long-term care and home care. More research is needed in these areas. See Table 15 on page 80 for research gaps and future implications.
This recommendation applies to PVADs. The expert panel did not feel that a recommendation on CVAD care was necessary, as there are many established multi-component care protocols (or "care bundles") currently in use. For more information on CVAD care, see Appendix M.
# PVAD daily review process
PVAD reviews were at minimum once per shift in some studies (107,109,110,112). They were once per day in others (91,101,102,109,110,112). Additionally, three protocols mandated hourly site assessment (104,108,111). One study required that assessment be completed whenever solutions changed or drugs were added to the intravenous therapy (105).
The acronym TLC (touch, look, compare) was used in one study (102), while ACT (assess, compare, touch) was used in another (104).
The acronym PIVCS formed the maintenance bundle in two studies: prompt removal, inspect hourly, vein patency by intermittent flush of 0.9% sodium chloride, clean hands, scrub the hub with 2%, chlorhexidine gluconate and 70% alcohol swab (108,111).
# PVAD dressings/ securement devices
Chlorhexidine antimicrobial bordered securement dressing (91).
Transparent dressing (91,101).
Semi-transparent polyurethane sterile dressing (106).
Sterile self-transparent adhesive gauze (105).
Bordered polyurethane dressing (108,111).
An additional elastic bandage was applied to reduce the risk of inadvertent withdrawal (105). The expert panel recommends that health providers use ultrasound-guided technique for the insertion of peripheral arterial catheters.
# RECOMMENDATIONS
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Moderate
# Discussion of Evidence: Benefits and Harms
Evidence suggests that the use of visualization technologies-specifically ultrasound-guided technique G -for the insertion of peripheral arterial catheters will increase the success rate on first attempts and will likely reduce complications (113)(114)(115)(116)(117)(118). Ultrasound-guided technique refers to ultrasound imaging (an image created by using sound waves within the body) that allows health providers to see surrounding anatomical structures such as arteries and veins (119). It is used to aid the health provider when inserting a PIV or peripheral arterial catheter. In particular, the use of ultrasound-guided technique was more effective when compared to the palpation technique in adult and pediatric populations (118).
Hematoma was the most frequently reported complication in the evidence. The systematic review reported fewer incidences of hematoma when using ultrasound-guided technique for arterial catheter insertion compared to palpation or traditional methods (118). Additional randomized controlled trials G that were included supported these findings (113)(114)(115)(116)(117).
Ultrasound-guided technique could provide greater value in the care of certain subpopulations. Based on subgroup analysis, one review noted that first attempt success rate of ultrasound-guided technique versus traditional palpation techniques for radial artery catheterization was particularly beneficial in children and persons undergoing emergent procedures (118).
There were no studies that reported on the outcome of patient satisfaction.
There were no harms reported in the studies.
The evidence was of moderate certainty due to some limitations in how individual studies were conducted. For more detailed information on the impact of the intervention (ultrasound-guided technique for arterial catheter insertion) on the prioritized outcomes (success rate on first attempt, patient satisfaction and complications), refer to the evidence profiles available here: https://RNAO.ca/bpg/guidelines/vascular-access-second-edition .
# RECOMMENDATIONS
Vascular Access -Second Edition Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
There was no evidence identified in the systematic review that reported on the values and preferences of persons with a VAD related to the use of ultrasound-guided technique for the insertion of a peripheral arterial catheter.
# Health Equity
It is important to note that implementation barriers such as the cost of ultrasound devices may limit the feasibility and accessibility of ultrasound-guided technique in some health-service organizations.
# Expert Panel Justification of Recommendation
The benefits of using ultrasound-guided technique outweigh the harms, and there was moderate certainty of evidence for this. The expert panel agreed that the technique was feasible in most health-service organizations, and that it was acceptable to patients.
Overall, the expert panel noted that the potential harms of not using ultrasound-guided technique can be severe.
The expert panel noted the potential for additional harms that were not captured in the body of evidence, including ischemia, hemorrhage and thrombosis. Therefore, the expert panel determined the recommendation to be strong.
# Practice Notes
# Considerations from the expert panel
Training on the use of ultrasound needs to include a basic understanding of ultrasound technology, as well as ongoing maintenance of competencies (not a one-time certificate). Additionally, health-service organizations are to document competency of staff and review competencies through a formal process on a regular basis.
Training of health providers in ultrasound-guided techniques should involve practical education with the technology (see Recommendation 2.1 for details on practical education).
Two health providers may be required when using ultrasound, depending on the expertise and experience level of the health provider (i.e., one to hold the ultrasound probe and the other to insert the needle).
When using ultrasound-guided technique for the insertion of arterial catheters, it is important that health providers ensure correct positioning of the VAD prior to initiating treatment.
See Appendix K for an example of ultrasound-guided technique.
Appropriate scope of practice and level of training or expertise needs to be considered when applying this recommendation and determining the most appropriate health provider to insert the peripheral arterial catheter.
# CAUTION
# RECOMMENDATIONS
Vascular Access -Second Edition (119). In subgroup analysis, it was noted that those with ultrasound expertise had a higher first attempt success rate than those with no expertise (119).
Previous experience may improve the results and success of ultrasound-guided technique (120).
# Details of ultrasound technique
Short axis view, out-of-plane (113,(118)(119)(120).
One review noted that there was higher incidence of first attempt success in the subgroup analysis of pooled trials that used short axis out-of-plane ultrasound-guided approach (118).
Dynamic Needle Tip Positioning (DNTP) technique (a modified ultrasound technique that requires confirmation of the needle tip position in the vessel before advancing the catheter) (113,117).
Long axis view, in plane (115,118).
Seldinger technique (119,120) Single or double wall technique (120).
Vascular transducer used (120).
# Supporting Resources
# RESOURCE DESCRIPTION
Bardin-Spender A, Spencer TR. The expert panel suggests that health providers use ultrasound-guided technique for the insertion of PVADs for persons with difficult intravenous access.
# Strength of the recommendation: Conditional
Certainty of the evidence of effects: Very Low
# Discussion of Evidence: Benefits and Harms
Evidence suggests that the use of visualization technologies, specifically ultrasound-guided technique, for the insertion of PVADs in persons with difficult intravenous access may increase the success rate on first attempts and decrease complications, and that it likely will increase patient satisfaction (121)(122)(123)(124)(125)(126)(127)(128). However, the certainty of the evidence was very low.
Ultrasound-guided technique refers to ultrasound imaging (an image created by using sound waves within the body) that allows health providers to see surrounding anatomical structures, such as arteries and veins (119). It is used to aid the health provider when inserting a PVAD or peripheral arterial catheter.
Ultrasound-guided technique can be particularly useful for persons with DiVA, which is defined as a clinical situation where multiple attempts or special interventions are required to obtain and maintain peripheral venous access (129). How DiVA was determined varied across studies and included previous failed attempts (121,122), history of difficult access (121,122,127), health provider assessment (121,122,124,125,128), self-report (121,130) or certain comorbidities, such as sickle cell disease, obesity or intravenous drug use (121,124). Some studies focused on pediatric populations with different levels of venous access difficulty, or different ages and behaviours that may have influenced their cooperation with the procedure (22,123).
In adults and children with DiVA, ultrasound-guided PVAD insertion resulted in a higher success rate when compared to traditional techniques of palpation and direct visualization (22,(122)(123)(124)(125)(126)(127)(128). Furthermore, the evidence reported that adults and children with DiVA (or their parents/guardians) who received ultrasound-guided technique for the insertion of PVADs reported higher patient satisfaction than those who did not receive PVADs through ultrasound-guided technique (122,124,125).
Most studies reported fewer complications during the use of ultrasound-guided technique (121,125). There were no additional harms reported in the studies.
Of note were two systematic reviews that examined the effect that the use of near-infrared devices during PVAD insertion had on the success rate of first attempts (21, 130). Both systematic reviews found no difference in first attempt success rate when using near-infrared devices. Due to the limited evidence on this intervention, it was determined more research is needed in this area. As a result, the recommendation is solely focused on ultrasoundguided technique. See Table 15 on page 80 for research gaps and future implications.
# RECOMMENDATIONS
Vascular Access -Second Edition
The evidence was of very low certainty due to limitations in how individual studies were conducted and inconsistency in the reported results. For more detailed information on the impact of the intervention (ultrasound-guided technique) on the prioritized outcomes (success rate on first attempt, patient satisfaction and complications), refer to the evidence profiles available here: https://RNAO.ca/bpg/guidelines/vascular-access-second-edition.
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
There was no evidence identified in the systematic review that reported on the values and preferences of persons with a VAD related to ultrasound-guided technique beyond the patient satisfaction outcome reported above.
# Health Equity
It is important to note that implementation barriers, such as the cost of ultrasound devices, may limit the feasibility and accessibility of ultrasound-guided technique in some health-service organizations. No evidence was identified in the systematic review that directly assessed the impact that visualization techniques for PVAD insertion had on health equity. More research is required on this topic. See Table 15 on page 80 for research gaps and future implications.
# Expert Panel Justification of Recommendation
There may be benefits to using ultrasound-guided technique in persons with DiVA in terms of insertion success rate and improvement of patient satisfaction. There was a reduction in the number of complications when using ultrasound-guided technique compared to traditional methods. The expert panel felt that the success of this recommendation would be dependent on individual considerations of the person receiving the PVAD and the expertise of the health provider. The certainty in the evidence was very low. Therefore, the expert panel determined the recommendation to be conditional.
# Practice Notes
# Considerations from the expert panel
Training on the use of ultrasound needs to include a basic understanding of ultrasound technology and ongoing maintenance of competencies (not a one-time certificate). Additionally, health-service organizations are to document and review competencies of staff on a regular basis through a formal process. See Appendix J for a validated scale on ultrasound-guided PVAD insertion and Appendix K for an example of ultrasound use during VAD insertion.
Health providers caring for persons in the community or home-care settings may need to refer persons with DiVA to an acute care setting to utilize ultrasound technology (if traditional methods of PVAD insertion are unsuccessful).
Appropriate scope of practice and level of training or expertise needs to be considered when applying this recommendation and determining the most appropriate health provider to insert the PVAD.
# CAUTION RECOMMENDATIONS
Vascular Access -Second Edition A validated scale can be used to determine DiVA. DiVA status should be assessed by an expert in PVAD insertion or a health provider who is appropriately trained to use the validated DiVA scale. Referral to VAS or VASTs may be needed to support the insertion of VADs in DiVA patients using ultrasound-guided technique (in organizations where available).
When using ultrasound-guided technique for the insertion of PVAD, it is important that health providers ensure correct positioning of the VAD prior to initiating treatment. It was noted that provider comfort and previous experience affected the success and implementation of the intervention (122,123,125).
One systematic review reported that provider expertise level and technique (e.g., one-person versus twoperson, and dynamic versus static) were associated with better results (122).
One study reported significant health provider effect on needle redirections, total time and needle manipulation time (123).
One study noted that attending physicians and nurses may have had higher success rates inserting PVADs than fellows because of more experience with placing ultrasound-guided VADs (125).
# Details of ultrasound technique
Dynamic Needle Tip Positioning (123,(125)(126)(127).
Short axis (121,123,125).
Long axis (121).
Single-operator technique (121,(125)(126)(127).
Two-provider technique (22,121,122).
One nurse operated the equipment and examined vessels in transverse and longitudinal directions with a 90-degree angle of the transducer, then chose the vein to be used. Another nurse performed skin antisepsis and the catheter insertion, analyzing the image on the screen (22).
# RECOMMENDATIONS
Vascular Access -Second Edition
# Should pain management strategies (including pharmacological and non-pharmacological strategies) during the insertion of a vascular access device be recommended?
Outcomes: Patient's rating of pain, patient comfort, fear/anxiety (related to poke/needle phobia) and patient satisfaction.
# RECOMMENDATION 7.1:
The expert panel recommends that health providers offer adults non-pharmacological and pharmacological pain management strategies during the insertion of a vascular access device.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Moderate
# Discussion of Evidence: Benefits and Harms
Evidence suggests that both pharmacological and non-pharmacological pain management interventions probably decrease pain, fear and anxiety, increase patient satisfaction during the insertion of a VAD for adults, and may increase patient comfort . Various needle procedures were examined across the studies, including CVAD insertion (131), arterial blood gas draw (147)(148)(149), intramuscular injections (141-143, 156), venipuncture (132,140,143,146), implanted port access (152), and PVAD insertion (132, 133, 136, 138, 143-145, 150, 151, 153-155).
Various types of pharmacological interventions were used in the studies, including fentanyl prior to CVAD insertion (131), a "needle-free powder lidocaine delivery system" given prior to venipuncture or PVAD insertion, and a variety of topical anesthetics (e.g., lidocaine-prilocaine cream, diclofenac patch, ketoprofen patch and tetracaine 4 per cent) (133-138, 148, 149). Specifically, the evidence reports that members of the "caine" family of drugs were estimated to be much more effective at reducing pain compared to no treatment (133).
Non-pharmacological interventions included both physical and psychological interventions (e.g., distraction techniques, acupressure, a vibrating cold device, vapocoolant spray, crushed ice, heat application, aromatherapy, a virtual reality device or hypnosis) (132,(140)(141)(142)(143)(144)(145)(146)(147)(148)(149)(150)(151)(152)(153)(154)(155)(156). The evidence reported that non-pharmacological techniques probably decrease pain and increase patient satisfaction (132,(140)(141)(142)(143)(144)(145)(146)(147)(149)(150)(151)(152)(153)(154)(155)(156).
The evidence demonstrated that overall, there was minimal or no difference in patient comfort levels when they were given pharmacological or non-pharmacological pain management interventions when compared to no pain management intervention (131,132,142,155). For the outcome of patient fear/anxiety, two systematic reviews demonstrated minimal to no difference when patients were given pharmacological or non-pharmacological pain management interventions when compared to no pain management intervention (132,143).
# RECOMMENDATIONS Vascular Access -Second Edition
The harms reported in the literature were due to side effects from pharmacological interventions. These included episodes of decreased oxygen saturation related to fentanyl use (131), nausea and pruritis related to fentanyl use (131), and mild skin reactions related to topical medications (e.g., skin blanching, rashes, petechiae, erythema and edema) (132,134,136,137).
The evidence was of moderate certainty due to how individual studies were conducted and inconsistency in the measurement of the outcomes. For more detailed information on the impact of the intervention (pharmacological and non-pharmacological pain management strategies) on the prioritized outcomes (patient's rating of pain, patient comfort, fear/anxiety related to poke or needle phobia, and patient satisfaction), refer to the evidence profiles available here: https://RNAO.ca/bpg/guidelines/vascular-access-second-edition.
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
Several studies reported on patient satisfaction. Persons reported they were satisfied with the experience of topical anesthetic application, and more than 76 per cent were willing to use the cream again (134). Persons given lidocaine by injection for their procedure were more likely to want it next time than those who had never had lidocaine (133). Many persons also had a preference for lidocaine when asked to choose between lidocaine, guided imagery or nothing prior to PVAD insertion (133). All of those who chose lidocaine said they were satisfied with the PVAD insertion compared to those who chose no pain relief (133).
For non-pharmacological pain management, it was noted that individual differences-such as the desire to attend a medical procedure-may impact an individual's ability to engage with a distraction intervention (143). In one study that used heat and cold application prior to PVAD insertion, 93.3 per cent of those in the hot application group stated that they were satisfied with the application, whereas 80.0 per cent stated that they wanted the application again (150). Conversely, 50 per cent of those in the cold application group stated that they were not satisfied with the application, and 56.7 per cent expressed that they did not want the application again (150).
# Health Equity
Minimal considerations related to health equity were reported in the evidence. There were some studies that discussed accessibility issues. Non-pharmacological pain management devices such as the "needle-free powder lidocaine delivery system" and vibrating cold devices are currently unavailable in Canada (as of May 2021) (157).
In addition, not all settings may have access to lidocaine-prilocaine cream (134), particularly in some developing countries that restrict its use as a routine medication for PVAD insertion (136). One study recommended using diclofenac gel instead of lidocaine-prilocaine cream because of increased accessibility and domestic production in general (135).
# Expert Panel Justification of Recommendation
There are likely benefits to offering non-pharmacological and pharmacological pain management strategies. Although there were some harms in the form of side effects associated with pharmacological pain management strategies, the expert panel felt that the benefits greatly outweighed the harms. The interventions were also highly valued by persons, and the expert panel felt that the recommendation aligned with person-and family-centred care principles. It is important to note that the expert panel chose the action word "offer" for this recommendation to highlight that pain
# RECOMMENDATIONS
Vascular Access -Second Edition management strategies need to be person-and family-centred and that ultimately the person with a VAD will make the decision whether or not to receive pain management. The certainty in the evidence was moderate. Therefore, the expert panel determined the recommendation to be strong.
# Practice Notes
Considerations from the expert panel Aseptic technique needs to be maintained during VAD insertion, regardless of the type of pain management strategy used.
The expert panel recognized that time constraints experienced by health providers may be a barrier to providing pain management strategies. In these situations, pain management strategies should still be offered. Health providers may consider faster acting strategies, such as thermotherapy or cryotherapy, while keeping in mind the preferences of persons and their families/caregivers.
The expert panel noted that some individuals may not prefer topical anesthetic due to the increase in overall procedure time (i.e., topical anesthetic can take longer to take effect).
A physician order may be required prior to administration of pharmacological pain management interventions.
Decisions around pharmacological pain management interventions may require an individualized risk-benefit assessment, including (but not limited to) factors such as the following:
person preference;
presence of needle phobia, or fear/anxiety about the procedure;
DiVA score/history of DiVA; and type of pharmacological intervention and potential side effects, such as vasoconstriction associated with some topical medications.
# RECOMMENDATIONS
Vascular Access -Second Edition Arterial catheter insertion: There were three studies that examined using ice or topical anesthetics for arterial blood gas draws, and these were found to be effective pain management strategies (147)(148)(149).
CVAD insertion: One study examined the use of fentanyl for CVAD insertion (131). This type of intervention may not be necessary for less invasive procedures, such as venipuncture or PVAD insertion.
# Local anesthetic administration
Choice of drug: One systematic review and network meta-analysis found that drug members of the "caine" family (e.g., lidocaine and iontocaine) were most effective in reducing patient pain when undergoing needle procedures (133).
Timing: Three studies reported that topical anesthetic cream should be applied 60 minutes prior to the procedure in order to be most effective (134)(135)(136).
# RECOMMENDATIONS
Vascular Access -Second Edition
# KEY INTERVENTION DETAILS FROM THE EVIDENCE Distraction
The evidence examined various types of distraction techniques (143,144,(152)(153)(154)(155).
Verbal cues were found to have a mixed effect in reducing a person's pain. These interventions included giving a verbal signal to the person to warn them of the impending needle poke (e.g., "sting" or "sharp scratch") (143).
Visual distraction techniques may include having people look through a kaleidoscope (143), distraction cards containing optical illusion pictures (154) or virtual reality devices (154).
Hypnosis was used in one study, involving classical non-verbal hypnotic tools adapted to the subject and indirect suggestion of comfort by body language (155).
Aromatherapy, including lavender, eucalyptus or peppermint essential oils inhaled by persons prior to needle insertion, was used in two studies (152,153). For aromatherapy interventions, health providers should be aware of any allergies prior to administering the aromatherapy oils.
Breathing techniques may include things such as the "cough trick" or Valsalva maneuver G (143) or spirometry (144). The Valsalva maneuver is a breathing technique that can be used as a pain management strategy during VAD insertion. It involves a deep inhale, followed by a forceful holding of the breath during which the venous cannulation insertion occurs (143).
For breathing techniques, health providers should be aware of the person's health history and status and related contraindications to the Valsalva maneuver or coughing, including respiratory conditions such as COPD and asthma.
# Scope of practice considerations
Acupressure: If considering acupressure as a pain management intervention, it is important to recognize that health providers would need additional education and training in order to utilize this pain management strategy.
Opioids: One study found that the use of intravenous fentanyl given prior to CVAD placement procedure was effective in reducing person's pain (131). Health providers need to be aware of scope of practice surrounding prescribing or administering opioids. They should consult with the interprofessional team about opioid administration in circumstances where it would be beneficial to advocate for this pain management strategy for the person with a VAD.
Hypnosis: One study examined the impact of hypnosis on PVAD insertion, but it is important to note that the health providers received additional certifications in hypnosis prior to delivering the intervention (155). Pain toolkit for older adults.
# RECOMMENDATIONS
Includes pain scales and pain management strategies.
# RECOMMENDATIONS
Vascular Access -Second Edition
# RECOMMENDATION 7.2:
The expert panel recommends that health providers offer non-pharmacological and pharmacological pain management strategies during the insertion of a vascular access device to infants and children, tailored to their age and developmental stage.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Low
# Discussion of Evidence: Benefits and Harms
Research evidence suggests that both pharmacological and non-pharmacological pain management interventions may decrease pain (139,156,(158)(159)(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175) fear and anxiety (162,164,166,171,173,174), and increase comfort (176), and that they probably increase patient or parent/guardian satisfaction ( 139) during the insertion of a VAD for infants and children.
The majority of studies examined non-pharmacological interventions. These included psychological interventions (e.g., distraction techniques, virtual reality devices, cartoons, aromatherapy and informational materials about the procedure) (164,165,168,(171)(172)(173)(174)(175) and physical interventions (e.g., breastfeeding and other feeding interventions, a vibrating cold device, ice, heat therapy, acupressure and holding/positioning techniques) (139, 156, 160-163, 166-168, 170, 176, 177, 179, 180, 182, 197-220). One systematic review showed that interactive distraction interventions-such as virtual reality, a toy accompanied by a reading activity and video games-were most effective in reducing fear/anxiety prior to the needle procedure (164). Furthermore, a meta-analysis reported a positive effect on the outcome of fear/anxiety among children who received distraction during the insertion of a VAD compared to those who did not receive distraction (164). Types of non-pharmacological interventions used in the studies varied with child and infant age and developmental stage. Further details of effective non-pharmacological pain management strategies are outlined below, under "Practice Notes. "
Various pharmacological interventions were used in the studies, including oral melatonin 30 minutes before venipuncture (221), and lidocaine-prilocaine cream (169), 5 per cent lidocaine cream (169), vapocoolant spray (156), amethocaine, paracetamol and ibuprofen before needle procedures (158,159). Lidocaine-prilocaine cream and oral melatonin were found to reduce pain scores, and it was noted that lidocaine-prilocaine cream had the highest probability of being most effective in reducing pain (158,159). In addition, children who received melatonin had lower anxiety than those treated with placebo (221). Paracetamol and ibuprofen were not shown to reduce pain scores (158).
The harms reported in the literature were due to side effects from pharmacological interventions or adverse events associated with non-pharmacological interventions. In one review, two studies reported skin blanching as an adverse effect of lidocaine-prilocaine cream application (159). Feeding-related adverse events included choking while drinking formula milk during vaccination (not leading to additional interventions or complications) (212), or infants coughing, gagging and vomiting following sucrose administration (116,160,199,207). One study reported that when using non-nutritive sucking, some infants may refuse to suck and should not be forced to do so, as it may increase distress (162). Mild to moderate nausea was noted in some children when participating in a virtual reality intervention (187), and in another study examining virtual reality as an intervention two children took off the headset
# RECOMMENDATIONS
Vascular Access -Second Edition during the procedure stating that they felt distressed (175). Finally, one study on breathing techniques reported adverse events: three of 50 children reported respiratory difficulties when asked to engage in a specialized form of deep breathing (164).
The evidence was of low certainty due to some concerns over how individual studies were conducted, inconsistency in the measurement of the outcomes, and variability in the types of needle procedures examined. For more detailed information on the impact of the intervention (pharmacological and non-pharmacological pain management strategies) on the prioritized outcomes (patient's rating of pain, patient comfort, fear/anxiety related to poke or needle phobia, and patient satisfaction), refer to the evidence profiles available here: https://RNAO.ca/bpg/guidelines/ vascular-access-second-edition.
Specific components of the intervention noted in the literature are outlined below, under "Practice Notes. "
# Values and Preferences
An important consideration reported in the literature was recognizing the developmental stage of the child and how it may influence their preferred pain management intervention. In addition, children in a study using a virtual reality intervention reported positive satisfaction: one child explained that he was "nervous at the idea of blood draw, [but] the virtual reality game truly helped distract [him] from the feeling of the needle being inserted" (187). Another study that used virtual reality as an intervention reported that users of the virtual reality headsets stated that the device was effective in reducing pain and anxiety and offered a pleasant experience (190).
The evidence also reported infant feeding/positioning preferences. Not all mothers may want to breastfeed (or formula feed) their child, especially during immunization, if they are anxious themselves (208). One study stated it is important to consider the parental wishes for infant procedures (e.g., they could stay in the room or leave during the procedure, or they could offer comfort measures to the child) (200). In one study, parents preferred to have their children sitting up for the injections (162).
# Health Equity
Multiple studies examined breastfeeding as an intervention and noted it to be inexpensive, readily available and convenient (182,209). However, it is important to recognize person-and family-centred care principles: not all persons have the ability to breastfeed, or they simply may prefer not to do so.
No additional considerations for health equity were reported in the studies.
# Expert Panel Justification of Recommendation
Conventionally based on GRADE, this recommendation could have been voted conditional since the certainty of the evidence of the effects was low. Based on the balance of benefits and harms, including the harms of not following the recommendation, as well as values and preferences, the expert panel came to consensus on a strong recommendation. There are likely benefits to offering non-pharmacological and pharmacological pain management strategies. Although there were some harms in the form of side effects associated with pharmacological pain management strategies and feeding, the expert panel felt that the benefits greatly outweighed the harms. The interventions were also highly valued by children, infants and parents/guardians, and the expert panel felt that they aligned with person-and family-centred care principles. It is important to note that the expert panel chose the action word "offer" for this
# RECOMMENDATIONS
Vascular Access -Second Edition recommendation to highlight that pain management strategies need to be person-and family-centred and that ultimately the decision whether or not to receive pain management is up to the child and/or parents/guardians.
The certainty of the evidence was low, but due to the reasons stated above, the expert panel determined the recommendation to be strong.
# Practice Notes
Considerations from the expert panel Aseptic technique needs to be maintained during VAD insertion, regardless of the type of pain management strategy used.
The expert panel emphasized the importance of offering children, infants and parents/guardians the choice of a variety of pain management interventions. The expert panel noted that some children do not prefer topical anesthetic due to the increase in overall procedure time (i.e., topical anesthetic can take longer to take effect). An additional example was given of some children disliking the feeling associated with cryotherapy (such as aerosol vapocoolant sprays).
A physician order may be required prior to administration of pharmacological pain management interventions.
# RECOMMENDATIONS
Vascular Access -Second Edition One study reported that "the receptivity of infants to distraction is hypothesized to vary due to developing motor and cognitive capacities. On the basis of developmental milestones, a two-month old would seem less likely to benefit from distraction. However, a child older than 12 months would seem to have greater ability to benefit from distraction" (165).
Another study reported that distraction methods such as toys or books are generally preferred for children aged 7-12 years (190).
Information and preparation materials should be tailored to the age of the child. Storybooks that include age-appropriate health education messages and pictures enable children to better understand their treatment regimen (189).
# Psychological techniques
Various distraction interventions may be used by health providers. These include movies, cartoons, video games, storybooks, toys, cards, blowing bubbles, chewing gum, balloon inflation, virtual reality, music, parent distraction, a medical clown or squeezing a rubber ball.
Interactive or directed distraction may confer a larger benefit than non-directed distraction interventions. For example, one study stated that passive distraction by watching a cartoon may be less effective in reducing procedural pain than virtual reality motion videos, such as riding a roller coaster (190).
One systematic review that examined combined cognitive behavioural therapy and breathing interventions for reducing children's needle-related pain or distress found that combining multiple psychological strategies can be beneficial (164).
Positioning and touch Positioning of infants for the vascular access procedure may be different than it is for children.
Children: Parents may want to hold their older child sitting upright during the procedure (162,214). Holding the child in a parent's lap in a gentle hug, with the child's legs on either side of the parent, may be one way to deliver this intervention (162).
Infants: Skin-to-skin, swaddling, hugging, caressing, or facilitated tucking may be appropriate interventions (161,162,219).
# Infant feeding
Breastfeeding was shown to confer the greatest benefit as a nonpharmacological pain management intervention, since it combines the therapeutic effects of feeding, skin-to-skin care and infant positioning (161).
Formula feeding, non-nutritive sucking and sucrose were also found to be effective interventions if breastfeeding is not an option based on person-and family-centred care principles (162,212).
One study noted that non-nutritive sucking may be particularly beneficial for infants with latching difficulties or those who are unable to breastfeed (173).
# RECOMMENDATIONS
Vascular Access -Second Edition
# KEY INTERVENTION DETAILS FROM THE EVIDENCE
Acupressure/massage Three studies examined acupressure or massage therapy (216,220,222).
One study reported that "acupressure is a safe, inexpensive and easy-tolearn technique. Therefore, nurses can teach this technique to patients and involve them in their own treatment, and thereby enhance their self-confidence" (222).
However, it is important to note that health providers need additional training to perform acupressure.
The study that used this intervention noted that the acupressure intervention was implemented in two steps, with a 30-minute interval in between, and that it was performed by someone who had received the necessary acupressure training from an acupressure specialist (222).
Another study also noted that the researcher performing acupressure received certification prior to performing the intervention (220).
# Aromatherapy
One study demonstrated that aromatherapy using inhaled lavender essential oil for infants prior to heel lance reduced pain (197).
A systematic review demonstrated that inhaled maternal milk odor prior to heel lance was also effective in reducing pain in infants (167).
For aromatherapy interventions, health providers should be aware of any known allergies prior to administering the aromatherapy oils.
# Heat therapy
Two studies examined forms of heat therapy prior to heel lance or PVAD insertion in infants and children (176,218).
Electric heating pad: In one study of children aged 5-18 years, an electric heating pad (40°C) was applied at the site of the identified PVAD insertion for 10 minutes before PVAD insertion (218). The child was asked to inform the health provider if the heating device caused discomfort when applied to the chosen site (218).
In another study, infants in the experimental group received a heating pad ("thermophore") application for five minutes before a heel lance procedure (176). The warmth of the pad was kept between 34-37˚C. To prevent the heating pad from directly contacting the sole of the infant's foot, it was wrapped in a cloth and placed on the sole from which the heel lance would be taken (176).
Health providers should be aware of the potential for burns, irritation and skin discomfort when using heat therapy interventions.
# RECOMMENDATIONS
Vascular Access -Second Edition
# Supporting Resources
# RESOURCE DESCRIPTION
# Research Gaps and Future Implications
In reviewing the evidence for this BPG, the RNAO best practice guideline development and research team and expert panel identified priority areas for future research (outlined in Table 15). Studies conducted in these areas would provide further evidence to support high-quality and equitable support for persons with VAD. The list is not exhaustive; other areas of research may be required. Studies that explore blood draws from a VAD and their impact on device dwell time.
The impact of blood draws from a VAD versus blood draw from venipuncture on person and family values and preferences.
Qualitative studies examining the impact of blood draw technique on person and family experience (including a range of ages and cognitive needs).
Studies that explore blood draws from CVADs and their impact on infection and specimen integrity.
# RECOMMENDATION QUESTION #5:
Should the daily review of peripheral vascular access devices by health providers be recommended?
Outcomes: Complications.
Randomized controlled trials exploring the effectiveness of multi-component care protocols or daily PVAD reviews.
Long-term follow-up studies exploring the effect of PVAD care on rare complications.
Qualitative studies examining the role of PVAD care in person and family experience. Studies exploring pain management strategies for CVAD insertion and arterial catheter insertion.
Studies exploring the impact of routine use of topical anesthesia for PVAD insertion or venipuncture in adults.
Studies exploring person and family satisfaction and experience with pain management strategies (including people of various ages and cognitive needs).
Qualitative studies exploring pain management strategies for VAD insertion in adults and children.
# Applicable to all recommendation questions
Studies exploring the health equity implications of VAD insertion and management.
# RECOMMENDATIONS
Vascular Access -Second Edition
# Implementation Strategies
Implementing guidelines at the point of care is multi-faceted and challenging. It takes more than awareness and distribution of BPGs for practice to change must be adapted for each practice setting in a systematic and participatory way to ensure that recommendations fit the local context (223). The RNAO Leading Change Toolkit™ (2021), available online at https://www.RNAO.ca/leading-change-toolkit provides evidence-informed processes for this (see Appendix Q).
The Leading Change Toolkit™ uses two complementary frameworks to guide evidence uptake and sustainability (see Figure 1). They can be used together to maximize and accelerate change.
# Figure 1: Leading Change Toolkit™ Two Complementary Frameworks to Accelerate your Success
The Social Movement Action Framework ( 224) is descriptive and identifies the defining elements of a social movement for knowledge (e.g., BPGs) uptake and sustainability. It integrates a 'bottom-up' , people-led approach to change for a shared concern (or common cause) in which change agents and change teams mobilize individual and collective action to achieve goals. The framework's elements, categorized as preconditions, key characteristics and outcomes, are dynamic, inter-related and develop spontaneously as the social movement evolves.
The Knowledge-to-Action Framework uses a process model of action cycle phases to systematically guide the adaptation of the new knowledge (e.g., BPG) to the local context and implementation. This framework suggests identifying and using knowledge tools/products, such as guidelines, to determine gaps and begin the process of tailoring the new knowledge to local settings.
# RECOMMENDATIONS
Vascular Access -Second Edition
The Leading Change Toolkit™ is based on emerging evidence in health and social sciences that successful uptake and sustainability of best practice in health care is more likely when:
BPGs are selected for implementation through a participatory process led by change agents and change teams;
The selected BPGs reflect priority areas for a shared concern that is credible, valued and meaningful, or an urgency for action;
Stakeholders are identified and engaged throughout implementation to engage in individual and collective action;
Receptivity for implementing BPGs, including environmental readiness, is assessed;
Implementation strategies are tailored to the local context and designed to address barriers;
Use of the BPG is monitored and sustained;
Evaluation of the BPG's impact is embedded in the process to determine if the goals and outcomes have been met;
There are adequate resources to complete all aspects of the uptake and sustainability of the BPG; and, The BPG is scaled up, out, or deep, where possible, to widen its influence and create lasting health improvements.
RNAO is committed to widespread deployment and implementation of our BPGs. We use a coordinated approach to dissemination, incorporating a variety of strategies, including the following:
1. The Nursing Best Practice Champion Network®, which develops the capacity of individual nurses to foster awareness, engagement, and adoption of BPGs.
2. The BPG Order Sets TM provide clear, concise and actionable intervention statements derived from practice recommendations. BPG Order Sets TM can be readily embedded within electronic records, but they can also be used in paper-based or hybrid environments.
3. The BPSO® designation supports implementation at the organization and system levels. BPSOs focus on developing evidence-based cultures with the specific mandate to implement, evaluate and sustain multiple RNAO BPGs.
In addition, we offer annual capacity-building learning institutes on specific BPGs and their implementation.
Information about our implementation strategies can be found at:
RNAO
# R E F E R E N C E S
Vascular Access -Second Edition
# A P P E N D I C E S
Vascular Access -Second Edition Good practice statement: A good practice statement is directed primarily to nurses and the interprofessional teams who provide care to persons and their families across the spectrum of care, including (but not limited to): primary care, acute care, home care and long-term care. It refers to a practice already accepted as beneficial or to practical advice.
In the case of this BPG, the good practice statement is believed to be so beneficial that conducting a systematic review to prove its efficacy would be unreasonable. These statements are not based on a systematic review and do not receive a rating of the certainty or confidence in the evidence or strength (i.e., conditional or strong) (7).
# Grading of Recommendations Assessment, Development and Evaluation (GRADE):
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) is a methodological approach to assess the certainty of a body of evidence in a consistent and transparent way, and to develop recommendations in a systematic way. The body of evidence across identified important and/or critical outcomes is evaluated based on risk of bias, consistency of results, relevance of studies, precision of estimates, publication bias, large effect, dose-response and opposing confounding (8).
When using GRADE, five components contribute to the assessment of confidence in the evidence for each outcome. These components are as follows:
1. Risk of bias, which focuses on the flaws in the design of a study or problems in its execution. 2. Inconsistency, which looks at a body of evidence and assesses whether the results point in the same direction, or if they are different. 3. Imprecision, which refers to the accuracy of results based on the number of participants and/or events included, and the width of the confidence intervals across a body of evidence. 4. Indirectness, whereby each primary study that supports an outcome is assessed and a decision is made regarding the applicability of the findings to the population, intervention and outcome outlined in the research question. 5. Publication bias, where a decision is made about whether the body of published literature for an outcome potentially includes only positive or statistically significant results (237).
Health provider: Refers to both regulated workers (e.g., nurses, physicians, and respiratory therapists) and unregulated workers (e.g., physician's assistants and paramedics) who are part of the interprofessional team.
# Regulated health provider:
In Ontario, the Regulated Health Professional Act, 1991 (RHPA) provides a framework for regulating 23 health professions, outlining the scope of practice and the profession-specific controlled or authorized acts that each regulated professional is authorized to perform when providing health services (5).
Unregulated health provider: These providers fulfill a variety of roles in areas that are not subject to the RHPA. They are accountable to their employers but not to an external regulating professional body (e.g., the College of Nurses of Ontario). Unregulated health providers fulfill a variety of roles and perform tasks that are determined by their employer and employment setting. Unregulated health providers only have the authority to perform a controlled act as set out in the RHPA if the procedure falls under one of the exemptions set out in the Act (6).
# A P P E N D I C E S
Vascular Access -Second Edition Health-service organization: In this BPG, health-service organization refers to any health setting or workplace in which persons and/or families receive care from a health provider related to a VAD. . Hemolysis: "Destruction of the membrane of the red blood cells, resulting in the liberation of hemoglobin, which diffuses into the surrounding fluid" (228) . Blood samples that are hemolyzed due to improper handling or drawing of blood samples cannot be processed. This is the leading cause of samples being rejected by clinical laboratories.
# Implanted vascular access device (IVAD):
Permanent catheters that are characterized by a subcutaneous reservoir with a diaphragm that acts as a receptacle for infusion. The reservoir is connected to a central vein in the chest with a catheter (229). Port-a-caths (single or double) and broviacs (single or double) are examples of IVADs.
Implementation science: Defined as "the scientific study of methods to promote the systematic uptake of research findings and other evidence-based practices into routine practice, and, hence, to improve the quality and effectiveness of health services and care" (page 1) (270).
Infiltration: "The inadvertent administration of medication or solution into the surrounding subcutaneous or subdermal tissue instead of into the intended vascular pathway" (238). This has been reported to be the most frequent complication that is associated with short PVADs, specifically when located in the hand (102).
Interprofessional team: team comprising multiple health providers (regulated and unregulated) who work collaboratively to deliver comprehensive and quality health services to people within, between and across health settings (4). Key interprofessional team members supporting persons with vascular devices may include: nurses, nurse practitioners, physicians, respiratory therapists, physician's assistants, paramedics and child life specialists. It is important to emphasize that persons with a VAD and their chosen family are at the centre as active participants of the team.
Meta-analysis: systematic review that uses statistical methods to analyze and summarize the results of the included studies (239).
# See systematic review
Multi-component care protocol: A group of evidence-based interventions that can ensure the delivery of a standardized method of care; when these interventions are performed together, they can have a better outcome than if performed individually (also sometimes called a "care bundle") (adapted from (100).
Nurse: "Refers to registered nurses, licensed practical nurses (referred to as registered practical nurses in Ontario), registered psychiatric nurses and nurses in advanced practice roles, such as nurse practitioners and clinical nurse specialists" (5).
# A P P E N D I C E S
Vascular Access -Second Edition Osmolarity: The number of osmotically active particles in a solution (228).
Outcomes: A dependent variable, or the clinical and/or functional status of a patient or population, that is used to assess if an intervention is successful. In GRADE, outcomes are prioritized based on if they are critical for decision making, important but not critical for decision making, or not important. In so doing, the literature search and systematic reviews are more focused (8).
# See Grading of Recommendations Assessment, Development and Evaluation (GRADE)
Peripherally inserted central catheter (PICC): "A catheter inserted through veins of the upper extremity or neck in adults and children. For infants, the PICC may be inserted through veins of the scalp or a lower extremity. The catheter tip is located in the superior or inferior vena cava, preferably at its junction with the right atrium, regardless of insertion site" (228).
Peripheral Vascular Access Device (PVAD): "VAD inserted in peripheral vein with its tip not extending into the central vasculature" (25).
Person: An individual with whom a health provider has established a therapeutic relationship for the purpose of partnering for health. Replaces the terms "patient, " "client, " and "resident, " which are used across healthservice organizations (235).
Person-and family-centred care: An "approach to care [that demonstrates] certain practices that put the person and their family members at the centre of health services. Person-and family-centred care respects and empowers individuals to be genuine partners with health providers for their health" (235).
Phlebitis: Redness, swelling, tenderness, pain, purulent discharge and/or induration (palpable cord) at the insertion site of a vascular device (240,241).
# PICO research question:
A framework to outline a focused question. It specifies four components: 1. The patient or population that is being studied.
2. The intervention to be investigated.
3. The alternative or comparison intervention. 4. The outcome that is of interest (8).
# Practical education:
For the purposes of this guideline, practical education refers to deliberate practice, supervised insertions of VADs, hands-on training or one-on-one training for health providers. Practical or skills lab training follows a structured teaching concept, takes place under supervision and in consideration of foundational concepts, and ideally creates an atmosphere that allows the repeated, risk-free practice of targeted clinical skills (50).
# A P P E N D I C E S
Vascular Access -Second Edition Quasi-experimental study: A study that estimates causal effects by observing the exposure of interest, but in which the experiments are not directly controlled by the researcher and lack randomization (e.g., before-andafter designs) (242).
Randomized controlled trial: An experiment in which the investigator assigns one or more interventions to participants who are randomly allocated to either the experimental group (receives intervention) and the comparison (conventional treatment) or control group (placebo or no intervention) (239).
Recommendation: A course of action(s) that directly answers a recommendation question (also known as a PICO research question). A recommendation is based on a systematic review of the literature and is made in consideration of its (a) benefit and harms, (b) values and preferences, and (c) health equity. All recommendations are given a strength-either strong or conditional-through panel consensus.
It is important to note that recommendations should not be viewed as dictates, because recommendations cannot take into account all of the unique features of individual, organizational and clinical circumstances (8).
# Recommendation question:
A priority research area of practice, policy or education identified by expert panel members that requires evidence to answer. The recommendation question may also aim to answer a topic area around which there is ambiguity or controversy. The recommendation question informs the research questions, which guides the systematic review (8).
Simulation (simulation learning): "Simulation is the imitation of some real thing, state of affairs or process.
In health professions education, simulation is a methodology to help achieve educational goals. Health-care simulation encompasses a range of activities that share a broad but common purpose: to improve the safety, effectiveness and efficiency of health-care services" (243). "Simulation activities can include computer-based simulation, e-learning, high-fidelity patient simulators, role playing and other blended approaches" (244).
Social movement in the context of knowledge uptake and sustainability: Individuals, groups and/or organizations who, as voluntary and intrinsically motivated change agents, mobilize to transform health outcomes (266).
Stakeholder: "An individual, group or organization that has a vested interest in the decisions and actions of organizations, and which may attempt to influence decisions and actions" (245). Stakeholders include all of the individuals and groups that will be directly or indirectly affected by the change or solution to the problem.
# Successful Observed Attempt (or Successful VAD insertion attempt):
A PVAD insertion attempt is deemed to be successful if there is evidence of blood flashback in the catheter upon insertion, and if the device flushes easily with no signs of infiltration, swelling or leakage upon flushing (adapted from ( 126), (127), and ( 128)).
Note: If ultrasound-guidance technique is used, it should be evident on ultrasound that the catheter is positioned properly in the vein. A CVAD insertion attempt should be confirmed with x-ray.
# A P P E N D I C E S
Vascular Access -Second Edition Systematic review: A comprehensive review of the literature that uses clearly formulated questions and systematic and explicit methods to identify, select and critically appraise relevant research. A systematic review collects and analyzes data from the included studies and presents them, sometimes using statistical methods (239).
# See meta-analysis
Ultrasound-guided Technique: Ultrasound imaging (an image created by sending sound waves through soft tissue) allows health providers to see surrounding anatomical structures (119). It can be used to aid the health provider when inserting a PVAD, CVAD or peripheral arterial catheter. Ultrasound guidance allows visualization of both the needle and the target vessel on the monitor, using either the short-axis or long-axis view (123).
Valsalva maneuver: A breathing technique that can be used as a pain management strategy during VAD insertion. It involves "a deep inhale, followed by a forceful holding of the breath, during which the venous cannulation insertion occurs" (143).
# Vascular access device (VAD):
Vascular access devices (VADs) are defined as a catheter (thin tube) inserted into veins that can be implanted or inserted under the skin, allowing fluids and medicines to be delivered into veins (adapted from ( 3)). Catheters inserted into arteries can be used to monitor therapy (adapted from ( 3)).
# Examples of VADs include:
peripheral vascular access devices (PVADs), such as short peripheral intravenous catheters (PIVs) and extended dwell, midline catheters;
central vascular access devices (CVADs), such as peripherally inserted central catheters (PICCs), tunneled catheters, non-tunneled catheters and implanted vascular access devices (IVADs); peripheral arterial catheters; and phlebotomy devices.
# Vascular access specialist team (VAST) or vascular access specialists (VAS)\
; "A grouping of health providers who have advanced knowledge and skills in the assessment, insertion, care and management of VADs" (3). This includes infusion/intravenous, intravenous therapy teams and individual vascular access specialists (nurses, physicians, respiratory therapists, laboratory technicians and physician assistants) (3).
Venipuncture: "A procedure in which a needle is used to take blood from a vein, usually for laboratory testing. Also called blood draw and phlebotomy" (246).
Vesicant: "An agent capable of causing tissue damage when it escapes from the intended vascular pathway into surrounding tissue" (228). Tissue damage can cause injury, blistering, necrosis and redness of the skin.
# A P P E N D I C E S
Vascular Access -Second Edition *Note: An updated edition of the infusion therapy standards of practice published in early 2021, and this updated version was used as a supporting resource in this BPG, and to inform the good practice statement, glossary and appendices where applicable.
Canadian Vascular Access Association. Canadian vascular access and infusion therapy guidelines. Pembroke (ON): Pappin Communications; 2019.
Score: 5 out of 7.
This guideline was used as a supporting resource in this BPG, and to inform the background, good practice statement, glossary and appendices.
# 3.
Telephone key informant interviews. Eleven interviews were conducted with experts in the field-including direct care health providers, researchers, educators and managers-to understand the needs of nurses, members of the interprofessional health team and persons with lived experience.
4. Telephone discussion group sessions. Three sessions were convened to understand the needs of nurses, members of the interprofessional health team and persons with lived experience.
# Assembly of the Expert Panel
RNAO aims for diversity in membership of an expert panel; this is in alignment with its Organizational Statement on Diversity and Inclusivity, which is part of the RNAO Mission and Values (248).
RNAO identifies and selects members of an expert panel through numerous different avenues. This includes the following:
searching the literature for researchers in the topic area;
soliciting recommendations from key informant interviews;
drawing from established professional networks, such as RNAO Interest Groups, the Nursing Best Practice Champions Network® and BPSOs®; and
drawing from other nursing and health provider associations, topic-relevant technical associations or organizations, and advocacy bodies.
For this BPG, the RNAO best practice guideline development and research team assembled a panel of experts from nursing practice, research and education, as well as other members of the interprofessional team, to represent a range of sectors and practice areas (see members of the RNAO Best Practice Guideline Expert Panel on page 24).
The expert panel engaged in the following activities:
approved the purpose and scope of this BPG, determined the recommendation questions and outcomes to be addressed in this BPG, participated in a consensus G development process to finalize recommendation statements, provided feedback on the drafts of this BPG, participated in the development of evaluation indicators, helped develop BPG Order Sets™, and identified appropriate stakeholders to review the draft guideline prior to publication.
# A P P E N D I C E S
Vascular Access -Second Edition
In addition to the above, the expert panel co-chairs engaged in the following activities:
participated in monthly meetings with the guideline development methodologists and guideline development project coordinator, facilitated expert panel meetings, provided in-depth guidance on clinical and/or research issues, and moderated voting processes.
# Conflict of Interest
In the context of RNAO BPG development, the term "conflict of interest" (COI) refers to situations in which an expert panel member's or RNAO staff member's financial, professional, intellectual, personal, organizational or other relationships may compromise their ability to conduct panel work independently. Declarations of COI that might be construed as constituting a perceived and/or actual conflict were made using a standard form by all members of the expert panel prior to their participation in guideline development work. Expert panel members also updated their COI at the beginning of each in-person guideline meeting and upon final review of the guideline. Any COI declared by an expert panel member was reviewed by both the RNAO best practice guideline development and research team and by expert panel co-chairs. No limiting conflicts were identified. See Declarations of Conflicts of Interest Summary at https://rnao.ca/bpg/guidelines/vascular-access-second-edition.
# Identifying Priority Recommendation Questions and Outcomes
RNAO systematic review questions are developed as per the PICO format (population, intervention, comparison and outcome).
The RNAO best practice guideline development and research team and expert panel convened in-person to determine the priority recommendation questions and outcomes for this BPG. A comprehensive list of recommendation questions that the BPG could potentially address was developed at the meeting. This was informed by:
the environmental scan of guidelines;
the review of the literature;
key informant interviews and discussion groups; and expert panel discussion at the in-person meeting.
This comprehensive list of potential recommendation questions was presented to the expert panel for a vote. Each expert panel member was allowed six votes for preferred recommendation questions. The six recommendation questions with the most votes were deemed the final recommendation questions. The recommendation question on VAST was originally a sub-question of the recommendation question on practical education, bringing the total to seven questions. Expert panel co-chairs did not participate in the vote.
Following this initial vote-and in alignment with GRADE standards for assessing and presenting the evidenceoutcomes were identified and prioritized per recommendation question. A comprehensive list of outcomes per recommendation question was developed at the in-person meeting, informed by the following:
the review of the literature;
key informant interviews and focus groups; and expert panel discussion at the in-person meeting.
# A P P E N D I C E S
Vascular Access -Second Edition
Based on the comprehensive list of outcomes, the expert panel was asked to rank-order the relative importance of each outcome per recommendation question. Each panel member participated in a confidential online rank-order vote. It was deemed feasible to have up to a total of 18 prioritized outcomes across the seven recommendation questions. Expert panel co-chairs did not participate in the vote as they functioned as co-facilitators. Voting results were presented to the expert panel and through a facilitated discussion, priority outcomes were determined per recommendation question.
The seven recommendation questions-and their respective PICO research questions-are presented below. Outcomes: Complications (including insertion-related complications), and number of successful observed attempts.
# A P P E N D I C E S
Vascular Access -Second Edition Expert panel members were asked to review their personal libraries for key studies not found through the above search strategies (see Appendix D). Detailed information on the search strategy for the systematic reviews, including the inclusion and exclusion criteria and search terms, is available from https://RNAO.ca/bpg/guidelines/vascularaccess-second-edition.
Systematic review search dates were limited to the last five years from the guideline launch in order to capture the most up-to-date evidence. All study designs were included in the search. As there was a large yield for research questions six and seven, an overview of reviews methodology was used. Systematic reviews and randomized controlled trials were included. Non-randomized controlled trials were not included. For research question two, the inclusion of systematic reviews and randomized controlled trials were prioritized, and non-randomized controlled trials were used to supplement outcomes not reported in the systematic review and randomized controlled trials.
In cases where there were multiple systematic reviews based on the same body of evidence, only the highest quality review was included as assessed using the ROBIS tool (249). In a case of two high-quality reviews, the most recent one was selected. Non-randomized controlled trials or randomized controlled trials included in systematic reviews were excluded to avoid double counting.
All studies were independently assessed for relevance and eligibility by two guideline development methodologists based on the inclusion and exclusion criteria. Any disagreements were resolved through consensus.
All included studies were independently assessed for risk of bias by study design using validated and reliable tools. Randomized controlled trials were assessed using the Risk of Bias 2.0 tool (250), while quasi-experimental studies G and other non-randomized studies were assessed using the ROBINS-I tool (251), and systematic reviews were assessed using the ROBIS tool (249). The risk of bias assessment of individual studies included in systematic reviews was extracted from the review when available; if unavailable, the two guideline development methodologists conducted a risk of bias assessment of the included individual studies using the appropriate tool. The two guideline development methodologists reached consensus on all scores through discussion.
For data extraction, the included studies were divided equally between the guideline development methodologists.
Each guideline development methodologist extracted information from their assigned studies, and this was reviewed by the other guideline development methodologist for accuracy.
In November 2020, the health science librarian conducted an update search for relevant research studies published in English between the end of the original search dates (late 2018 or early 2019) and November 2020 that answer the research questions. The search was applied to the following databases: Cumulative Index to Nursing and Allied Health (CINAHL), Medline, Medline in Process, Cochrane Central, Cochrane Database of Systematic Reviews, Embase and Emcare. Results from 56 studies were incorporated into the discussions of evidence for all Recommendations. In April 2021, the health science librarian conducted a final update search from November 2020 that answer the research question. Results from 17 studies were incorporated into the discussions of evidence for Recommendation 1.1, 2.1, 6.1, 7.1 and 7.2. See the PRISMA diagrams in Appendix D for studies included in the update search.
# A P P E N D I C E S
Vascular Access -Second Edition
# Determining Certainty and Confidence of Evidence
# Certainty of Evidence
The certainty of quantitative evidence (i.e., the extent to which one can be confident that an estimate of an effect is true) is determined using GRADE methods (8). First, the certainty of the evidence is rated for each prioritized outcome across studies (i.e., for a body of evidence) per research question (8). This process begins with the study design and then requires an examination of five domains-risks of bias, inconsistency, imprecision, indirectness and publication bias-to potentially downgrade G the certainty of evidence for each outcome. See Table 16 for a definition of each of these certainty criteria.
# Risk of bias
Limitations in the study design and execution that may bias study results. Valid and reliable quality appraisal tools are used to assess the risk of bias. First, risk of bias is examined for each individual study and then examined across all studies per defined outcome.
# Inconsistency
Unexplained differences (heterogeneity) of results across studies. Inconsistency is assessed by exploring the magnitude of difference, and possible explanations in the direction and size of effects reported across studies for a defined outcome.
# Indirectness
Variability between the research and review question and context within which the recommendations would be applied (applicability). There are four sources of indirectness which are assessed: 1. differences in population, 2. differences in interventions, 3. differences in outcomes measured, [and] 4. differences in comparators.
# Imprecision
The degree of uncertainty around the estimate of effect. This is usually related to sample size and number of events. Studies are examined for sample size, number of events and confidence intervals.
# Publication bias
publication of studies based on study results. If publication bias is strongly suspected, downgrading is considered.
Source: Reprinted from: Schunemann H, Brozek J, Guyatt G, et al., editors. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach [Internet]. [place unknown: publisher unknown]; 2013. Available from: https://gdt.gradepro.org/app/ handbook/handbook.html#h.svwngs6pm0f2. Reprinted with permission.
# A P P E N D I C E S
Vascular Access -Second Edition Following the initial consideration for rating down the certainty of quantitative evidence, three factors are assessed that can potentially enable rating up the certainty of evidence for observational studies:
1. Large magnitude of effect: If the body of evidence has not been rated down for any of the five criteria and a large estimate of the magnitude of intervention effect is present, there is consideration for rating up. 2. Dose-response gradient: If the body of evidence has not been rated down for any of the five criteria and a doseresponse gradient is present, there is consideration for rating up. 3. Effect of plausible confounding: If the body of evidence has not been rated down for any of the five criteria and all residual confounders would result in an underestimation of treatment effect, there is consideration for rating up (8).
GRADE categorizes the overall certainty of evidence as high, moderate, low or very low. See Table 17 below for the definitions of these categories.
For this BPG, the five GRADE quality criteria for potentially downgrading quantitative evidence and the three GRADE quality criteria for potentially rating up were independently assessed by the two guideline development methodologists. Any discrepancies were resolved through consensus. An overall certainty of evidence per recommendation was assigned based on these assessments. The certainty of evidence assigned to each recommendation was based on the certainty of prioritized outcomes in the studies that informed the recommendation.
# High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
# Very Low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
# A P P E N D I C E S
Vascular Access -Second Edition
# Formulating Recommendations
# Summarizing the Evidence
Studies were grouped according to themes based on consensus by the two guideline development methodologists for each research question. Draft recommendation statements were developed based on the themes. For each draft recommendation, GRADE evidence profiles were constructed by the two guideline development methodologists. GRADE evidence profiles are used to present decisions on determining the certainty of evidence, as well as general information about the body of research evidence, including key statistical or narrative results (8).
The evidence profiles for the body of quantitative studies presented the decisions made by the two guideline development methodologists on the five key GRADE certainty criteria for rating down the population included in the studies, the countries where the studies were conducted, the key results, and the transparent judgments about the certainty underlying the evidence for each outcome (8). The evidence profiles for quantitative studies presented the relative importance of outcomes as determined by the expert panel through a confidential online vote using a ninepoint Likert scale that ranged from 1 (less important) to 9 (most important). For this BPG, meta-analyses G were not performed; therefore, results were synthesized using narrative.
The GRADE evidence profiles for each recommendation, organized per outcome, can be accessed online at https:// RNAO.ca/bpg/guidelines/vascular-access-second-edition.
# Evidence-to-Decision Frameworks
Evidence-to-Decision (EtD) frameworks G outline proposed recommendations and summarize all necessary factors and considerations based on available evidence and expert panel judgement for formulating the recommendation statements. EtD frameworks are used to help ensure that all of the important factors (i.e., certainty of the evidence, benefits and harms, values and preferences, and health equity) required to formulate recommendation statements are considered by the expert panel (8). The guideline development methodologists draft the EtD frameworks with available evidence from the systematic reviews.
For this BPG, the EtD frameworks included the following areas of consideration for each drafted recommendation statement (see Table 18):
Background information on the magnitude of the problem.
This includes the PICO question and general context related to the research question.
The balance of benefits and harms of an intervention.
Certainty of the evidence.
Values and preferences.
Health equity.
# Decision Making: Determining the Direction and Strength of Recommendations
Expert panel members are provided with the EtD frameworks to review prior to a scheduled two half-day virtual meeting to determine the direction (i.e., a recommendation for or against an intervention) and the strength (i.e., strong or conditional) of a BPG's recommendations. Expert panel members are also given access to the complete evidence profiles and full-text articles.
# A P P E N D I C E S
Vascular Access -Second Edition For this guideline, the expert panel convened virtually to determine the direction and strength of the guideline's recommendations The expert panel co-chairs and the two guideline development methodologists facilitated the virtual meeting to allow for adequate discussion for each proposed recommendation.
The decision on direction and strength of each recommendation statement was determined by discussion and a consensus vote of at least 70 per cent of voting panel members. The voting process was anonymous, using a virtual poll through the online meeting platform. It was moderated by the expert panel co-chairs, guideline development methodologists and guideline development project coordinator. In determining the strength of a recommendation statement, the expert panel was asked to consider the following (see Table 18):
the balance of benefits and harms of an intervention,
the certainty and/or confidence of the evidence, values and preferences, and health equity.
There was one recommendation that was not voted on during the virtual meetings due to time constraints (Recommendation 1.1). This recommendation was voted on by the expert panel through an online survey platform in the week following the virtual meetings. Expert panel members were able to vote on the strength and direction of the recommendation, and provide any feedback through this survey.
# Benefits and harms
Potential desirable and undesirable outcomes reported in the literature when the recommended practice or intervention is used.
"The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a conditional recommendation is warranted" (252).
Includes research exclusively from the systematic review.
# Certainty of evidence
The extent of confidence that the estimates of an effect are adequate to support a recommendation. The extent of confidence that a review finding is a reasonable representation of the phenomenon of interest (253).
Recommendations are made with different levels of certainty or confidence; the higher the certainty or confidence, the higher the likelihood that a strong recommendation is warranted (252).
Includes research exclusively from the systematic review.
# A P P E N D I C E S
Vascular Access -Second Edition
# FACTOR DEFINITION SOURCES
# Values and preferences
The relative importance or worth of the health outcomes of following a particular clinical action from a person-centred perspective.
"The more values and preferences vary or the greater the uncertainty in values and preferences the higher the likelihood that a conditional recommendation is warranted" (252).
Includes evidence from the systematic review (when available) and other sources, such as insights from the expert panel.
# Health equity
Represents the potential impact of the recommended practice or intervention on health outcomes or health quality across different populations.
The greater the potential for increasing health inequity, the higher the likelihood that a conditional recommendation is warranted (254).
Includes evidence from the systematic review (when available) and other sources, such as insights from the expert panel.
# Developing Good Practice Statements
Following the in-person meeting, the good practice statement was developed by the RNAO best practice guideline development and research team to capture the need for health providers to complete a systematic assessment prior to initiating vascular access. The expert panel was sent a survey asking them to respond to five questions pertaining to each statement:
1. Is the statement clear and actionable? 2. Is the message really necessary in regards to actual health practice? 3. After consideration of all relevant health outcomes and potential downstream consequences, will implementing the good practice statement result in large net positive consequences? 4. Is a systematic review of the evidence necessary or required for this recommendation? 5. Is there a clear and explicit rationale to support this good practice statement?
Thirteen out of 17 panel members completed the survey on the good practice statement on assessment prior to initiating vascular access. The results are as follows:
For the first question, 12 of 13 respondents answered "yes. "
For the second question, 12 of 13 respondents answered "yes. "
For the third question, 9 of 13 respondents answered "yes. "
For the fourth question, 9 of 13 respondents answered "no. "
For the fifth question, 12 of 13 respondents answered "yes. "
# A P P E N D I C E S
Vascular Access -Second Edition
# Determining Supporting Resources and Appendices
Content for the supporting resources and appendices was submitted throughout the guideline development process by expert panel members and stakeholders. The two guideline development methodologists reviewed the content based on the following five criteria:
1. Relevance: Supporting resources and appendices should be related to the subject of the BPG or recommendation.
In other words, the resource or appendix should be suitable and appropriate in relation to the purpose and scope of the BPG or the specific recommendation(s). 2. Timeliness: Resources should be timely and current. Resources should be published within the last 10 years or in line with current evidence. 3. Credibility: When assessing credibility, the trustworthiness and expertise of the source material's author or authoring organization is considered. Potential biases are also assessed, such as the presence of advertising or the affiliation of the authors with a private company selling health products. 4. Quality: This criterion assesses the accuracy of the information and the degree to which the source is evidenceinformed. The assessment of quality is in relation to the subject of the resource. For example, if a tool is being suggested, is that tool reliable and/or valid? 5. Accessibility: This criterion considers whether the resource is freely available and accessible online.
# Drafting the Guideline
The guideline development methodologists wrote the draft of this BPG. The expert panel reviewed the draft and provided written feedback. The BPG then proceeded to external stakeholder review.
# Stakeholder Review
As part of the guideline development process, RNAO is committed to obtaining feedback from: (a) nurses and other health providers from a wide range of practice settings and roles, (b) knowledgeable administrators and funders of health services, and (c) stakeholder associations.
Stakeholder reviewers for RNAO BPGs are identified in two ways. First, stakeholders are recruited through a public call issued on the RNAO website (RNAO.ca/bpg/get-involved/stakeholder). Second, individuals and organizations with expertise in the guideline topic area are identified by the RNAO best practice guideline development and research team and the expert panel, and are directly invited to participate in the review.
Stakeholder reviewers are individuals with subject matter expertise in the guideline topic or those who may be affected by its implementation. Reviewers may be nurses, members of the interprofessional team, nurse executives, administrators, research experts, educators, nursing students, or persons with lived experience and family members.
Reviewers are asked to read a full draft of the BPG and participate in its review prior to its publication. Stakeholder feedback is submitted online by completing a survey questionnaire. The stakeholders are asked the following questions about each recommendation and the good practice statement: In addition, stakeholder reviewers were given the option to enter additional comments or suggestions. Survey submissions are compiled and feedback is summarized by the RNAO best practice guideline development and research team. Together with the expert panel, they review and consider the survey results. If necessary, BPG content and recommendations are modified prior to publication to reflect the feedback received.
For this BPG, the stakeholder review process was completed between November 11, 2020 and December 2, 2020. Diverse perspectives provided feedback (see Stakeholder Acknowledgement).
# Procedure for Updating the Guideline
The RNAO commits to updating all BPGs, as follows:
1. Each BPG will be reviewed by a team of specialists in the topic area every five years after publication of the previous edition.
2. RNAO International Affairs and Best Practice Guidelines Centre staff regularly monitor for new systematic reviews, randomized controlled trials and other relevant literature in the field.
3. Based on that monitoring, staff may recommend an earlier revision period for a particular BPG. Appropriate consultation with members of the original expert panel and other specialists and experts in the field will help inform the decision to review and revise the BPG earlier than planned. 3. Compiling a list of specialists and experts in the field for potential participation on the expert panel. The expert panel will be comprised of both members from the original expert panel and new ones.
5. New editions of BPGs will be disseminated based on established structures and processes.
# A P P E N D I C E S
Vascular Access -Second Edition Steps 1 and 2
Step 3
Step 6
Step 4
Step 5
# A P P E N D I C E S
Vascular Access -Second Edition Appendix F: Overview of Types of Vascular Access Devices VAD inserted in peripheral vein with the tip not extending into the central vasculature (25).
#
In extremes of pH-use PVAD with caution (25).
See details for specific types of PVAD devices below.
# 1a) Short peripheral vascular access device (PVAD)
A short, usually winged device that provides access to peripheral veins of the arm or foot or the external jugular vein in the neck. Short PVADs can be placed at the patient's bedside by various health providers (229).
Use an accessible peripheral vein in the upper extremity for the duration of therapy (25).
Use for short-term duration of therapy (e.g., < 7 days) (25).
#
Consider the infusate characteristics (e.g., irritant, vesicant or osmolarity) in conjunction with the anticipated duration of infusion therapy and availability of peripheral vascular access sites (37).
Do not use short PVADs for continuous vesicant therapy, parenteral nutrition or infusates with an osmolarity greater than 900 mOsm/L (37).
#
Select the smallest-gauge short PVAD catheter that will accommo date the prescribed therapy and patient need (37):
20-24 gauge for most infusion therapies. For pediatric populations: Consider veins in the hand, forearm and upper arm below the axilla. Avoid the antecubital area, which has a higher failure rate. For infants and toddlers, also consider veins of the scalp, and if not walking, the foot. For pediatric populations: Consider veins in the hand, forearm and upper arm below the axilla. Avoid the antecubital area, which has a higher failure rate. For infants and toddlers, also consider veins of the scalp, and if not walking, the foot.
# A P P E N D I C E S
Vascular Access -Second Edition A VAD inserted in peripheral vein in upper arm, with the tip residing near or at the level of the axilla and distal to the shoulder (25).
Use an accessible peripheral vein in the upper extremity, above the antecubital fossa (ACF) (25).
Select sites in the upper arm (preferred) or the region of the antecubital fossa (secondary option), using the basilic, cephalic, median cubital and brachial veins, with the basilic vein preferred (37).
For neonates and pediatric patients, additional site selections include veins in the leg with the tip below the groin, and in the scalp with the tip in the neck, above the thorax (37).
#
Use when the duration of therapy is less than 4 weeks (25).
Consider a midline catheter for medications and solutions, such as antimicrobials, fluid replacement and analgesics, with characteristics that are well tolerated by peripheral veins (37).
Do not use midline catheters for continuous vesicant therapy, parenteral nutrition or infusates with an osmolarity greater than 900 mOsm/L (37). Suitable peripheral access is unavailable.
# Central vascular access device (CVAD)
Osmolarity of continuous solution and/or medication is greater than 900 mOsm/L (e.g., parenteral nutrition).
Continuous vesicant infusion is needed (i.e., infusion required for more than 60 minutes).
#
Consider implanted or tunneled CVAD for long-term therapy.
#
Consider long-term intermittent vesicant infusion.
#
Consider CVAD for irritant infusion that is required to infuse longer than 60 minutes, or ongoing intermittent infusion (i.e., irritant medication infusion multiple times per day, for multiple days) (25).
See details for specific types of CVAD devices below.
# A P P E N D I C E S
Vascular Access -Second Edition Tunnelled: Permanent or temporary devices that are characterized by the creation of a subcutaneous tunnel between the insertion of the catheter on the skin and the point of puncture in the vein. Tunneled catheters always terminate in central veins.
Non-tunnelled: Often referred to as "acute" or "short-term" CVCs, these are often inserted for durations of 7 to 14 days. They are typically 15 to 25 cm and are placed via direct puncture (often using ultrasonography) and cannulation of the internal jugular, subclavian or femoral veins (229).
Can be cuffed or un-cuffed. The cuff is a silicone-based flange that provides tethering to the subcutaneous tissue and prevents the catheter from migrating. The cuff may also provide protection against infection (229).
Confirmation of the anatomic location of the catheter tip is needed prior to initial use, and as needed for evaluation of VAD dysfunction (37).
A permanent dialysis line is an example of a tunnelled catheter.
# A P P E N D I C E S
Vascular Access -Second Edition Permanent catheters that are characterized by a subcutaneous reservoir with a diaphragm that acts as a receptacle for infusion. The reservoir is connected to a central vein in the chest with a catheter (229).
Requires a minor surgical procedure for placement and removal.
#
Confirmation of the anatomic location of the catheter tip is needed prior to initial use, and as needed for evaluation of VAD dysfunction (37).
Consider an implanted vascular access port for patients who are anticipated to require intermittent long-term infusion therapy (e.g., antineoplastic therapy or chemotherapy). When used intermittently, ports have a lower incidence of catheter-related bloodstream infection, but continuous port access has infection rates that are similar to other long-term CVADs (37).
# Peripheral arterial catheter
Device that can be inserted peripherally or centrally and can be used to monitor blood pressure and the hemodynamic status of people in critical care settings (225).
Place a peripheral arterial catheter for short-term use for hemodynamic monitoring, obtaining blood samples and analyzing blood gas in critically ill patients (37). Perofrmance of the procedure according to current guidelines for hygiene and intravascular procedures.
Shows no regard to hygiene.
Follows guidelines partially. Follows guidelines.
# A P P E N D I C E S
Vascular Access -Second Edition
# Appendix K: Example of Ultrasound-guided Device Technique
This figure provides an example of how ultrasound-guided technique may be used for the insertion of a VAD. There are two visualization techniques that can be used: the long axis ("in plane") view or the short axis approach.
This example is meant to be used for general information purposes only, and is not to be used as a sole resource when teaching health providers ultrasound-guided technique for VAD insertion. See the American Institute of Ultrasound in Medicine's Practice Parameter for the Use of Ultrasound to Guide Vascular Access Procedures for further details on ultrasound-guided technique (258). The following scales have been validated for determining DiVA. The DIVA scale has been validated for use in children (see Table 21) and the A-DIVA scale has been validated for use in adults (see Table 22) (259,260). For the DIVA scale, a score of 4 or higher identifies children in whom PIV access is likely to fail the first time it is attempted (259).
In adults, the A-DIVA scale is used to determine whether a person is at low risk (score 0-1), medium risk (score 2-3) or high risk (score 4 plus) for DiVA (260). Health providers should be trained on the appropriate use of these scales prior to using them in practice. It is important to note that although skin colour can be a predictor variable, it should not be the only determinant of DiVA.
# A P P E N D I C E S
Vascular Access -Second Edition
# History of difficult intravenous access
Was it difficult to insert a peripheral intravenous catheter in the past?
1
# Visual Appearance
Is it impossible to identify the target vein by visualizing the upper extremity?
1
# Unplanned indication for surgery
Is the patient at an emergency indication for surgery?
1
# Diameter of the vein ≤ 2 millimeters
Does the target vein have a diameter of at most 2 millimeters?
1 Note: the A-DIVA scale is represented as an additive scoring system to calculate the predicted risk for an individual patient; the scores for existing risk factors are added to give an approximate estimation of a difficult intravenous access. Score are added after answering a quetsion with "yes." Vapocoolant spray.
# A P P E N D I C E S
Vascular Access -Second Edition
# OTHER CONSIDERATIONS (FOR ALL AGES)
Discuss the plan of care with the child and their family/caregiver.
Offer multiple pain management strategies, and consider child and/or family/caregiver preference in deciding which pain management strategy to use for the procedure.
Adopt the least invasive approach. Group blood drawings, when possible.
Involve a child life therapist (if available).
Combining multiple non-pharmacological psychological interventions can be beneficial.
# If using distraction techniques:
Children older than 12 months have a greater ability to benefit from distraction techniques.
Storybooks that include age-appropriate health education messages and pictures enable children to better understand their treatment regimen.
Interactive or directed distraction may confer a larger benefit than non-directed distraction interventions. For example, passive distraction by watching a cartoon video may be less effective in reducing procedural pain than virtual reality motion videos, such as riding a roller coaster.
Be cautious of mild to moderate nausea if using virtual reality as an intervention.
If using breastfeeding, formula feeding or sucrose administration:
Be cautious of feeding-related adverse events (e.g., choking, gagging and vomiting).
If using lidocaine-prilocaine cream:
Apply cream 30 to 60 minutes before the procedure.
Maximum application time of 4 hours in children, or a maximum of 1 hour in infants equal to or less than 3 months of age.
Side effects include vasoconstriction, methemoglobinemia and hypersensitivity.
Contraindications include: allergy, application on mucosae or an open wound, methemoglobinemia or G6PD.
If using vapocoolant spray:
Spray 10 seconds or until blanching (use a maximum of twice at the same site).
Immediate onset.
Side effects include: burning sensation and frostbite.
Contraindications: less than 3 years of age, hypersensitivity, or application on mucosae or an open wound.
References: (139, 160-165, 177-190, 199-214, 261-265)
# A P P E N D I C E S
Vascular Access -Second Edition
# Figure 17: Social Movement Action Framework
The KTA Framework is a planned cyclical approach to change that integrates two related components: the knowledge creation and the action cycle. The knowledge creation process is what researchers and guideline developers use to identify critical evidence results to create a knowledge product, like an RNAO BPG. The action cycle is comprised of seven phases in which the knowledge created is implemented, evaluated and sustained (267). Many of the action cycle phases may occur or need to be considered simultaneously. The KTA Framework is depicted in Figure 18 (269).
# A P P E N D I C E S
Vascular Access -Second Edition Implementing and sustaining BPGs to effect successful practice changes and positive health outcomes for patients/ persons and their families, providers, organizations and systems is a complex undertaking. The Leading Change Toolkit™ is a foundational implementation resource for leading this process. It can be downloaded at https://www. rnao.ca/leading-change-toolkit.
# Acknowledgements
We acknowledge that the office of the RNAO is located on the traditional and unceded territory of the Huron-Wendat, Haudenosaunee, and most recently, the territory of the Mississaugas of the Credit. This territory was the subject of the Dish With One Spoon Wampum Belt Covenant, an agreement between the Iroquois Confederacy and the Ojibwe and allied nations to peaceably share and care for the resources around the Great Lakes. This land is still the home to many First Nations, Inuit and Métis peoples from across Turtle Island and we are grateful to have the opportunity to work on this territory. By making a land acknowledgement, we are taking part in an act of reconciliation, honouring the land and Indigenous heritage, which dates back over 10,000 years. We encourage you to learn about the land you reside on and the treaties that are attached to it; land acknowledgements are an act of reconciliation and we must all do our part.
# Acknowledgements
External review provided by:
# Appendix A: Glossary of Terms
Arterial catheter: Device that can be inserted peripherally or centrally, and that can be used to monitor blood pressure and the hemodynamic status of people in critical care settings (225).
Aseptic Non Touch Technique (ANTT®): Aseptic Non Touch Technique (ANTT®) is a unique, standardized approach to aseptic practice that has been shown to support the reduction of health care-acquired infection" (34).
Best practice guidelines: "Best practice guidelines are systematically developed, evidencebased documents that include recommendations for nurses and the interprofessional team, educators, leaders and policy-makers, persons and their families on specific clinical and healthy work environment topics. BPGs promote consistency and excellence in clinical care, health policies and health education, ultimately leading to optimal health outcomes for people and communities and the health system" (226).
Caregiver: "A family member, friend or person of choice who gives unpaid care to someone who has care needs due to a disability, a physical, neurological or mental condition, a chronic illness, frailty or age" (227). In this BPG, care needs may be related to a VAD.
# Central line-associated bloodstream infection (CLABSI): "A central line-associated bloodstream infection
(CLABSI) is a serious infection that occurs when germs (usually bacteria or viruses) enter the bloodstream through the central line" (16).
# Central vascular access device (CVAD):
"A catheter that is inserted into a peripheral or large vein of the chest or groin with the tip advanced to a central position, either the superior or inferior vena cava" (228).
# Central venous catheter (CVC):
"Non-tunneled central venous catheters (CVCs) are often referred to as "acute" or "short-term" CVCs. These are often inserted for durations of 7 to 14 days. They are typically 15 to 25 cm in length, and are placed via direct puncture (often using ultrasonography) and cannulation of the internal jugular, subclavian or femoral veins" (229).
Tunneled CVCs can be permanent or temporary devices. They are characterized by the creation of a subcutaneous tunnel between the insertion of the catheter on the skin and the point of puncture in the vein. Tunneled catheters are generally placed in the interventional radiology suite or in the operating room by radiologists or surgeons (229).
Colonization: When a skin contaminant is repeatedly isolated from cultures taken from a catheter (i.e., central or arterial catheter), but peripheral catheter cultures remain negative (230).
Complications: Adverse events associated with a VAD, such as phlebitis, infiltration, extravasation, infection, pain, bleeding or embolism. Insertion-related complications are those that occur at the time of insertion, such as arterial puncture or hematoma.
Comprehensive health teaching: Any combination of learning experiences designed to help individuals and communities improve their health by increasing their knowledge or influencing their attitudes (adapted from (231).
Consensus: A process used to reach agreement among a group or panel during a Delphi or modified Delphi technique (232). A consensus of 70 per cent agreement from all panel members was required for the strength of recommendations within this BPG.
Contamination: "Introduction or transference of pathogens or infectious material from one source to another" (228).
# Difficult intravenous access (DiVA):
In general, difficult intravenous access (DiVA) is defined as a clinical situation where multiple attempts or special interventions are required to obtain and maintain peripheral venous access (129).
# Downgrade:
In GRADE, when limitations in the individual studies potentially bias the results, the certainty of evidence will decrease (233). For example, a body of quantitative evidence for one priority outcome may begin with high certainty, but due to serious limitations in one or more of the five GRADE criteria, it will be rated down by one or two levels (233).
# See Grading of Recommendations Assessment, Development and Evaluation (GRADE)
Evidence-based nursing practice: The "integration of best research evidence with clinical expertise and patient values" (234). It unifies research evidence with clinical expertise and encourages the inclusion of patient preferences (234).
# Evidence-to-Decision (EtD) framework:
A table that facilitates guideline panels to make decisions when moving from evidence to recommendations. The purpose of the Evidence-to-Decision (EtD) framework is to summarize the research evidence, outline important factors that can determine the recommendation, inform panel members about the benefits and harms of each intervention considered, and increase transparency about the decision-making process in the development of recommendations (8).
Extravasation: "Inadvertent infiltration of vesicant solution or medication into surrounding tissue; rated by a standard tool or definition" (228).
# See vesicant
Family: A term used to refer to individuals who are related (biologically, emotionally or legally) to and/or have close bonds (friendships, commitments, shared households and child rearing responsibilities, and romantic attachments) with the person receiving health [services]. A person's family includes all those whom the person identifies as significant in his or her life (e.g., parents, caregivers, friends, substitute decision-makers, groups, communities and populations). The person receiving care determines the importance and level of involvement of any of these individuals in their care based on his or her capacity (adapted from (235) and ( 236)).
# Appendix B: RNAO Guidelines and Resources That Align with This Guideline
The following are topics that align with this BPG, suggested RNAO guidelines and resources from other organizations.
# TOPIC RESOURCE(S)
Assessment and management of pain This appendix presents an overview of the RNAO guideline development process and methods. RNAO is unwavering in its commitment that every BPG be based on the best available evidence. To meet international standards, the GRADE methods have been implemented.
# Scoping the Guideline
The scope sets out what an RNAO guideline will and will not cover (see Purpose and Scope on p. 6). To determine the scope of this BPG, the RNAO best practice guideline development and research team conducted the following steps:
1. A review of previous BPGs. The RNAO BPGs Care and Maintenance to Reduce Vascular Access Complications (1) and Assessment and Device Selection for Vascular Access (2) were reviewed to inform the purpose and scope of this BPG.
2. An environmental scan of guidelines. Two guideline development methodologists searched an established list of websites for guidelines and other relevant content between March and July 2018. This search was then updated in May 2020. The purpose of the environmental scan was to gain an understanding of existing guidelines about vascular access in order to identify opportunities to develop the purpose and scope of this BPG. The resulting list was compiled based on knowledge of evidence-based practice websites and recommendations from the literature. Detailed information about the search strategy for existing guidelines, including the list of websites searched and the inclusion criteria used, is available on the RNAO https://RNAO.ca/bpg/guidelines/vascular-access-secondedition.
The guidelines were reviewed for content, applicability to nursing scope of practice, accessibility and quality. The two guideline development methodologists appraised 13 international guidelines using the AGREE II tool (247).
Guidelines with an overall score of 6 or 7 (on a 7-point Likert scale) were considered to be of high quality and therefore, considered for GRADE-ADOLOPMENT (237). GRADE-ADOLOPMENT provides a framework for adopting or adapting trustworthy recommendations from existing guidelines (237). However, the expert panel did not identify any priority recommendations from the existing guidelines to be adopted or adapted for this BPG.
The following guidelines were appraised as indicated:
# Appendix E: Indicator Development Process
The RNAO indicator development process steps are summarized below (see Figure 10):
# Appendix G: UK Vessel Health Preservation Framework
The following framework in an evidence-based tool that includes a device selection algorithm ("right line decision tool") and details of peripheral vein assessment and daily review ("daily assessment"). Vessel health preservation involves following a specific clinical pathway of care that adheres to evidence-based practice, the outcomes are optimized, veins are preserved, and the treatment plan is completed while minimizing delays and complications (255). Vessel health preservation also promotes person-centred care.
Further readings and descriptors can be found in the associated publication, which can be accessed here: https:// www.ips.uk.net/vessel-health-and-preservation-framework-2020.
# Appendix H: List of Vesicant Medications
The following list includes some commonly administered vesicant drugs capable of causing injury if they escape from the intended vascular pathway into surrounding tissue (256)
# When you get home:
Your PICC will need routine care such as weekly dressing changes and routine flushing. A visiting nurse will see you in your home or nearby clinic. The nurse will give you medications, change the dressing, provide PICC care and teach you about caring for the PICC at home. The Local Health Integration Network (LHIN) will organize your homecare nursing appointments and delivery of supplies to your home. It is important to keep the supplies in a safe place that is clean and dry.
# The dressing:
The PICC site must always be covered with a dressing. This is important to keep this area free of germs. Keeping the dressing covered and dry reduces the chance of germs entering the body and causing an infection.
# Bathing:
To help prevent infection, you should shower/bathe every day. Keep the dressing dry while you shower/bathe by wrapping the PICC in plastic wrap. After bathing, change into clean clothes every day to help your PICC stay clean. Appendix J: Peripheral Ultrasound-guided Vascular Access (P-UGVA) Global Rating Scale
# A P P E N D I C E S
Vascular Access
The Peripheral Ultrasound-guided Vascular Access (P-UGVA) global rating scale has been validated for ultrasoundguided PIV insertion (257). This scale may be used for training and skill assessment of health providers using ultrasound guidance to insert PVADs. Additionally, it may be used as an example to develop other skills checklists.
# Appendix L: Example of a Peripheral Vascular Access Device (PVAD) Assessment Protocol
The following is an example of a PVAD assessment protocol used in an acute, pediatric health-service organization.
The protocol may need to be adapted for other populations or health-service organizations. In adult settings, assessment every four hours while infusing may be more appropriate (25). Additionally, more frequent assessments are necessary in a variety of situations, such as for infusion of vesicants or blood products and for persons who may be critically ill. Follow a standardized blood sampling protocol or organizational policy. Venipuncture is the preferred method of blood sampling. If this method is not feasible following an individualized risk-benefit assessment, then a blood draw from a VAD may be considered.
# Maintain VAD following a multi-component VAD care protocol.
PVAD care protocol involves at minimum a daily review and documentation. Refer to Recommendation 5.1 for more information on PVAD multi-component care protocols. Refer to Appendix M for a list of CVAD Care Guidelines.
# Document care provided.
# Health-service organizations may consider implementing practical education on the insertion and management of vascular access devices for health providers.
Health-service organizations may consider implementing vascular access specialists or vascular access specialist teams to support the insertion and management of VADs. Appendix Q: Description of the Leading Change Toolkit TM BPGs can only be successfully implemented and sustained if planning, resources, organizational and administrative supports are adequate and there is appropriate facilitation. Active engagement and involvement of formal and informal leaders (e.g., change agents, peer champions) are also essential. To encourage successful implementation and sustainability, an international expert panel of nurses, researchers, patient/person advocates, social movement activists and administrators has developed the Leading Change Toolkit™ (2021) (10). The toolkit is based on available evidence, theoretical perspective and consensus. We recommend the Leading Change Toolkit™ for guiding the implementation of any BPG in health-care or social service organizations.
The Leading Change Toolkit™ includes two frameworks -the Social Movement Action (SMA) Framework ( 266) and the Knowledge-to-Action (KTA) Framework ( 267)-for change agents and change teams leading the implementation and sustainability of BPGs. Both frameworks outline the concept of implementation and its inter-related components.
As such, either framework -the SMA or the KTA -can be used to guide change initiatives, including the implementation of BPGs. Using both frameworks serves to enhance and accelerate change (224).
The SMA Framework includes elements of social movements in a context of evidence uptake and sustainability G that have demonstrated powerful impact and long-term effects. Based upon the results of a concept analysis, the framework includes 16 elements categorized as preconditions (i.e., what must be in place prior to the occurrence of the social movement), key characteristics (i.e., what must be present for the social movement to occur) and outcomes (i.e., what may happen as a result of the occurrence of the social movement) (224,268). The three categories and elements of the SMA Framework are shown in Figure 17.
# Best Practice Guideline
This project is funded by the Government of Ontario. | None | None |
09b64f06aab58633ef9ac7ffe9fd68c98c5fb4af | cma | None | This statement is not meant to address what happened in that tragic situation, the details of which remain largely unknown. Rather, this statement is intended to address more broadly the subject of home dosing with food allergens, whether in the specific context of a food ladder or in the general context of food immunotherapy.
Food immunotherapy and milk/egg ladders are valid management options for food allergy as long as key considerations are met:
- They must be supervised and administered by a trained and experienced healthcare provider with the necessary expertise and experience in food allergy and anaphylaxis management, the performance of oral food challenges, and the careful selection of patients for food immunotherapy. - A proper medical clinic set-up for food immunotherapy should mirror that which is required for oral challenges. This includes procedures for assessing whether patients are well enough on their appointment day to receive build-up doses, proper preparation and administration of the food item(s) by well-trained and experienced staff, layered close nursing and/or medical supervision for the patient, a management plan for reactions including having appropriate resuscitation equipment available, and an adequate post-feeding patient observation period. - Informed consent must be obtained prior to initiation of food immunotherapy, and the documentation should set out in detail the risks and benefits of food immunotherapy, and confirm that these risks and benefits were clearly explained to and understood by the patient or caregiver. This practice should be extended to those on milk/egg ladders or taking regular full servings of baked milk/egg. - A comprehensive plan should be established that includes protocols and procedures for home dosing between office visits and assessment of effectiveness of the therapy after a period of maintenance dosing (i.e. follow-up oral challenges). - With regards to careful patient selection, the following factors are paramount: o asthma must be optimally controlled prior to and throughout the food immunotherapy process, with protocols in place when control deteriorates, such as during asthma exacerbations o coexisting atopic and other medical conditions must be well controlled o the family must be willing, able, and ready to recognize and treat allergic reactions, including using self-injectable epinephrine properly and in a timely manner o the family must understand conditions under which the food dose should not be taken, and when to contact the prescriber for further guidance related to dosing o adherence is essential, including ladder-based approaches to food immunotherapy o many are not appropriate candidates for food immunotherapy for reasons including, but not limited to: § extremely low threshold for reactions, § inadequately controlled asthma or other atopic conditions, § reluctance to using epinephrine promptly, and § psychosocial factors, such as a history of poor adherence to prior therapy of one or more atopic conditions, unreliability for follow up, and language and other barriers to understanding the protocol and all other factors related to successful treatment - Whether to choose milk/egg ladders or milk/egg oral immunotherapy (OIT) depends on the likelihood of resolution ("outgrowing") versus persistence of milk/egg allergy. Specifically, baked milk/egg ladders are intended for use in low-risk cases with resolving food allergies. OIT, in contrast, is indicated where milk/egg allergy is more likely to persist, such as in older children (e.g. usually beyond 5 years old) and those with prior history of severe anaphylaxis to milk/egg or high milk/egg sIgE levels. As such, OIT is associated with a higher risk of allergic reactions, including potentially life-threatening anaphylaxis. - The baked milk/egg ladder presupposes that in the early phases of reintroduction, the patient receives a low-dose of well-cooked milk or egg protein as a minor ingredient in baked goods. Caution should be exercised with certain types of baked goods (i.e. muffins, loaves, cakes) where cooking may be uneven in the centre, potentially exposing the patient to considerably higher doses of less well-cooked milk or egg than intended, thereby predisposing them to a higher risk of potentially life-threatening allergic reactions.
Milk/egg ladders and milk/egg OIT are to be contrasted with the approach of challenging a milk/egg allergic patient to full age-appropriate servings of baked milk/egg, followed by regular (e.g. daily) ingestion of full servings of baked milk/egg. With this approach, there is no "build-up" process as tolerance of a full serving of baked milk/egg is a prerequisite.
When patients are carefully selected by practitioners with the necessary experience in conducting oral challenges and food immunotherapy, the risks of food immunotherapy are not excessive, nor do they exceed the risks involved with providing other commonly available forms of non-food-allergen immunotherapy (i.e. subcutaneous immunotherapy injections for aeroallergens also carry a risk of severe and rarely fatal reaction). Also, the risk of a fatal reaction with food immunotherapy does not exceed the risk of a fatal reaction with avoidance. Knowing these risks as a provider and discussing these risks with every patient considering food immunotherapy, along with the potential benefits, is essential.
As clinicians, we must continually remind ourselves of the significance of proper patient selection, education, and supervision, and of putting sufficient office and home protocols in place to enable us to continue providing food immunotherapy to eligible patients in the safest and most effective manner possible. | #
This statement is not meant to address what happened in that tragic situation, the details of which remain largely unknown. Rather, this statement is intended to address more broadly the subject of home dosing with food allergens, whether in the specific context of a food ladder or in the general context of food immunotherapy.
Food immunotherapy and milk/egg ladders are valid management options for food allergy as long as key considerations are met:
• They must be supervised and administered by a trained and experienced healthcare provider with the necessary expertise and experience in food allergy and anaphylaxis management, the performance of oral food challenges, and the careful selection of patients for food immunotherapy. • A proper medical clinic set-up for food immunotherapy should mirror that which is required for oral challenges. This includes procedures for assessing whether patients are well enough on their appointment day to receive build-up doses, proper preparation and administration of the food item(s) by well-trained and experienced staff, layered close nursing and/or medical supervision for the patient, a management plan for reactions including having appropriate resuscitation equipment available, and an adequate post-feeding patient observation period. • Informed consent must be obtained prior to initiation of food immunotherapy, and the documentation should set out in detail the risks and benefits of food immunotherapy, and confirm that these risks and benefits were clearly explained to and understood by the patient or caregiver. This practice should be extended to those on milk/egg ladders or taking regular full servings of baked milk/egg. • A comprehensive plan should be established that includes protocols and procedures for home dosing between office visits and assessment of effectiveness of the therapy after a period of maintenance dosing (i.e. follow-up oral challenges). • With regards to careful patient selection, the following factors are paramount: o asthma must be optimally controlled prior to and throughout the food immunotherapy process, with protocols in place when control deteriorates, such as during asthma exacerbations o coexisting atopic and other medical conditions must be well controlled o the family must be willing, able, and ready to recognize and treat allergic reactions, including using self-injectable epinephrine properly and in a timely manner o the family must understand conditions under which the food dose should not be taken, and when to contact the prescriber for further guidance related to dosing o adherence is essential, including ladder-based approaches to food immunotherapy o many are not appropriate candidates for food immunotherapy for reasons including, but not limited to: § extremely low threshold for reactions, § inadequately controlled asthma or other atopic conditions, § reluctance to using epinephrine promptly, and § psychosocial factors, such as a history of poor adherence to prior therapy of one or more atopic conditions, unreliability for follow up, and language and other barriers to understanding the protocol and all other factors related to successful treatment • Whether to choose milk/egg ladders or milk/egg oral immunotherapy (OIT) depends on the likelihood of resolution ("outgrowing") versus persistence of milk/egg allergy. Specifically, baked milk/egg ladders are intended for use in low-risk cases with resolving food allergies. OIT, in contrast, is indicated where milk/egg allergy is more likely to persist, such as in older children (e.g. usually beyond 5 years old) and those with prior history of severe anaphylaxis to milk/egg or high milk/egg sIgE levels. As such, OIT is associated with a higher risk of allergic reactions, including potentially life-threatening anaphylaxis. • The baked milk/egg ladder presupposes that in the early phases of reintroduction, the patient receives a low-dose of well-cooked milk or egg protein as a minor ingredient in baked goods. Caution should be exercised with certain types of baked goods (i.e. muffins, loaves, cakes) where cooking may be uneven in the centre, potentially exposing the patient to considerably higher doses of less well-cooked milk or egg than intended, thereby predisposing them to a higher risk of potentially life-threatening allergic reactions.
Milk/egg ladders and milk/egg OIT are to be contrasted with the approach of challenging a milk/egg allergic patient to full age-appropriate servings of baked milk/egg, followed by regular (e.g. daily) ingestion of full servings of baked milk/egg. With this approach, there is no "build-up" process as tolerance of a full serving of baked milk/egg is a prerequisite.
When patients are carefully selected by practitioners with the necessary experience in conducting oral challenges and food immunotherapy, the risks of food immunotherapy are not excessive, nor do they exceed the risks involved with providing other commonly available forms of non-food-allergen immunotherapy (i.e. subcutaneous immunotherapy injections for aeroallergens also carry a risk of severe and rarely fatal reaction). Also, the risk of a fatal reaction with food immunotherapy does not exceed the risk of a fatal reaction with avoidance. Knowing these risks as a provider and discussing these risks with every patient considering food immunotherapy, along with the potential benefits, is essential.
As clinicians, we must continually remind ourselves of the significance of proper patient selection, education, and supervision, and of putting sufficient office and home protocols in place to enable us to continue providing food immunotherapy to eligible patients in the safest and most effective manner possible. | None | None |
bae12fb8fc645768512c65c103b280f05e402b9d | cma | None | Background: Oral immunotherapy (OIT) is an emerging approach to the treatment of patients with IgE-mediated food allergy and is in the process of transitioning to clinical practice. Objective: To develop patient-oriented clinical practice guidelines on oral immunotherapy based on evidence and ethical imperatives for the provision of safe and efficient food allergy management. Materials and methods: Recommendations were developed using a reflective patient-centered multicriteria approach including 22 criteria organized in five dimensions (clinical, populational, economic, organizational and sociopolitical). Data was obtained from: (1) a review of scientific and ethic literature; (2) consultations of allergists, other healthcare professionals (pediatricians, family physicians, nurses, registered dieticians, psychologists, peer supporters), patients and caregivers; and patient associations through structured consultative panels, interviews and on-line questionnaire; and (3) organizational and economic data from the milieu of care. All data was synthesized by criteria in a multicriteria deliberative guide that served as a platform for structured discussion and development of recommendations for each dimension, based on evidence, ethical imperatives and other considerations.The deliberative grid included 162 articles from the literature and media reviews and data from consultations involving 85 individuals. Thirty-eight (38) recommendations were made for the practice of oral immunotherapy for the treatment of IgE mediated food allergy, based on evidence and a diversity of ethical imperatives. All recommendations were aimed at fostering a context conducive to achieving objectives identified by patients and caregivers with food allergy. Notably, specific recommendations were developed to promote a culture of shared responsibility between patients and healthcare system, equity in access, patient empowerment, shared decision making and personalization of OIT protocols to reflect patients' needs. It also provides recommendations to optimize organization of care to generate capacity to meet demand according to patient choice, e.g. OIT or avoidance. These recommendations were made acknowledging the necessity of ensuring sustainability of the clinical offer in light of various economic considerations.# Background
IgE-mediated food allergy is a condition that imposes food-related restrictions on patients and their caregivers in order to prevent allergic reactions. The burden of disease stems from both the actual and perceived risks of accidental ingestion, including the possibility of a lifethreatening allergic reaction. This burden manifests itself in variable levels of anxiety and social limitations and significantly impacts quality of life. The current standard management for food allergy is complete avoidance of the offending allergen in the diet, combined with training on how to recognize and treat allergic reactions. And while avoidance is currently recognized as a safe approach, it has a limited ability to improve a patients' perception of safety or sense of control over the condition and its associated limitations-this leads many to seek alternative management options .
Oral immunotherapy (OIT) consists of daily ingestion of the offending food allergen (food dosing), starting below a patient's threshold dose (i.e. the minimum amount that would elicit a reaction), and increasing the dose over time with a goal of increasing clinical tolerance to that food. It had been proposed as a potential alternative to avoidance throughout the 20th and into the early 21st centuries , yet its development had been limited until recently. This is mainly due to the risk of allergic reactions associated with OIT, which is difficult to reconcile with current practice standards that focus on the avoidance of reactions at all cost and are arguably rooted in a culture of fear.
OIT can be viewed as a disruptive innovation as it challenges the current paradigm of care in food allergy and highlights its limitations in responding to patient needs. There is a need for patient-centered ethical clinical practice guidelines (CPGs) that include patients and caregivers as well as other stakeholders in the consultation and deliberation process, in order to develop best practice recommendations for providing OIT for food allergy. It is essential to understand patient and caregiver perspectives to ensure proper interpretation of published evidence and understand the ethical issues involved.
Previous CPGs on OIT have used more traditional approaches, focusing mainly on quantitative clinical evidence. However, in order to ensure a clear vision of all that OIT entails and to benefit all patients with food allergy in need of care, CPGs must not only be based on experimental data (e.g., clinical trials) but also on observational, economic and sociopolitical data, as well as experiential narrative data from both patients and healthcare professionals. The optimal provision of OIT must also account for ethical and organizational data to promote the equitable, sustainable and responsible development of this treatment. In fact, evidence-based medicine has been defined as "the application of the best available research to clinical care, which requires the integration of evidence with clinical expertise and patient values . " The development of these CPGs on OIT followed the Guidelines International Network 2015 recommendations including a policy for the management of conflicts of interests . They were commissioned by the Canadian Society of Allergy and Clinical Immunology (CSACI), and was developed through a collaboration with the University Hospital Center Sainte-Justine and the methodological support of the Institut National d'Excellence en Santé et Services Sociaux (INESSS). CSACI acted as the sponsor and was responsible for creating a diversified Working Group. This working group and the executive team opted for a reflective multicriteria methodology, which has been used in the past to develop CPGs using the EVIDEM (Evidence and Values Impact on Decision Making) ethical framework . This approach encourages the collection of data from diverse sources, including both the scientific literature and consultations, thus offering a 360° view of the subject. This framework was also used to organize, analyze and ultimately integrate the data into a deliberation guide, providing an efficient and consistent approach throughout the project.
# Materials and methods
# Multidisciplinary team
A multidisciplinary team comprised of experts from a diversity of fields was assembled, including allergists and other healthcare professionals, ethicists, and those with expertise in multicriteria deliberation methodology, literature review, consultations and sociology. Bégin et al. Allergy Asthma Clin Immunol (2020) 16:20
# Multicriteria methodology
The aim of the methodological approach was to support reflection by all stakeholders during the development of fair and reasonable recommendations. To this end, a patient-centered and ethics-based multicriteria framework was used throughout the process. The framework was adapted from EVIDEM, included three additional patient focused criteria and organized 22 criteria into five dimensions defined to cover all relevant aspects of OIT. The framework also builds on the Accountability for reasonableness (A4R) conditions set forth by Daniels and Sabin and the Triple Aim of healthcare systems set forth by Berwick and colleagues . The five dimensions of the framework include:
- How the use of OIT can contribute to a sociopolitico-cultural context conducive to The Common Good (sociopolitical dimension), - How OIT contributes to a fair and equitable distribution of services (populational dimension), - How OIT responds to a need for health and wellbeing in an adequate way (clinical dimension), - How the use of OIT can contribute to improve the quality, organization and governance of healthcare services (organizational dimension), and - How OIT optimizes the use of resources and the associated costs to ensure sustainability of healthcare systems (economic dimension).
Each dimension contains criteria for operationalization, organized into a multicriteria grid. Data from the literature review and consultations were collected and organized per criterion to allow for a comprehensive assessment of OIT and provide a knowledge platform for the development of the CPG recommendations.
All documentation was compiled using a data management software program (CITAVI), which was adapted to organize data by criteria and provided an interactive interface for review by the working group. | Background: Oral immunotherapy (OIT) is an emerging approach to the treatment of patients with IgE-mediated food allergy and is in the process of transitioning to clinical practice. Objective: To develop patient-oriented clinical practice guidelines on oral immunotherapy based on evidence and ethical imperatives for the provision of safe and efficient food allergy management. Materials and methods: Recommendations were developed using a reflective patient-centered multicriteria approach including 22 criteria organized in five dimensions (clinical, populational, economic, organizational and sociopolitical). Data was obtained from: (1) a review of scientific and ethic literature; (2) consultations of allergists, other healthcare professionals (pediatricians, family physicians, nurses, registered dieticians, psychologists, peer supporters), patients and caregivers; and patient associations through structured consultative panels, interviews and on-line questionnaire; and (3) organizational and economic data from the milieu of care. All data was synthesized by criteria in a multicriteria deliberative guide that served as a platform for structured discussion and development of recommendations for each dimension, based on evidence, ethical imperatives and other considerations.The deliberative grid included 162 articles from the literature and media reviews and data from consultations involving 85 individuals. Thirty-eight (38) recommendations were made for the practice of oral immunotherapy for the treatment of IgE mediated food allergy, based on evidence and a diversity of ethical imperatives. All recommendations were aimed at fostering a context conducive to achieving objectives identified by patients and caregivers with food allergy. Notably, specific recommendations were developed to promote a culture of shared responsibility between patients and healthcare system, equity in access, patient empowerment, shared decision making and personalization of OIT protocols to reflect patients' needs. It also provides recommendations to optimize organization of care to generate capacity to meet demand according to patient choice, e.g. OIT or avoidance. These recommendations were made acknowledging the necessity of ensuring sustainability of the clinical offer in light of various economic considerations.# Background
IgE-mediated food allergy is a condition that imposes food-related restrictions on patients and their caregivers in order to prevent allergic reactions. The burden of disease stems from both the actual and perceived risks of accidental ingestion, including the possibility of a lifethreatening allergic reaction. This burden manifests itself in variable levels of anxiety and social limitations and significantly impacts quality of life. The current standard management for food allergy is complete avoidance of the offending allergen in the diet, combined with training on how to recognize and treat allergic reactions. And while avoidance is currently recognized as a safe approach, it has a limited ability to improve a patients' perception of safety or sense of control over the condition and its associated limitations-this leads many to seek alternative management options [1][2][3][4][5][6].
Oral immunotherapy (OIT) consists of daily ingestion of the offending food allergen (food dosing), starting below a patient's threshold dose (i.e. the minimum amount that would elicit a reaction), and increasing the dose over time with a goal of increasing clinical tolerance to that food. It had been proposed as a potential alternative to avoidance throughout the 20th and into the early 21st centuries [7], yet its development had been limited until recently. This is mainly due to the risk of allergic reactions associated with OIT, which is difficult to reconcile with current practice standards that focus on the avoidance of reactions at all cost and are arguably rooted in a culture of fear.
OIT can be viewed as a disruptive innovation as it challenges the current paradigm of care in food allergy and highlights its limitations in responding to patient needs. There is a need for patient-centered ethical clinical practice guidelines (CPGs) that include patients and caregivers as well as other stakeholders in the consultation and deliberation process, in order to develop best practice recommendations for providing OIT for food allergy. It is essential to understand patient and caregiver perspectives to ensure proper interpretation of published evidence and understand the ethical issues involved.
Previous CPGs on OIT [8][9][10] have used more traditional approaches, focusing mainly on quantitative clinical evidence. However, in order to ensure a clear vision of all that OIT entails and to benefit all patients with food allergy in need of care, CPGs must not only be based on experimental data (e.g., clinical trials) but also on observational, economic and sociopolitical data, as well as experiential narrative data from both patients and healthcare professionals. The optimal provision of OIT must also account for ethical and organizational data to promote the equitable, sustainable and responsible development of this treatment. In fact, evidence-based medicine has been defined as "the application of the best available research to clinical care, which requires the integration of evidence with clinical expertise and patient values [11]. " The development of these CPGs on OIT followed the Guidelines International Network 2015 recommendations including a policy for the management of conflicts of interests [12]. They were commissioned by the Canadian Society of Allergy and Clinical Immunology (CSACI), and was developed through a collaboration with the University Hospital Center Sainte-Justine and the methodological support of the Institut National d'Excellence en Santé et Services Sociaux (INESSS). CSACI acted as the sponsor and was responsible for creating a diversified Working Group. This working group and the executive team opted for a reflective multicriteria methodology, which has been used in the past to develop CPGs [13] using the EVIDEM (Evidence and Values Impact on Decision Making) ethical framework [14][15][16][17]. This approach encourages the collection of data from diverse sources, including both the scientific literature and consultations, thus offering a 360° view of the subject. This framework was also used to organize, analyze and ultimately integrate the data into a deliberation guide, providing an efficient and consistent approach throughout the project.
# Materials and methods
# Multidisciplinary team
A multidisciplinary team comprised of experts from a diversity of fields was assembled, including allergists and other healthcare professionals, ethicists, and those with expertise in multicriteria deliberation methodology, literature review, consultations and sociology. Bégin et al. Allergy Asthma Clin Immunol (2020) 16:20
# Multicriteria methodology
The aim of the methodological approach was to support reflection by all stakeholders during the development of fair and reasonable recommendations. To this end, a patient-centered and ethics-based multicriteria framework was used throughout the process. The framework was adapted from EVIDEM, included three additional patient focused criteria and organized 22 criteria into five dimensions defined to cover all relevant aspects of OIT. The framework also builds on the Accountability for reasonableness (A4R) conditions set forth by Daniels and Sabin [18] and the Triple Aim of healthcare systems set forth by Berwick and colleagues [19]. The five dimensions of the framework include:
• How the use of OIT can contribute to a sociopolitico-cultural context conducive to The Common Good (sociopolitical dimension), • How OIT contributes to a fair and equitable distribution of services (populational dimension), • How OIT responds to a need for health and wellbeing in an adequate way (clinical dimension), • How the use of OIT can contribute to improve the quality, organization and governance of healthcare services (organizational dimension), and • How OIT optimizes the use of resources and the associated costs to ensure sustainability of healthcare systems (economic dimension).
Each dimension contains criteria for operationalization, organized into a multicriteria grid. Data from the literature review and consultations were collected and organized per criterion to allow for a comprehensive assessment of OIT and provide a knowledge platform for the development of the CPG recommendations.
All documentation was compiled using a data management software program (CITAVI), which was adapted to organize data by criteria and provided an interactive interface for review by the working group.
# Conflict of interest management and respect of persons
To avoid the impact of COI or conflicts of roles on the process, explicit guidelines regarding their declaration, evaluation and management were developed based on the GIN 2015 recommendations (see Additional file 1: Appendix 1) [12]. Each potential participant was required to complete a conflict of interest declaration, which was then analyzed by an ethicist. Participants who were deemed at risk of bias on a particular subject were excluded from the room during the deliberation meeting for the time during which the related recommendations were being discussed.
Every step was taken to ensure that best practices for respect of persons were carried out, with respectful atmosphere created by chairs for each group discussion and by interviewers for each individual interview; as well documentation was provided ahead of time to give each participant time to prepare. All patients completed an informed consent; they were informed that only their perspective on the topic was solicited, not personal clinical data, and that psychological support was available.
# Literature review
# Sources of data
An extensive literature review was performed. The primary sources of data were peer-reviewed full-text publications retrieved through searching multiple sources, including PubMed, MEDLINE (Ovid), Embase, EBM Reviews, CINAHL and Web of Science bibliographic databases. Searches for OIT clinical data were performed on April 17-18, 2019, and searches for epidemiological and burden of disease data were performed on May 30-31, 2019. Search terms are presented in Additional file 1: Appendix 2A. These searches aimed to collect data for all dimensions of the framework, including the sociopolitical, populational, clinical, organizational and economic dimensions. Bibliographical database searches were supplemented by individually searching the tables of contents of pertinent recent periodicals (up to September 2019), as well as bibliographies of key publications. Websites from government agencies, HTA bodies, professional associations and patient associations were also consulted. In order to capture the perception of OIT in the media, a review of the Canadian news media of the last 5 years was conducted via the FACTIVA Global News Monitoring & Search Engine using 'oral immunotherapy' and 'immunothérapie orale' (French) as search terms.
# Data selection for each dimension
Retrieved records were screened based on title and abstract to select those for further assessment in full-text format. For the clinical dimension, patient focus groups or surveys providing insight on the importance of the therapy and its outcomes for patients, were considered for inclusion in addition to clinical studies (see details below), qualitative studies, and published CPGs. For the sociopolitical dimension, different types of publications on relevant topics such as the history of OIT and regulatory aspects were reviewed. Stakeholder's positions were collected and informed by the media press review. For the populational dimension, records such as recent systematic reviews of epidemiological studies, original studies conducted in large, representative populations, preferably in the Canadian context, and recent reviews of qualitative research were considered for inclusion. For the organizational dimension, data concerning the healthcare system's organization and requirements for the provision of OIT was sought. For the economic dimension, data collected included economic studies, such as cost of illness studies or economic analyses, and cost data (i.e., the costs of products and procedures for OIT). An analysis of associated ethical issues was included for each criterion throughout the framework, as applicable.
# Selection of clinical studies and assessment of their methodological quality
Clinical studies were selected using eligibility (inclusion/ exclusion) criteria listed in Additional file 1: Appendix 2B. Study designs included experimental, comparative studies, randomized [RCTs], non-randomized controlled clinical trials [CCTs], and observational studies reporting outcomes from clinical practice. RCTs are best suited to answer the questions whether an intervention is efficacious and safe, compared to another intervention or management option. These, however, can be limited in their ability to answer certain specific questions that arise in clinical practice, including how patient characteristics may impact outcomes or how to adapt to what happens over the course of treatment [20]. These limits stem from highly selective patient eligibility criteria, rigid study protocols, non-patient-centered end-points, short follow-up durations or small population sizes. A blinded study design, in particular, is not best suited to study personalized care, nor to investigate the impact of a treatment on patient-reported quality of life outcomesexamples include topics such as food-allergy related anxiety and the burden of allergen avoidance, both of which require awareness of the treatment received and the results achieved (e.g., level of desensitization). Observational studies can complement experimental comparative studies, especially when they involve larger less strictly selected patient populations that are closely followed over a long-term horizon in a real world practice setting.
The methodological quality of RCTs was assessed according to the Cochrane risk of bias approach [21], using published risk of bias assessments from systematic reviews, whenever available [22][23][24]. For case series, the Institute of Health Economics Quality Appraisal of Case Series Studies Checklist was applied [25]. Among its 20 items, 10 core items on study conduct and reporting were selected to operationalize quality assessment. A case series was deemed of high methodological quality (low risk of bias) if all 10 were positive, moderate if 8 to 9 were positive, and low (high risk of bias) if less than 8 were positive. The methodological quality of meta-analyses was determined by checking whether all eligible studies had been included, and by repeating key analyses based on the data reported in the original publications.
# Extraction, analysis and synthesis
Clinical study data was extracted and synthesised in evidence tables in a per-criterion report format. The extraction tool was validated by a clinical expert. The report was validated by two assessors and then reviewed and revised by the Working Group. Clinical data was further synthesized and integrated into the multicriteria grid for the deliberation. Data pertaining to the other dimensions were directly synthesized in the multicriteria grid.
# Consultations Objective
The objective of the consultation process was to capture relevant experiential and contextual data from diverse perspectives to develop a comprehensive understanding of the topic. Data for each dimension of the multicriteria grid was collected through discussions with allergists, patients and other healthcare professionals. Healthcare professionals were able to provide insight into two main aspects: first, to validate and enrich the data collected through the literature review, and second, enhance the data with relevant clinical practice experience that might not have been elucidated from published studies. Patients with food allergy contributed their unique perspective of the condition and its impact, as well as their view and experience of food allergy therapy, including its benefits and its constraints.
# General approach
In order to ensure diversity of participants, an open call for applications was posted on the website of applicable patient associations and the CSACI, and targeted calls were made by sending e-mail invitations to relevant professional societies and all CSACI members. The calls provided a short text explaining the objectives of the project, as well as the goals and format of the consultation, followed by a link to a small questionnaire covering the necessary information to enable selecting a diversity of participants to be consulted. The recruitment process was completed by applying a chain-referral sampling strategy. For each potential consultant, the geographical location, gender, general opinion of OIT and, when relevant, the type of practice (e.g. academic vs community, pediatric vs adult) were considered for participant diversification.
Selected participants were contacted and, upon confirmation of participation, asked to complete COI Bégin et al. Allergy Asthma Clin Immunol (2020) 16:20 and consent forms. Subsequent steps differed depending on the format of the consultation for each specific group. Possible steps were discussion panels, individual interviews and an online questionnaire. Discussion panels served to create a debate around the various aspects of OIT from different contexts and viewpoints. Individual interviews allowed for the collection of in-depth data from a specific context and its implications. The online questionnaire allowed for the collection of a broad range of experience from a greater number of experts than would have been possible through discussion panels and interviews alone. For every consultation, participants received a consultation guide with questions adapted to their contexts and expertise, which was based on the multicriteria grid and grouped by criteria, in order to facilitate data collection and analysis. All participants were provided with the consultation document a week prior to the consultation in order to give time to familiarize themselves with it. During the discussion panels, the Chatham House Rule [26] was applied, which guarantees anonymity of all information provided by participants. These panels were led by co-chairs experienced in data appropriation while fostering an environment of respect, attentiveness and constructive exchanges.
# Allergists
Consultations with allergists were twofold, with two different groups. A panel discussion was first conducted with the 15 Working Group members to identify key points on which to focus the CPGs. The group was well diversified in terms of experience with OIT: some participants had never offered it, some had offered it only in research settings, and those offering it in clinical practice reported using different methods and protocols. The discussion followed the multicriteria questionnaire, discussing every issue per criteria. Data was collected through recording and notetaking. Secondly, 42 CSACI members completed an online questionnaire, following the same structure. The data obtained from both the panel discussion and the questionnaire were compiled per criteria. Key themes within each criterion were identified through thematic analysis.
# Patients and caregivers
Consultations with patients also occurred in two formats to fit two purposes. A panel discussion was held with 8 participants, diversified according to their individual context pertaining to OIT, which included whether or not they had direct experience with it, what their vision of the therapy was and the type and impact of their food allergy condition. Discussions were guided by the multicriteria grid. Patient perspective narrative data was collected for each of the criteria through recording and notetaking. The second consultation format consisted of individual interviews with 6 participants, following the same diversification criteria and using the same questionnaire as the panel discussion. The data from both sources was then compiled in the same way as the allergist consultations and analyzed thematically to identify key points raised by the patients.
# Other healthcare professionals and lay representatives
These consultations served the purpose of obtaining the viewpoints of stakeholders involved in the care of food allergy patients other than allergists, namely family physicians, pediatricians, nurses, registered dieticians, psychologists and caregivers engaged in peer support activities. They were consulted via a discussion panel involving 10 participants diversified by their professions and the differences in their experience with OIT, which followed the same format as the patient panel. Another two healthcare professionals completed an online questionnaire. Representatives from patient associations were also interviewed, via phone, using the same questionnaire as the panel, to provide patient-centered contextual knowledge on OIT. This data was collected through notes and recording, per criteria, compiled in the same way as for the other consulted groups, and thematically analyzed, bringing forward essential notions associated with OIT provision to include in the CPGs.
# Data from milieu of care
Data from Canadian clinical practices (milieu of care) was collected in the form of economic data provided by the working group members from their clinical practice offer of OIT, which was extracted and compiled into criteria of the economic dimension.
# Deliberation
# Data integration
Compiled data from the literature review, consultations and milieu of care were integrated into the deliberation guide in a highly synthesized format in order to facilitate comprehension of the data by all participants during the deliberation. Prior to this integration, the data from the literature review was revised and enriched by the Working Group. Data for each criterion was separated into three sections: literature review data, consultation data and ethical aspects. The deliberation guide consisted of the synthesized data integrated into a multicriteria grid, with an additional column in which participants were invited to add their interpretation of the data provided in order to facilitate discussion. Empty Bégin et al. Allergy Asthma Clin Immunol (2020) 16:20 recommendation boxes at the end of each dimension were also included to allow discussion and the formation of informed recommendations for one subject at a time.
# Deliberation process
The participants in the deliberation included the allergists of the Working Group along with selected participants from the consultations, in order to provide relevant data from a global patient perspective. These included two patients with different and longstanding experiences, two family physicians, a pediatrician, a nurse, a registered dietician, a pharmacist and a peer supporter. Each participant received a copy of the deliberation guide 1 week prior to the meeting. The deliberation meeting was chaired by three methodologists who were experts in multicriteria deliberation, multicriteria literature review and synthesis and multicriteria consultations, for a total of 22 participants. The deliberation was divided into four sessions according to the dimensions of the multicriteria grid, during which the literature review and consultation data were presented by the co-chairs. Corresponding recommendations were discussed and determined at the end of each session. All recommendations were based on a group consensus-recommendations for which a COI was identified were based on a consensus of the group excluding those with a COI.
# Rationales for recommendations
Recommendations were based on a variety of rationales that included evidence from consultations and scientific studies, ethical imperatives, such as promotion of equity or patient autonomy, and other considerations, such as general standards of clinical care, clinical reasoning, and biological plausibility.
For recommendations that included evidence from clinical studies, the strength of the evidence supporting the recommendation was determined using a method that builds on the approach of the Oxford Centre for Evidence-Based Medicine [8,27]. The risk of bias was assessed using the Cochrane approach [21] and the Institute for Health Economics (IHE) method for case series [25]. These methods, developed for quantitative data, were adapted to include qualitative data from consultations such that the strength of the evidence supporting the recommendation takes into account:
• risk of bias (study design, including the methodology chose for data collection and analysis can affect the risk of misleading results); • type of study (meta-analyses, RCTs, non-randomized controlled trials (CCTs), case series); studies could be carried out in usual clinical practice or in a research context;
• consistency of evidence across studies; and • the level of coherence between evidence from studies and data obtained from the consultation process.
The amount, quality and consistency of the evidence supporting the recommendation is defined at three levels:
• High Large amount of consistent evidence from RCTs (or meta-analyses) and large studies in clinical practice, ideally at a low risk of bias; AND coherence with data from consultations and/or qualitative studies. • Moderate Moderate amount of consistent evidence from RCTs (or meta-analyses) and/or studies in clinical practice, ideally at a moderate or low risk of bias; AND coherence with data from consultations and/or qualitative studies. • Low Small amount of evidence OR evidence with some incoherence in data from RCTs (or metaanalyses) and/or studies in clinical practice OR data at moderate to high risk of bias; AND coherence with data from consultations and/or qualitative studies.
# Strength of recommendations
The strength of recommendations in CPGs is often graded based on the quality of clinical evidence regarding the efficacy and safety of an intervention. However, this approach does not apply to recommendations that do not rest on clinical trial outcomes, but for which the body of evidence from clinical research and practice shows a clear clinical benefit because conducting such trials would neither be reasonable nor ethical [28]. Moreover, grading in such a way does not take into account factors other than clinical outcomes, such as ethical imperatives, social context or economic considerations, which can be key elements of the rationale underlying a recommendation. Therefore, to ensure that all types of recommendations in these CPGs will be regarded on an equal footing, the strength of recommendations was not given a rating. Rather, in the spirit of accountability for reasonableness (A4R) [18], the rationale for each recommendation, the level of supporting evidence, where appropriate, and the necessary contextualization and nuances were all clearly stated.
# Results
# Multicriteria grid
The multicriteria grid used for this project included five dimensions divided into 22 criteria and is shown in Fig. 1.
# Data used as basis for recommendations
The literature review yielded a total of 8157 records; 468 of them were assessed for eligibility in full-text records and 145 were included in the multicriteria grid (Fig. 2). Bégin et al. Allergy Asthma Clin Immunol (2020) 16:20 An additional 17 articles were included from the media press review.
A total of 14 patients or caregivers, 13 allergists and 16 other healthcare professionals or patient association representatives were consulted through panel discussions or individual interviews. In addition, 42 CSACI allergists responded to the online consultation survey.
Data on the economic aspects of OIT was available from three Canadian practices, and data on quality of life impact of OIT was collected from one practice.
The synthesis of the data collected through the literature review, consultations and from the milieu of care is presented by criteria along with complete references in the deliberation guide (Table 1). Detailed clinical evidence tables with results of quality assessments are available in Additional file 1: Appendix 3.
# Deliberation guide
The deliberation guide includes the synthesized data for each criterion along with a section prompting participants to interpret and discuss the data. Boxes for the development of recommendations were added at the end of each dimension.
# Recommendations
Recommendations are presented in the following format:
1. A lay summary of the data synthesis that led to the recommendation(s) written in a format that is accessible to a non-physician audience (for the clinical dimension, detailed narrative summaries of the data are available in Additional file 1: Appendix 4). 2. Additional key points discussed during deliberation that led to the recommendation(s)' development.
# Recommendations and rationales.
To facilitate the understanding of the presented data, key concepts and definitions pertaining to OIT are illustrated in Fig. 3.
# Sociopolitical dimension: promotion of the common good
# Recommendations for a sociopolitical context for optimized food allergy management
Summary of data synthesis (see details and references in Table 1, Sociopolitical dimension, criteria 1 and 2): Data collected for the sociopolitical dimension illustrates that the main practice in food allergy management is avoidance, in which patients and caregivers carry most of the responsibility. Although this management method is certainly appropriate for some, there has been a growing demand for an interventional approach in food allergy, leading to recent developments in OIT. With OIT treatment growing in popularity, two opposing perceptions have arisen: one of fear and one of hope. Confusing misinformation concerning risks and benefits of OIT further contributes to a polarizing discussion surrounding OIT. Within this unconducive context, OIT has only recently been introduced in a limited number of clinical practices. Access disparities are further exacerbated by increasing demand, the lack of specialized care in urban and, even more so, rural areas, and a potentially inadequate billing system in some Canadian provinces. Additionally, some proponents assert that OIT should only be administered using pharmaceutical products, such as pre-packaged food doses, indented as a life-long treatment, rather than using readily available food for OIT, creating issues that could adversely affect both patients and sustainable development of OIT. Additional key points from deliberation It is essential that patients with food allergy have the ability to control the management of their condition so that it reflects their needs and objectives. As such, they should be able to access OIT when it is requested. Patients will be able to reach these objectives more effectively when adequately informed about their treatment, to manage anxiety related to food allergy and to prevent unrealistic expectations about the benefits of OIT or an overestimation of its risks. A fully standardized approach would not be adequate in this context since it cannot respond to each patient's situation and needs-this calls for research designs on food allergy care to be directed towards answering key questions of personalized care, such as long-term outcomes and real-life needs.
# Populational dimension: promotion of equity
# Recommendations for the equitable provision of OIT
# Summary of data synthesis (see details and references
in Table 1, Populational dimension, criteria 3 to 7): The burden of food allergy can be described in two ways: based on the risk of severe reactions which is relatively low or based on its impact on the psychosocial wellbeing of patients and caregivers, which is extensive (see details and references in Table 1). Food allergy affects many spheres of life for patients and their caregivers and may lead to isolation or vulnerability to bullying. These impacts may be lifelong for those in whom food allergy does not resolve naturally with time.
A management strategy based solely on avoidance is often characterized by a number of unmet needs, as patients and caregivers are often left to manage their condition by themselves. Society can help reduce risk and burden with measures such as appropriate food labeling regulations or food restriction/management protocols in schools and restaurants. However, even with these measures in place, patients and caregivers will continue to have many limitations and few options to establish control over their risk of reaction.
Up to 50% is directly or indirectly affected by food allergy, according to some estimates, including patients, family and caregivers, their immediate social circles and society. Despite this, there is low investment in this area by the healthcare system, with a low capacity of care for both accurate diagnosis and management. There are disparities in access to specialized care, which is generally limited, both in urban and rural areas. not disproportionately displaced toward OIT, so as to ensure that patients will continue to receive optimal care if opting for the traditional approach of food avoidance. show that a majority of patients can achieve protective levels of desensitization and that a substantial proportion can achieve complete desensitization, which can be maintained with continued consumption of the food. Studies show that many patients do continue consuming the food allergen regularly in the longer term. A variable smaller proportion can maintain tolerance to the food allergen even after a period of prolonged avoidance; however, this data is scarce and only available for the major food allergens.
Patients undergoing OIT will more likely experience allergic reactions than those who are avoiding the food. This is because treatment dictates that they intentionally consume their food allergen. A majority of OIT patients have at least one allergic reaction, varying mild to severe (i.e. anaphylaxis), and some may require the use of epinephrine. According to many studies across different designs and food allergens, the Key additional points from the deliberation A culture of fear currently exists regarding food allergy and includes widespread erroneous concept that all allergies should be considered equally dangerous. As a result, many believe that the only acceptable management option is strict avoidance. Instead, the risk of reaction is extremely variable and hard to predict. This results in a disparity between populational epidemiological data and actual individual risk. Individuals vary with respect to their level of comfort with risk as well as their perception of the extent of benefit derived from a treatment. Thus, the decision to pursue OIT should be left to the well-informed patient as much as clinically possible, rather than based on external criteria.
It was strongly felt that in the development of OIT within the healthcare system as an option of care, steps must be taken to ensure that resources in food allergy are frequency and/or severity of allergic reactions declines as the treatment progresses. A few studies also observed that the frequency of reactions from accidental exposure declines in patients undergoing OIT. Even after a prolonged period of maintenance dosing, systemic reactions may occur in some patients. These reactions usually occur in the presence of a cofactor (e.g. exercise, sleep deprivation, illness and fever, certain medications) that transiently increases the likelihood of reaction, but the risk appears to decrease with longer time on maintenance.
While some patients ultimately discontinue OIT due to adverse events, other factors may also result in discontinuations and include anxiety or refusal to ingest the food doses. avoidance in the short term, the anxiety associated with these is generally manageable because they are expected and can be planned for, which contributes to patients' sense of control. The burden of these reactions is generally offset by the protection granted against unexpected reactions from accidental exposures outside of food dosing, which creates a sense of empowerment by lifting the burden of constant vigilance and provides a sense freedom. For many patients, the burden of these reactions diminishes over time as they learn to self-manage.
The variability in safety outcomes between studies may be due to various factors, including a treatment center's experience in OIT. This will affect the ability of providers to personalize treatment plans, shaping the instructions offered to patients on how to take the dose and manage reactions.
# Box 3: Recommendations on eligible food allergens and types of clinical outcomes that can be achieved by OIT
# Ethical imperative, data or other considerations in support of the recommendation
# Level of evidence (applicable when recommendations are based on outcome data from clinical studies)
There is no convincing evidence of a clinically significant difference between food allergens in terms of safety and efficacy outcomes in OIT for the treatment of IgEmediated food allergy. Therefore, all recommendations in these CPGs are generally applicable to all food allergens, unless there is specific evidence to demonstrate otherwise
# This recommendation is based on the principle of equity of eligibility
It is supported by large amount of consistent clinical evidence, considering the absence of demonstrated lack of efficacy or of a consistent safety issue for any specific food despite a large number of clinical studies for a variety of foods [22][23][24][29][30][31][32][33][34][35][36][37][38]. Level of evidence: HIGH It is also supported by the lack of biological plausibility that the mechanism of OIT would differ from one allergen to another.
OIT is recommended as a treatment to achieve desensitization. A majority of patients will achieve a level desensitization to a daily dose of the allergen that will be sufficient to provide protection against trace exposure, while a sizable proportion of patients will be able to tolerate a full serving This recommendation is based on the principle of beneficence. Whether or not the outcomes (i.e. desensitization, continued consumption or sustained unresponsiveness) are worth pursuing remains patients' prerogative, in line with the principle of patient autonomy It is supported by a large amount of consistent clinical evidence, which includes three metaanalyses [22][23][24] (together covering 31 published OIT controlled clinical trials), three additional RCTs [31,34,39] and two non-randomized controlled clinical trials (CCTs) [36,38], five large case series in clinical practice (N > 150) [29,30,32,33,40], and two smaller case series [35,37]. This body of evidence includes 10 RCTs rated as being at low risk of bias [34,[41][42][43][44][45][46][47][48][49] and is coherent with data from consultations. Level of evidence: HIGH OIT can be recommended for long term management since a sizable proportion of patients will continue to regularly consume a sufficient amount of the food to maintain desensitization after reaching maintenance, without reverting to complete avoidance This recommendation is based on the principle of beneficence. Whether or not the outcomes (i.e. desensitization, continued consumption or sustained unresponsiveness) are worth pursuing remains patients' prerogative, in line with the principle of patient autonomy It is supported by a moderate amount of consistent clinical evidence, from three long-term, 2-arm follow-up studies of RCTs (high risk of bias due to open-label; mean follow-up 2.5 to 5 years; completeness of follow-up: 77 to 90%) [50][51][52], three large case series in clinical practice (N ≥ 145) (moderate risk of bias using the IHE tool due to single-center, retrospective design; median follow-up: 1.5 to 6.5 years; completeness of follow-up: 83 to 99%) [33,53,54], and four smaller single-arm, follow-up studies (N = 43 to 100) at low to high risk of bias (completeness of follow-up: 82 to 100%) [35][36][37]55]. This is coherent with data from consultations. Level of evidence: MODERATE OIT may be recommended to achieve sustained unresponsiveness, but data is limited and variable This recommendation is based on the principle of beneficence. Whether or not the outcomes (i.e. desensitization, continued consumption or sustained unresponsiveness) are worth pursuing remains patients' prerogative, in line with the principle of patient autonomy It is supported by a small amount of evidence with some incoherence in findings, including one meta-analysis (covering 4 RCTs) [22], three additional RCTs [34,46,56], one CCT [57], one prospective trial with retrospectively-matched controls [58] and one case series in clinical practice [40]. This is coherent with data from consultation concerning pre-school children.
# Level of evidence: LOW
Additional key points from deliberation Although reactions are more frequent during OIT than with
# Recommendations on who could benefit from OIT (indications)
Summary of data synthesis (see details and references in Table 1, Clinical dimension, criteria 8 to 12): The allergists consulted highlighted the need for accurate diagnosis of food allergy before initiating treatment, since many patients are either mislabeled or wrongly believe they are allergic.
Most OIT studies included children and adolescents across a wide age range. Several report that the treatment is very efficacious and well tolerated in toddlers and preschoolers. A few studies focused on adults and suggested that they can also achieve desensitization.
Additional key elements from deliberation An accurate diagnosis of IgE-mediated food allergy may require an oral food challenge, especially if the patient does not have a convincing medical history or a high food-specific IgE level. In addition to confirming the diagnosis, an advantage of performing a food challenge prior to starting OIT is that it can inform the initial escalation dose. This advantage must be weighed against other practical considerations, including the burden of inducing a highly probable allergic reaction and available resources to perform food challenges.
Toddlers and preschoolers are an attractive group for OIT due to the high efficacy and relative ease of treatment in this group. However, it is important that efforts are not focused solely on an age group where treatment appears to be more cost-effective, as specific clinical expertise should also be developed to address the need in other age groups, including adults. A careful balance must thus be found between the promotion of sustainability and the promotion of equity of access.
# Box 4: Recommendations on who could benefit from OIT (indications) Ethical imperative, data or other considerations in support of the recommendation
# Level of evidence (applicable when recommendations are based on outcome data from clinical studies)
An accurate diagnosis of IgE-mediated food allergy is essential before proceeding with OIT Regardless of therapeutic option considered, accurate diagnosis of food allergy is the basis for proper care to avoid futile treatment, including unnecessary avoidance. This recommendation is thus based on the principles of nonmaleficence and sustainability OIT is indicated for toddlers and preschoolers Important consideration While the likelihood of spontaneously outgrowing milk or egg allergy may be greater than for other foods, their impact on patients and families, if not outgrown, is high. Caregivers should be included in shared decision-making about, whether to initiate OIT early for these foods and based on individual prognosis, considering that OIT is well tolerated and has high efficacy in this age group This recommendation is based on the principle of equity in eligibility as well as proportionality between risks and benefits, considering patient's goals and perspectives For desensitization, it is supported by a large amount of consistent clinical evidence. Many OIT studies (RCTs [34,41,43,47,49,59,60] as well as large clinical practice case series [32,33,40,54]) enrolled children starting from the age of 4 or 5 years; some have started enrolment from age three [29,61] or one [46,62]. In addition, there is a moderate amount of consistent evidence specifically for this age group from one RCT of milk OIT (unclear risk of bias-Cochrane) [63], one large (N = 270) prospective, multi-center case series in clinical practice of peanut OIT (low risk of bias-IHE tool) [30] and one small (N = 37) prospective, uncontrolled clinical trial of peanut OIT [58]. This is coherent with data from consultations.
Level of evidence: HIGH For sustained unresponsiveness, it is supported by a small amount of clinical evidence (1 prospective clinical trial of peanut OIT with retrospectively matched controls observing a large effect size [58]) and is overall coherent with data from consultations. Level of evidence: LOW
# OIT is indicated for school-age children and adolescents
This recommendation is based on the principle of equity in eligibility as well as proportionality between risks and benefits, considering patient's goals and perspectives. For desensitization, it is supported by a large amount of consistent clinical evidence. Most of the evidence for desensitization stems from studies that enrolled children and adolescents with median/mean ages in the range of 6 to 12 years (RCTs [31, 34, 39, 41, 43, 46, 49, 59-61, 64, 65] and large clinical practice case series [32,33,40,54]) In nine RCTs [34,39,41,43,44,47,59,61,64] and five large clinical practice case series [29,32,33,40,54], the upper age limit for enrolment was 16 years or older (up to 27 years [32]). This is coherent with data from consultations. Level of evidence: HIGH For sustained unresponsiveness, it is supported by a small amount of consistent clinical evidence. Most of the limited evidence that is available for sustained unresponsiveness stems from studies that enrolled children with median/mean ages in the range of 6 to 9 years (RCTs [34,46,49,56,59,66], CCT [57] and clinical practice case series [40]). Level of evidence: LOW OIT may be indicated for adults This recommendation is based on the principle of equity in eligibility as well as proportionality between risks and benefits, considering patient's goals and perspectives. For desensitization, it is supported by only a small amount of consistent clinical evidence. The limited data available for patients 18 years of age and older, from one double-blind RCT that included a small number of adults [47,67] and one small case series [44] suggest that desensitization is possible in this age group.
# Recommendations regarding contraindications
# Summary of data synthesis (see details and references in
Table 1, Clinical dimension, criteria 8 to 12): A history of anaphylactic reactions to the targeted food allergen was generally not an exclusion criterion in OIT studies. Some studies suggested that a history of anaphylaxis had an impact on OIT outcomes, but most of these patients were able to achieve at least partial desensitization. The number of food allergies a patient has appears to have no effect on treatment efficacy in terms of reaching the target maintenance dose to one food.
Most OIT studies included patients with controlled asthma, but generally excluded patients with uncontrolled or severe asthma (i.e. severe asthma defined as the requirement for extensive medication to achieve control). Patients with asthma tended to have a higher risk of adverse reactions and, in certain studies, some experienced a worsening of their asthma. Nevertheless, most patients with controlled asthma were able to achieve at least partial desensitization.
OIT requires that patients and their caregivers attend visits regularly and are able to understand and follow instructions regarding how to administer the treatment at home. Patients must also be able to recognize and treat adverse events.
Additional key elements from deliberation Successful OIT requires a significant commitment from both patients and caregivers -it is essential to ensure all are informed and understand the importance of this commitment. Psychological support can help if there is significant anxiety or other psychological issues and should ideally be sought before beginning OIT.
# Box 5: Recommendations regarding contraindications Ethical imperative, data or other considerations in support of the recommendation
# Level of evidence (applicable when recommendations are based on outcome data from clinical studies)
Previous history of anaphylaxis to the targeted food is not a contraindication for OIT
# This recommendation is based on the principle of equity in eligibility
It is supported by a large amount of clinical evidence A history of anaphylactic reactions to the targeted food allergen was generally not an exclusion criterion in OIT studies. Some RCTs [43,46,47,49,59,63] and clinical practice case series [30] excluded patients with a history of severe anaphylaxis; others included them (RCTs [41,61,64]; case series [29,40]). Evidence from large case series on whether baseline history of anaphylaxis had an impact on OIT outcomes is inconsistent [32,40,53,54], but most patients with a history of anaphylaxis were able to achieve at least partial desensitization [32,40]. This is coherent with data from consultations. Level of evidence: HIGH
# Multiple food allergies are not a contraindication to OIT This recommendation is based on the principle of equity in eligibility
It is supported by a moderate amount of consistent clinical evidence from two case series (N = 111 and N = 280; moderate risk of bias [IHE tool] [32,54]) and additional clinical studies targeted towards patients with multiple food allergies [68][69][70][71]. Level of evidence: MODERATE Uncontrolled asthma is an absolute contraindication to OIT. Asthma must be controlled before beginning OIT and pro-actively managed during OIT This recommendation is based on the principle of nonmaleficence In many RCTs [31,39,41,43,46,47,60,61] and clinical practice case series [30,32,54], severe and/or poorly controlled or unstable asthma was an exclusion criterion for OIT. However, most patients with controlled asthma were able to achieve at least partial desensitization [33,40,54,72]. This is coherent with data from consultations. 1, Clinical dimension, criteria 8 to 12): Clinical studies of OIT report that reactions requiring the use of epinephrine, including anaphylaxis, may occur in the clinic as well as during home dosing.
# Recommendations for the safe provision of OIT
# Summary of data synthesis (see details and references in Table 1, Clinical dimension, criteria 8 to 12): (see details and references in Table
Eosinophilic esophagitis (EoE) is more prevalent in children with food allergy, especially those with milk or egg allergy, as compared to the general pediatric population, and may emerge during OIT. Certain studies report that EoE was managed with dose adjustments, though some patients discontinued OIT because of EoE.
Additional key points from deliberation Some patients have gastro-intestinal symptoms that occur independently of the timing of food dosing. These can often be controlled by modifying the treatment schedule or by adding specific medication. Patients and families should be informed that endoscopy-directed biopsy may be required when symptoms compatible with EoE or eosinophilic gastro-intestinal disease (EGID) arise during OIT.
# Box 6: Recommendations for the safe provision of OIT Ethical imperative, data or other considerations in support of the recommendation
# Level of evidence (applicable when recommendations are based on outcomes data from clinical studies)
OIT providers and patients should be prepared to recognize and treat allergic reactions, including anaphylaxis, during OIT. Food escalation should only be performed in a clinic with appropriate equipment and infrastructure* available to treat anaphylaxis A personalized action plan should be provided to patients to guide management of reactions occurring at home Providers should only offer OIT in age groups in which they have training or experience in treating anaphylaxis (*see Additional file 1: Appendix 5 for guidance on equipment and infrastructure requirements)
This recommendation is based on the principle of nonmaleficence It is supported by a large amount of consistent clinical evidence indicating that there is a risk of anaphylactic reactions during OIT [22][23][24]. A proportion of these reactions occur outside the healthcare setting [29,32,36,[38][39][40]. This is coherent with data from consultations. A few studies directly compared different OIT protocols. One study indicated better efficacy and fewer moderate to severe reactions with more gradual up-dosing. Another study observed that patients were more likely to adhere with continued allergen consumption when the maintenance dose was lowered. The frequency of maintenance dosing had an impact on reactions and adherence in one study, while another study found no difference after 1 year of maintenance. When considering clinical factors that could be used to define treatment plan, the only prognostic factor consistently associated with treatment outcome was the baseline allergen-specific IgE level.
# Recommendations on personalized OIT protocols
# Summary of data synthesis (see details and references in
When considering multiple food OIT protocols, similar rates of reaction were observed in studies treating up to 5 food allergens simultaneously, as compared to single-food OIT. In addition, time to reach desensitization for all the foods with multiplefood OIT was only a few months longer than for one food with single-food OIT.
Studies have also looked at the use of omalizumab as part of an OIT protocol. A short course of omalizumab combined with an accelerated OIT schedule not only reduced the rate of dosing-related reactions, but helped improve desensitization rates. In contrast, extended use of omalizumab within a standard slow OIT schedule did not improve the final success rate.
Additional key points from deliberation Decisions regarding when to initiate OIT, the initial food escalation, and the rate of escalation should be based on the same factors that help predict reactivity during food challenges and adapted to patient context. For example, it may be appropriate to proceed directly to OIT for a toddler with a recent reaction to relatively high amount of the culprit food whose food allergy has been confirmed with a skin test rather than to delay therapy while waiting for further confirmatory laboratory results. The objective is to respect the time patients and families have available, optimize the use of limited healthcare resources, and avoid missing a window of opportunity before a potentially unfavorable natural evolution of the disease.
In an ideal world, the rate of dosing escalation would be adjusted to match the patient's change in reactivity threshold, which may not follow a linear trajectory. In practice, however, this is not always feasible for logistical reasons. In addition, fixed up-dosing schedules are also more easily implemented by OIT providers with less experience.
There is limited data on the advantage of a high maintenance dose over a lower dose when long term outcomes are assessed. Conceptually, the demonstrated efficacy of sub-lingual immunotherapy (SLIT) and epicutaneous immunotherapy (EPIT) suggests that a high dose may not be needed to modulate the immune response. Adherence with lower food doses is often easier, and a potentially more important goal than an unproven theoretical benefit a higher dose may have on sustained tolerance. Ultimately, however, determination of the target dose should include a consideration of the patient's goals and preferences.
Treatment objectives can vary between patients as well as over time during therapy for a given patient. Some patients may desire the ability to stop treatment for a prolonged period (i.e., several weeks) without losing tolerance, while others should like to know that they can safely skip treatment for a few days, that they no longer need to be careful of certain co-factors or that they can safely ingest large amount of the food. Oral food challenges are necessary to assess many of these treatment objectives but consume time and resources. Therefore, monitoring plan should be personalized to specifically assess only the treatment outcomes that are relevant to a patient. Measurements of food-specific IgE and IgG4 are inexpensive and may also be helpful in the decision whether to proceed with an oral food challenge to test for these outcomes.
Assessing for sustained unresponsiveness requires a prolonged period of discontinuation of ingestion of the food and carries the risk of unnecessarily losing progress made with desensitization. Unless allergy testing has become negative, the preferred approach is to assess for sustained unresponsiveness is to progressively increase dosing intervals such that that dosing intervals can again be shortened if and when reactivity returns.
Because of its cost, recourse to omalizumab should occur responsibly and judiciously, as widespread unjustified use could jeopardize treatment sustainability. Despite its excellent safety profile, it is an injectable biologic drug, which can limit its acceptability for some patients.
# Box 7: Recommendations on personalized OIT protocols Ethical imperative, data or other considerations in support of the recommendation
# Level of evidence (applicable when recommendations are based on outcomes data from clinical studies)
OIT can be performed with many different food products This recommendation is based on the principles of equity of access and sustainability. Unless the superiority of a specific food product is demonstrated over other forms of the same allergen, choice of the product should be guided by availability, cost and practicality It is supported by data from consultations with stakeholders. In addition, despite a theoretical concern for the variability of non-standardized food products there is no evidence on the superiority of OIT protocols that use pharmaceutical products. (One meta-analysis of peanut OIT RCTs found that both proprietary and non-proprietary OIT products led to desensitization compared to placebo or usual care [24])
The goals of OIT can be achieved with many different protocols. There is little evidence that specific dosing schedules are superior to others. Reference protocols* can be useful to guide therapy but need to be selected and adapted based on the patient' s specific situation See Additional file 1: Appendix 6 for sample protocols This general recommendation as well as the specific recommendations (A to D) that follow are supported by data from consultations with stakeholders and a large amount of successful published protocols that follow the same general approach (see OIT protocol variables in clinical studies or published clinical practice in Additional file 1: Appendix 3)
A. The initial dose that will be ingested at home should be determined during an initial dose escalation in clinic (day 1). This consists of a graded introduction of the allergen to identify the highest tolerated dose at baseline. The planned starting and ending doses for the initial escalation in clinic should be below the expected reactivity threshold and determined through shared decision making with patients and families. The objective is not necessarily to identify the reactivity threshold and induce a reaction as this can become a barrier to treatment. An alternative to multi-step escalation is to start treatment directly with a single dose assumed to be below the patient' s reactivity These recommendations are based on the principle of patient' s best interest to limit the burden of unnecessary visits while preserving patient safety, as well as on the principle of sustainability and best use of healthcare resources The use of a flexible approach reflects the key elements of personalized care and contributes to empowering patients in the self-management of their food allergies. This is in line with earlier recommendations (see Box 1) to practice OIT in the spirit of personalized care and to promote patient empowerment B. After initiating daily home ingestion of the tolerated dose, up-dosing increments should be adapted to patient evolution throughout therapy.
Transient mild local reactions are to be expected in the first days following a dose increase. In the absence of any signs of reaction, the protocol could be accelerated. In the event of persistently recurring, moderate to severe or systemic reactions, dose progression must be decreased. The up-dosing intervals can be prolonged for medical or logistical reasons, or for personal preferences C. The final target dose for the therapy should be guided by the patient' s individual clinical response and personal goals, which can range from protection against accidental exposures to small amounts to unrestricted inclusion of the allergen into the diet. There is a lack of evidence that high maintenance doses will increase the likelihood of sustained unresponsiveness This recommendation is based on the principle of autonomy to allow patients to achieve their individual goals according to their contexts.
D. During follow-up, persistence of desensitization is monitored by documenting a patient' s continued consumption of the food allergen. A decision to test for other outcomes should be guided by a patient' s personal objectives. Complete desensitization can be assessed by performing a high threshold challenge to the food. The risk of a dosing reactions associated with cofactors can be assessed by performing a food challenge in the presence of cofactors (e.g. alcohol and non-steroidal anti-inflammatory drugs, exercise).
# Sustained unresponsiveness can be assessed by the progressive increase in dosing intervals
This recommendation is based on the adequacy of the intervention in addressing the actual needs of patients When performing OIT in patients with multiple food allergies, the preferred approach is to treat multiple foods simultaneously This recommendation is based on the principle of sustainability and on practical consideration for patients It is supported by a small amount of consistent clinical evidence: one small nonrandomized study observing similar safety outcomes between multiple-food OIT (targeting up to 5 foods simultaneously) as compared to single-food OIT and a small difference in treatment duration [68]. Additional small studies lend further support to suggesting the feasibility of multi-food OIT with [69,71] or without [70] the concomitant use of omalizumab. This is coherent with data from consultations. Level of evidence: LOW
# Short-term concomitant use of omalizumab can be considered in challenging cases
This recommendation is based on the principles of nonmaleficence and equity of access in the specific context of challenging cases. Limiting recourse of omalizumab to such challenging cases is based on the principle of sustainability It is supported by a moderate amount of consistent clinical evidence including two small placebo-controlled RCTs rated as being at low-risk of bias, in which, compared to placebo, the concomitant use of omalizumab allowed for more rapid up-dosing with similar or fewer adverse reactions [71,73]. This is coherent with data from consultations. Level of evidence: MODERATE
# Recommendations for patient-centered care
Summary of data synthesis (see details and references in Table 1, Clinical dimension, criteria 8 to 12): One of the most important goals patients have regarding the management of their food allergy is to reduce the anxiety and achieve a sense of control by reducing the risk associated with accidental exposure. This can be achieved in different ways, including through OIT.
OIT involves ingesting an allergen that was previously avoided, which can initially be very challenging and an understandable source of anxiety. Reactions can occur with food dosing, and as is the case in all food reactions, including those due to unintentional exposures, both patients and clinicians find it difficult to distinguish between allergic symptoms and symptoms due to anxiety.
OIT is time-consuming for multiple reasons, including the number of clinic visits necessary for up-dosing, and a period of reduced activity that is required before and after food dosing to reduce the risk of reactions. A patient can be bothered by the amount and taste of food they must consume for OIT. Nevertheless, published studies and consultation data suggest that most patients do not consider OIT an overwhelming burden.
Misconceptions regarding risks and outcomes of OIT have the potential to create unrealistic expectations or concerns. Interestingly, one clinical study showed that anxiety was reduced and adherence with OIT improved when the occurrence of mild reactions was presented in a positive light as being part of the process and indicative of progress towards treatment goals.
The majority of studies on OIT show that patients receiving OIT report improved food allergy-related quality of life, particularly with respect to anxiety. A subset of patients can experience a deterioration in quality of life measures at the beginning of treatment, but this tends to resolve upon reaching maintenance. The greatest improvements in quality of life are reported by patients for whom food allergy had the strongest impact on quality of life before starting treatment.
Additional key points from deliberation Shared decision-making is a key component of patientcentered food allergy management. Providers must communicate effectively to explain all treatment options, including continued avoidance and food OIT, so that patients are able to make a choice that aligns with their preferences, values and clinical needs. Communication between patients and their provider before initiating OIT and throughout treatment is of the utmost importance to ensure that patient and provider treatment goals are aligned, expectations remain realistic, and anxiety is well managed.
During the maintenance phase of OIT, many patients want to be informed about their treatment progress beyond their level of desensitization to the daily doses. This includes information about whether they also have tolerance to food amounts above the treatment dose, the actual risk associated with skipping doses and the relevance of various cofactors in allergic reactions to foods. The observation of longitudinal changes in the underlying immune response is highly relevant to patients and is used in some clinical practices to guide decisions. Monitoring food-specific IgE and IgG4 levels may be useful in that regard; however, more research is needed to clarify the real-life interpretation and relevance of these within the context of OIT.
Research on the impact of other interventions, such as food allergy education, on quality of life would contribute to inform best approaches and optimise care and resource use.
# Organizational dimension: promotion optimized organization of care
# Recommendations for the promotion of optimized organization of care
Summary of data synthesis (see details and references in Table 1, Organizational dimension, criteria 13 and 14): OIT is a viable therapeutic option and so falls within the mandate of the healthcare system. Healthcare resources for food allergy are currently based on an approach to management focused on the complete avoidance of the offending allergen; thus, the implementation of OIT will require a complete reorganization of food allergy care, while also maintaining support for patients who continue with avoidance alone.
All physicians involved in administering OIT must be able to recognize and manage different types of adverse food reactions and must have access to equipment required to treat severe reactions. A multidisciplinary approach to OIT can improve patient outcomes and optimize the use of resources by including other relevant healthcare personnel who can assist the physician, including nurses, registered dieticians and psychologists.
Additional key elements from deliberation A multidisciplinary approach could contribute to improved quality of care and a sustainable wide scale offer of OIT by relieving OIT providers of certain tasks that other healthcare professionals can perform. Nurses can be essential as a point of contact for patients and for coordinating care. Registered dieticians can provide unique support in identifying equivalent food alternatives for home dosing and to monitor nutritional needs. Psychologists can offer support within the context of individual or group interactions. Group interactions have the unique potential to offer professional support within the context of sharing issues with others, supporting others with similar concerns and questions, and collaboratively identifying solutions. Patient groups can also provide an outlet to discuss issues that might not otherwise arise if the patient interacts with healthcare professionals only. Integrating peer supporters into the clinical team can help ensure the alignment of key messages.
Regarding access disparities, offering training and support to pediatricians and family doctors who wish to offer OIT under the direct supervision of a subspecialist allergist could greatly contribute to make the treatment accessible to a much larger number of patients in rural areas, where few or no allergists are available, or in urban areas, where there are not enough allergists to respond to patient demand. Conditions for the safe provision of OIT (see Box 6) need to be always maintained, including equipment and infrastructure requirements.
The majority of clinical and research OIT initiatives have focused on children to this point which creates a risk of a knowledge deficit in the adult allergy/ immunology training curriculum that could impact future capacity to offer treatment in this patient group. The price of a commercial product developed for peanut OIT is based on the cost of pharmaceutical development, which makes it approximately 100 times higher in cost a similar non-pharmaceuticalbased approach produced within the healthcare system. When using non-pharmaceutical products, the cost of OIT treatment derives primarily from healthcare practitioner's services, whereas when using pharmaceutical product, the commercial food OIT product represents a significant additional and long-term expense without reducing base costs. With the commercially developed peanut OIT product, the economic model assumes lifelong treatment based on the manufacturer's stated indication, while a non-pharmaceutical-based approach assumes that patient can use regular food. This raises ethical issues regarding the best interests of a patient, which is to have an open diet, and the best interest of the healthcare system, which is to ensure sustainability over the long term.
On the patient side, data shows that avoidance is associated with significant costs to patients, because as one patient said, "fear makes us spend". OIT, in the short term, will increase cost associated with physician visits (including time off work), which will be reduced and possibly lower than avoidance once on maintenance. From the societal side, OIT is perceived as a good investment which could prevent future healthcare and productivity issues, especially when performed early.
Additional key points from deliberation A pharmaceutical-based-approach to OIT carries the risk of diverting limited resources in food allergy care to cover high cost products and away from strengthening treatment capacity within the healthcare system.
The notion of "off-label" use does not apply to foodcharacterizing the practice of OIT with common food as "off-label" in reference to an alternative commercial product is in neither the best interest of patients nor of the healthcare system. To this point, foods for other medical procedures, including diagnostic food challenges, are currently bought at the grocery store and measured in clinic. The cost of a prepackaged standardized food dose should reflect its true value in clinic, which is ultimately of a practical nature, rather than the fact that it has been categorized as a drug.
# Discussion
This development process of these CPGs consisted of a comprehensive approach to both the data collection and the collection of perspectives from all stakeholders. This allowed for the collaborative development of 38 recommendations guided by the five principles of the common good, equity, health and wellbeing, optimized organization of care and sustainability of healthcare systems, allowing a 360° view of OIT. This comprehensive approach included the full extent of a traditional review of the available clinical data. The large number of both RCTs and diverse observational studies provided a rich body of complementary evidence. In addition, the inclusion of patients in both the consultation and the deliberation phases provided key experiential knowledge and contributed to the interpretation of data and the development of recommendations. Similar involvement of first line and allied healthcare professionals ensured a multidisciplinary perspective for optimal organization and provision of care as well as efficient use of healthcare resources. Throughout the aforementioned steps, the multicriteria methodology drove the systematic collection of scientific and experiential knowledge for all dimensions, the sociopolitical, populational, clinical, organizational and economic. This was instrumental in developing balanced recommendations allowing us to address issues beyond what is usually covered by traditional CPGs.
This was critical in the specific context of OIT, which poses challenges beyond its clinical aspects. Offering OIT requires adapting the organization of care in a setting of highly limited resources. It marks a rupture with a culture focusing on avoiding reactions at all cost, which creates confusion and tensions. Competing developments as a drug-based versus a food-based therapy also create a number of ethical issues. The methodology provides an ethics-based framework to identify and address these issues in the elaboration of recommendations.
The 360° approach necessitates a team with diverse expertise in various methodological domains and fields of knowledge to collect and integrate the body of knowledge in the multicriteria grid. Expertise in communicating in lay language and chairing a discussion on all these aspects is essential to ensure an understanding by all. The inclusion of participants with diverging perspectives is important to stimulate individual and group reflection during discussions. A tailored multidisciplinary team and a method that allows for efficient organization of data per criteria are essential to the process and key to promote understanding of numerous complex concepts and fulfill the A4R conditions.
Accountability for Reasonableness (A4R) defines four main conditions that can enhance legitimacy and help stakeholders develop a mutual basis for decision making: publicity of rationales for choices; relevance of criteria agreed to by a broad range of stakeholders; revisability of the decision in light of new evidence or arguments; and enforcement that means the other conditions are met [14]. The multicriteria approach facilitates meting these four conditions. The use and publication of the multicriteria grid completed with the data, from which detailed and lay rationales were developed, addresses the publicity and the relevance conditions. The multicriteria grid also offers a pragmatic tool to update the CPGs as significant advancements in knowledge emerges, which contributes to revisability. The implication of a large number of stakeholders, of methodologists and ethicists, the participation of external observers at the deliberation, as well as oversight by the CSACI board contributed to the enforcement of these three conditions.
Clinical recommendations developed here are generally concordant with those from the European Academy of Allergy and Clinical Immunology (EAACI) [8]. That said, in addition to the recommendations made outside the clinical dimension, there are some noteworthy differences between the CPGs, which likely stem from the difference in methodology. The authors of the EAACI guidelines explicitly stated in their discussion that "there is no evidence that the efficacy and safety are affected by the type and nature of the food allergen used in allergen immunotherapy". However, their methodology resulted in limiting the indication for OIT to milk, egg and peanut only. The current guidelines diverge from those from EEACI in a few other recommendations, namely regarding the indication for OIT in children less than 4 years of age or in adults and the recognition that OIT can promote sustained unresponsiveness in some patients, over the long term.
There was also a difference in the overall vision surrounding the development of OIT. In the EAACI guidelines, the need for standardized protocols and products was identified as a high priority, while these CPGs emphasize that there is a need for more personalization. Standardization is often seen as a desirable objective in modern medicine because it allows generating quantitative data that can be used as the basis for more recommendations using a traditional CPG methodology. However, the ability to adapt protocols to patients' needs is essential in OIT. Standardized products and protocols have not been shown to provide clinical benefits over their adaptable alternatives and can actually increase barriers and costs, thus threatening sustainability and access.
Personalized approaches, however, represent a challenge for the transfer of expertise. The development of training initiatives, clinical tools, and organizational models adapted to the delivery of personalized care should therefore be made a priority. Shared decisionmaking tools should include clear information on food allergy management, consent forms, home dosing instructions, and a reaction management plan. Specific training tools directed toward allergists, primary care physicians and allied healthcare professionals should focus on the biological, psychological and social aspects of the therapy and be included in training curricula and continuing professional development (CPD).
Clinical tools will be developed collaboratively as a second step of these CPGs and made available online at http://www.csaci .ca/OIT-guide lines .
These CPGs also identified a number of data gaps that require further research, including:
• long-term patient-centered outcomes • underrepresented groups, e.g. adults • optimal use of biomarkers to guide therapy • optimal use of medication to support treatment • determinants of reactivity, e.g. cofactors, individual differences in absorption and distribution of allergens • benefits and optimal use of nutritional, psychological, and peer support • economic and organizational aspects of the treatment. • Currently in North America, food allergy is most often managed by avoidance of the allergen. Avoidance is therefore the predominant response to food allergy in our society, with all the societal implications of food labeling and food restrictions in social activities. However, recently certain jurisdictions (e.g., British Columbia 76) encourage exposure of babies to allergens to limit development of food allergies. Avoidance defers the greatest part of the responsibility for food allergy management to patients and their families 77 (which maybe suited for certain patients), while OIT provides an avenue to treat this condition.
# OIT DEVELOPMENT:
• 100-year-old approach: first documented treatment attempt in 1908 (Schofield 1908).
•
# Network of allergists:
The increasing prevalence of food allergies created a growing demand of patients for interventional approaches, which led allergists to develop immunotherapy protocols and products to alleviate this health issue. Following a death due to dosing error in a clinical trial on subcutaneous peanut immunotherapy (allergy shots) in 1995, there was a shift of focus towards OIT with the beginning of controlled trials. To differentiate themselves from alternative health providers working outside their area of expertise and to legitimize the field of OIT, interested allergists networked to initiate and sustain the production of evidence on OIT, developing different approaches and indications. This has led to the development of two schools of thought, which have contributed to some divisions in the food allergy community. On one side, some centers continue to conduct formal clinical trials, on the other side others have started introducing OIT in practice based on the available evidence. In Canada, opinions appear less polarized with some clinicians combining both approaches. The introduction of OIT as a clinical offer has been made possible via oral food challenges, which is an approved and reimbursed practice in several provinces, and has been sustained by clinicians' enthusiasm ('OIT was the most important things they have done in medicine'
# 78
). This situation, as well as medical and organizational barriers to meeting the high demand, has led to the desire to formalize and standardize the practice of OIT with the understanding that this is an evolving field.
• Pharmaceutical industry: More recently, with the promise of a large market for OIT (estimated at billions of dollars 79), came an interest from investors in the pharmaceutical industry and research investigators to create a product (peanut powder in a capsule or a sachet) to be tested in clinical trials and submitted for FDA approval, leading to the creation of AImmune.
80
The FDA granted a fast track process and breakthrough therapy designation to this product (Palforzia Some researchers argue that the risks of allergic reactions with current OIT approaches do not outweigh their benefits and that research into other treatment approaches with an enhanced safety profile should be developed.
# 24
• Rapidly evolving situation: Changing perception of OIT from being an experimental treatment towards acceptance as an established service; the recent FDA position contributes to this change.
•
# Comprehensive clinical practice guidelines (CPGs):
A careful review of up to date evidence as well as a refined understanding of the complexity of the topic in all its dimensions (sociopolitical, clinical, economic, populational and organizational) are essential for providing this service to patients in a safe and sustainable manner. The
# OIT-
CPG Canadian working group and deliberative committee was constituted for that purpose.
# CANADIAN SETTING
• Reimbursement: Each province has their own rules around billing codes concerning OIT that can or cannot be used by allergists for this purpose, creating a difficult situation for those seeking to provide the service.
• Resources for food allergy: currently hospital resources dedicated to food allergy are calculated based on the practice of avoidance and are already saturated with an unmet demand for oral food challenges.
# ETHICAL ISSUES.
• There could be a perceived conflict between the current culture of avoidance oriented towards protection from exposure to the allergen and a potentially evolving culture that seeks to actively take control of the allergy by ingesting the allergen. Both cultures need to cohabit in solidarity, while respecting individual choices.
• There is some controversy regarding the commercialization of food products using the usual pharmaceutical channels (e.g. FDA approval). Although the best interest of patients should be the primary objectives, fear of legal jeopardy and the potential market appear to be important drivers of commercial development. 79
# 81
• In a vision of OIT as a personalized approach, the OIT protocol should be adapted to each patient; however, traditionally clinical trials require standardized protocols, which creates tension for attempting to address evidence gaps. 81
# 82
# •
The FDA approval of the peanut powder may create a sense of security that is not fully legitimate since FDA approval of the product in itself does not assure that it will be used properly to prevent serious allergic reactions.
# C2-Stakeholder visions DIVERGING VISIONS REGARDING FUTURE DEVELOPMENTS TO MAKE OIT ACCESSIBLE:
• Commercial approach: Proponents of a standardized drug treatment argue that a drug with an FDA-approved indication and protocol is necessary since some physicians perceive that the benefit-risk ratio of OIT is unclear and do not provide it because the "medicolegal jeopardy [risk of lawsuits] associated with peanut OIT outweighed the benefits", 81 and they do not have a billing code.
80
Commercialization through approval of a product by regulatory agencies, such as the FDA, is usually made on the basis of randomized controlled trials (RCT) with predefined and standardized protocols. Regulatory approval facilitates reimbursement and the creation of billing codes but comes at the cost of purchasing the commercial product for the healthcare system.
# 79
• Personalized approach relying on food products. Proponents of food based OIT-argue that "the key element of food allergy is food, and that food allergy does not need a drug but can be effectively treated with a food'. (C Wasserman, 2018
# 78
) and that the evidence gap should be closed by longitudinal studies of personalized care tailored to each individual.
# 82
Several allergists have indeed successfully developed OIT approaches using food products prepared in clinic by skilled staff to support patient needs worldwide ). In this vision, clinical practice guidelines should be developed based on evidence and ethical imperatives associated with food allergies and the provision of OIT.
# MEDIA:
The media message evolved from focusing on OIT as being dangerous (e.g., in 1910) to being a hope for patients with food allergies, the rate of which is increasing and who are currently left with the only choice of avoidance and its limitations. At the moment, there no consensus in the media on OIT, since it is associated with many feelings, excitement, caution and some unanswered questions. Anxiety remains a key issue both for avoidance and OIT (Media Review). The recent FDA decision is spurring a debate on the pros and cons of the commercial approach featuring a lifetime treatment indication for OIT with headings such as: "The US healthcare system found a way to make peanuts cost $4,200".
# Table 1 (continued)
# DIMENSION
# Criteria Data collected from the literature, milieu and consultations (in italics)
Pushing for OIT are: a portion of allergists, healthcare providers, patients and caregivers; pushing against: another portion of allergists, pharmaceutical companies, government officials. ETHICAL ISSUES:
• The best interest of patients, which are in need of services, and the sustainability of healthcare systems may come into conflict with commercial interests: regulatory approval of a commercialized product does not come with clinical practice guidelines and may confer a false sense of security to patients and providers. Commercialized products are likely to come at a significant cost to the healthcare system, which may limit patient access.
# 79
# •
The call for more research into other options (so far with limitations) rather than pursuing with OIT may not be well aligned with the patients' perspective of risks and benefits and conflicts with the current high unmet need
# •
The current system facilitates development and reimbursement of standardized treatments through a commercial approach, while the production of a simple food product by the healthcare system is more difficult; the best interest of patients (personalized approach) and of healthcare systems (sustainability associated with simple food-based products) calls for developing system facilitators for non-commercial approaches. ) and 0.2% in adults.
# C3-
# 97
# HEALTH-RELATED QUALITY OF LIFE (HRQOL):
• Fear of accidental exposure: uncertainty, anxiety and distress in parents, children
# DIMENSION
# Criteria Data collected from the literature, milieu and consultations (in italics)
healthcare system, interferes with this goal (principle of equity).
# •
The impact of food allergies on the lives of patients and caregivers increases if they had severe allergic reactions; however, history of severe reactions is sometimes used as an exclusion criterion for OIT, which may increase inequity of access.
# C4-Size of the target population
• Prevalence of food allergy in Canada (random survey of 5734 Canadians): Any perceived food allergy:
7.5%; probable allergy: children: peanuts (2.2%), tree nuts (1.5%), egg (1.0%), fish (0.9%), shellfish (0.8%), milk, wheat (0.2%); adults: shellfish (1.6%), tree nuts (1.0%), peanut (0.6%), egg, fish (0.5%), milk, wheat, sesame (0.2%).
# CONSULTATIONS
Patients: Allergy has a deep impact on patients, but also on their caregivers since they always have to stay informed and prepared to any eventuality. Friend, family, life companions, colleagues, classmates, especially in early childhood environments, and all public services linked to food also feel the burden of allergy and have to be educated and mindful about it. Some parents of other children at school can be unpleasant and reluctant to accept restrictions due to lack of understanding.
# Allergists: Not applicable
Other healthcare professionals: There is a strong impact on the family of a child: the patient(s), their parents and their siblings have to learn about allergy, watching for misconceptions such as comments like: 'just don't eat it' or 'injections are easy to do'. There is a very strong impact on both the parents of an allergic child, in some cases especially on the mother of the patient, who sometimes sees herself in the nourishing role, which can add to the psychological impact of the condition. Patients and their parents also have to quickly develop a response in possible dangerous situations, since allergy also touches schools, kindergartens, workplaces and all social setting of the patient. ETHICAL ISSUES:
# •
The burden of food allergies affects not only those who live with food allergies but also their surroundings as well as a sizable proportion of the society and is currently not alleviated by the healthcare system, although it falls under its mandate.
# C5-Ability to reach the entire target population (access)
•
The number of allergists in Canada is small; and the percentage of allergists who practise OIT in Canada is unknown, but this service is currently limited and mostly available in large cities.
# 113
# CONSULTATIONS
Patients: Lack of availability of OIT is a problem, which can imply having to travel several hours to a clinic offering it. There are few allergists in rural areas, and fewer offering OIT. Adults wishing to receive OIT can have a difficult time even finding allergists for themselves. People living outside of large cities find it also challenging to stay well informed. Allergists: The Canadian healthcare system is currently unable to provide OIT according to demand, which outweighs the available providers; some of those providing OIT feel that they are not always fairly compensated. We are not yet ready to make OIT a standard treatment, since there are not enough regulations or residency training programs. Other healthcare professionals: Currently, there are not enough allergists to treat all patients in Canada, so improving the number of professionals able to treat allergies would be the first priority. Educating family doctors and pediatricians to administer OIT in addition to allergists could improve access everywhere. ETHICAL ISSUES:
# •
The lack of allergists who provide OIT and the fact that the few who provide this service are mostly in large cities creates inequity of access at several levels.
# C6 -Extent of unmet needs
The currently dominant practice of food allergy management is avoidance of food allergens: ). It is currently unclear whether consumption of baked food products can accelerate the development of tolerance to unbaked forms of the food (i.e., liquid milk, raw egg).
•
130
Two small RCTs comparing baked-milk and baked egg protocols to OIT found lower rates of desensitization (statistically significant in 1 RCT) with the baked food protocol and similar rates of adverse events. 56 131
# CONSULTATIONS
Patients: Current standard management of allergy is avoiding the allergen and epinephrine autoinjectors utilization, both of which require constant surveillance of the patient and a limited diet (avoiding desserts, having to eat at home, vague labeling like 'may contain'). Avoidance can make social activities difficult (dinner with friends, birthdays, travelling, restaurants). This method provides no hope of change, a limited sense of control for the patients and creates a weight on everyday life. Some allergists state awaiting guidelines before providing OIT. Allergists: Avoidance is difficult to maintain (i.e. in restaurants), partly because of the vague food labeling 'may contain'. It doesn't help reduce anxiety, and doesn't always achieve anything long term, although a number of children outgrow milk and egg allergies on avoidance. Desensitization can lead to patients growing out of their allergy. The SLIT and EPIT treatments have higher costs and less efficacy (doses too low for meaningful response) than OIT. These treatments can subject the patient to higher anaphylaxis risks and have fewer potential long-term effects.
Other healthcare professionals: The anxiety associated with allergies makes avoidance the first response for many patients, because they feel that this is the only way to proceed. It isn't however a solution, since it doesn't bring any changes and largely limits opportunities for patients and caregivers, depending on how common the allergen is. Avoidance also requires relying on other people and depending on their knowledge of allergy and its seriousness. For patients who are allergic to an uncommon food (shellfish), OIT might not be worth the trouble in their opinion, versus one with an allergy very difficult to avoid, who can see it as a hope for needed change (milk, wheat).
# Avoiding doesn't however impose as heavy a schedule as OIT (2 hours after administering the dose). ETHICAL ISSUES:
• In institutions such as school, food prohibition "may actually increase safety risks posed to students dealing with allergies because of the false sense of security such bans create"; in addition, such institution should be exempted from heavy accommodations related to food allergies. Avoiding total bans is in most cases in the best long-term interests of all parties, including allergic students.
# 132
• Since currently, there is no treatment for food allergy, emphasis is placed upon behavioral change, which, in a way, aims at empowering the patient, but very often, people are feeling "alone" without sufficient support from the healthcare system and "the treatment seems to rely entirely in [their] responsibility".
# 77
C7-Social priorities Management of food allergy in general is not an established social priority in Canada, nor is OIT.
# CONSULTATIONS
Patients: Not applicable Allergists: The Canadian healthcare system is currently unable to provide OIT accordingly, since the demand outweighs the available practitioners, and some of those who provide OIT feel they are not always fairly compensated. We are not yet ready to make OIT a standard treatment, since there are not enough regulations or training programs. Other healthcare professionals: It would be helpful to identify which patients would benefit the most from OIT. ETHICAL ISSUES:
# •
The lack of interest in food allergy by the healthcare system generates a situation where there is a lack of skills for OIT, which further contributes to deepen inequities.
# CLINICAL DIMENSION AND PROMOTION OF HEALTH AND WELL-BEING (OUTCOMES OF THE INTERVENTION) CLINICAL PERSPECTIVE
# C8-Clinical efficacy A. EFFICACY OF OIT IN CLINICAL TRIALS AND CLINICAL PRACTICE
# C4. MAINTENANCE FREQUENCY •
In one clinical study, there was no difference in maintaining desensitization between eating the maintenance dose daily or every other day (tolerating 1 raw egg white after 6 months of maintenance: 93% vs 83%) (RCT: 55 N=29 daily, 24 every other day)
# C5. MULTI-FOOD OIT •
In one clinical study, 68 there was no difference in desensitization (reaching 10-fold increase in reaction threshold) between patients undergoing OIT for peanuts plus up three other foods at the same time and patients allergic to peanuts only (88% vs 80%) but patients on multi-food OIT required more time to reach that outcome (14 weeks • Combination with standard OIT: One study found no significant difference in desensitization at 28 months (10-g milk: 89% omalizumab vs 71% placebo, P=0.18)
and no significant difference in sustained unresponsiveness at 32 months (89% omalizumab vs 71% placebo, P=0.42), but there were fewer doses required to achieve maintenance with omalizumab (198 vs 225, P =0.008).
# 133
(N=57, omalizumab discontinued at 28 months)
• Combination with accelerated OIT: Two studies observed a higher rate of desensitization with omalizumab than with placebo at 14-28 weeks (8 peanuts: 79% vs 12%, P<0.01,16 peanuts: 76% vs 12%, P=0.002; 2 g protein of ≥2 foods: 83% vs 33%, P=0.
(N=37 to 48, omalizumab discontinued at 7-8 weeks into OIT)
# CONSULTATIONS
Patients: The possibility, if desensitization is achieved, of a life without allergy, offsets the disadvantages that can be associated with OIT. Age might not need to be considered a factor, since, even though the success rate is seen as higher for children, the treatment also works for adults, provided they are willing to put in time and resources. However, the sooner the better in a patient's life to start the treatment, since they are more trusting and compliant when young. Some allergists include baseline severity as an exclusion factor, since they consider the treatment could be associated with too many complications. Allergists: OIT's effectiveness is mainly good, especially in preschoolers, it can be less effective in older children. Most patients do however reach and tolerate maintenance dose or achieve desensitization, which often leads to improved quality of life for them and their caregivers. Age needs to be taken into account, as OIT is more effective in younger patients, 5 and under, (most efficient at 2-3 years old. Baseline severity of previous reactions doesn't have much of an impact, however some allergens make the protocols slower (sesame, cashew, walnut, wheat). Milk can be more difficult to treat than nuts.
Other healthcare professionals: OIT works, depending on the objective (desensitization is more attainable than a complete cure) but like any other treatments, some factors (genetic or otherwise) can create constraints.
If a patient's baseline allergy tests are very high, it is less likely for them to achieve desensitization. The treatment is also most efficient with young children. ETHICAL ISSUES: Although desensitization or tolerance achieved with OIT could be lost if regular consumption of the allergen is ceas ed, OIT can alleviate the burden of food allergy, even if regular consumption of the food allergen is necessary to maintain protection from anaphylactic reactions.
# 79
# C9-Clinical adverse effects A. CLINICAL ADVERSE EVENTS OF OIT IN CLINICAL TRIALS AND CLINICAL PRACTICE A1. ANY ALLERGIC REACTIONS / LOCAL ADVERSE REACTIONS
# A3. SEVERE REACTIONS AND EPINEPHRINE USE
• Serious adverse event (SAE): an event that causes death, a life-threatening state, hospitalization, disability, congenital abnormality, or an important medical event such as an urgent intervention to prevent the other outcomes • Anaphylaxis: an allergic reaction that involves two or more organ systems, or isolated hypotension with known allergen exposure
• Epinephrine-treated reaction (ETR): an allergic reaction that is treated with (intramuscular) epinephrine injection
• Grade 4 reaction: WAO classification:
135
Respiratory failure and/or hypotension (and/or profound lethargy -modified)
Sampson classification:
136 diarrhea and/or hoarseness, "barky" cough, difficulty swallowing, dyspnea, wheezing, cyanosis and/or dysrhythmia and/or mild hypotension and/or "Light headedness," feeling of "pending doom" • One meta-analysis estimated an approximately doubled risk of serious adverse events with peanut OIT (6.2% vs 3.0% control).
# 24
Quality assessment based on original source publications indicated misclassification of adverse events in some cases, suggesting that the rate of serious adverse events may be similar between OIT and control groups. Additional studies report as well that the occurrence or severity of allergic reactions declines as the treatment progresses (not in figure).
30 39 49 60 61 One long-term study reported that 14% of patients treated with milk OIT experienced anaphylaxis at least once after the build-up phase over 1 to 11 years of follow-up (median 6.5 years) (case series: N=237; moderate risk of bias).
33
Experiencing epinephrine-treated reactions in the clinic versus at home:
• 17 to 20% of patients receiving walnut or sesame OIT experienced an epinephrine-treated reaction in the clinic during the build-up phase and 8.3 to 15% at home (also shown in figure above); 36 38 for milk OIT, the respective values were 48% and 17% (the latter associated with 0.08% of doses).
32
Another milk OIT study reported that 66% of anaphylactic allergic reactions occurred at home vs 34% in the hospital.
39
Similarly, in peanut OIT clinical practice, overall, 63% (build-up only) to 71% of epinephrine-treated reactions occurred at home. 29 40 During peanut OIT in pre-school children, 0.26% of doses were associated with an epinephrine-treated reaction in the clinic and ; some have started enrolment from age 29 61 or one. 46
# 62
• There was no association between baseline age and safety outcomes in four large reports of OIT practice with children and adolescents (age≥4 years) while avoidance reactions mostly generate anxiety and additional diet restrictions. Clarity about the risks associated with each option is thus necessary, and individualized protocols and clear communication on the meaning of allergic reactions during OIT would be beneficial to patients.
# C10 -Type of clinical benefit offered by the intervention
The potential clinical benefits of OIT are:
• Reducing the risk of allergic reactions due to accidental exposure: An increase in the eliciting dose from ≤ 100 mg to 300 mg peanut protein (approx. 1 peanut) may lead to > 95% reduction in the risk of an allergic reaction related to residual peanut protein in packaged foods. Other healthcare professionals: OIT can provide a sense of control to the patients, being able to control the setting of the reactions is empowering. It can reduce the patients and caregivers' anxiety to be in a controlled environment, and significantly improves their quality of life. For some allergies that are harder to avoid (milk, wheat, eggs), the possibility of including them in the diet is much bigger a benefit than something that is not as present in many foods.
# USER PERSPECTIVE
# C11-Acceptability and capacity to empower users and caregivers PATIENTS' GOALS AND EXPECTATIONS
• may include developing a buffer against reactions due to accidental exposure, 155 translating to increased sense of freedom in daily life, 156 ability to freely eat the food allergen, 155 157 to consume a limited amount of the food allergen with caution, 155 or to reduce the risk of a fatal food reaction. 157 Page • OIT requires patients (and/or their caregivers) to regularly attend visits, to adhere to the treatment at home (including administering the doses and complying with instructions for reduced activity 2 hours after the dose), and to be able to recognize and treat adverse events. Logistics of food allergen dose administration First OIT dose typically administered by allergist; dedicated nurse monitors the patient and may administer later doses (up-dosing) Observation requires 1 to 2 hours of use of an examination room or food challenge area Personnel should be able to provide at least 12 hours of observation in case of adverse reactions related to OIT. Prolonged monitoring units (up to 24 hours) in the medical center in the event of severe anaphylaxis (or in pediatric department in the case of children)
# CONSULTATIONS
Patients: Constantly available support for the patients would be appropriate, in the case of more than anticipated severe reactions. Different healthcare professionals could help on different aspects of the treatment. Telephone support 24h would be reassuring, more so than a chat system, since talking to someone makes it more trustworthy. The current HCS organization isn't equipped for OIT, since some allergists, and many family doctors, aren't familiar with OIT, or willing to administer it. Allergists: To administer OIT, it is necessary to have allergist training and experience in order to be able to treat anaphylaxis, or any other reaction. It is also needed to master oral challenges and be able to understand and educate the patients and their caregivers. Some patients feel that it would be important for the provider to be willing to be available at all times.
The allergist should see the patient at the initial consultation (and then yearly), even if via a videoconference, and develop the initial treatment plan. This plan can be delivered by a local family physician under continuing guidance of the allergist (e.g., through telephone calls) in certain cases.
To perform OIT, it is necessary to have a dedicated nursing staff to assist, adequate safety equipment, access to epinephrine, clinic space to monitor patients and for a waiting room, and resuscitation facilities. It should be done in a hospital context.
For increased OIT access, there needs to be increased access to allergists for easier diagnostics, more allergists need to be educated to perform OIT, billing codes should be revised to encourage the practice, and more hospital-based clinics should be created for OIT to be provided in.
Other healthcare professionals: For the treatment administration, education should be made available to family doctors and pediatricians in addition to allergists would be best, in order to make sure the method used is the best one (understanding of challenges, understanding of the patient's issues, understanding of different types of reactions and how to manage them). There should at least be the possibility of access to registered dieticians in order to help the patients and caregivers develop an appropriate diet that is kept varied. There should also be offered psychological support, especially in the form of group discussion, which would minimize costs, and allow the patients to benefit from peer support which would help solve issues more than one patient encounter, or help children discuss thing with people other than their parents. Some issues might come out more effectively this way, amongst people sharing their experiences, which would help add ress them in the best way. For the more complex cases, individual support by a psychologist would also be ideal. Pharmacists could be involved in the process as advisors, in order to answer questions for the patients, or to compound and measure doses. • Acquisition cost of allergen food product acquisition for OIT: estimates between less than $10 to $50 per patient (data on file from two Canadian OIT clinics).
• Cost of producing peanut doses by skilled staff in healthcare system (25 mg or 125 mg peanut protein): ); lifetime treatment (i.e., for 10 years = US$36,000 to US$48,000)
# COST OF OMALIZUMAB AS AN ADJUNCT THERAPY
Omalizumab is sometimes used to increase the threshold of adverse reactions while providing OIT, in a temporary manner (usually between 2 to 6 months), with the objective of allowing a safe and rapid progression of food dosages that will provide protection once omalizumab is weaned
# HEALTHCARE RESOURCES COST FOR AVOIDANCE
There are significant hidden costs related to food allergen avoidance, such as emergency department visits, physician visits and pharmacotherapy. 124
# 168
# OIT VS AVOIDANCE
In theory, reducing outpatient and emergency department visits and the need for rescue therapy with epinephrine, could lead to lower direct medical cost for patients with food allergy (Cannon, 2018); However, data from RCT do not support the idea that patients would have less reactions overall and consume less care, but rather to be cost-neutral.
# CONSULTATIONS
Patients: In the short term, implementing OIT at a great scale would imply an important budget in the therapeutic field of allergy.
On the long term, there could be possible reductions in doctor visits, in reactions, in possible ambulance emergencies, in ER visits, in other medical expenses related to the effects of allergies (psychological, nutrition) or in EpiPen use, which might reduce costs compared to now. Preventive costs are essential. If reactions were too frequent with OIT, it could be too costly Allergist: OIT is considered a moderate to high cost treatment, since it requires some resources (staff, infrastructure to have sufficient space) in order to ensure the patients' safety. OIT will be cost-adding in the first years of treatment (also because of an increased frequency of reactions) and if sustained unresponsiveness cannot be achieved. In this case, the benefit lies in the improvement of QoL. In the long term, cost savings may come from a reduced need for psychiatrists, psychologists or registered dieticians associated with avoidance.
Other healthcare professionals: The burden of cost is currently mainly on the patients, so they would be the ones feeling changes the most. Patients would still need to carry an epinephrine autoinjector, so there wouldn't be changes that way, but if a large part of the allergic population used OIT, there would be an impact on the number of ER visits. ETHICAL ISSUES: Not applicable
# C17-Costs for the user / caregiver COST OF OIT TO PATIENTS & FAMILIES
• May include costs associated with regular appointments (transportation, parking, taking time off from work and school), cost of buying the food allergen (may be significant for shellfish), and co-payments for any prescribed adjuvants (such as omalizumab), if these are used, and for medications to treat adverse reactions (e.g., autoinjectable epinephrine, antihistamines). Bégin
# CONSULTATIONS
Patients: For the patients and their caregivers, going to see their allergists regularly for a limited period (the time of the treatment) will be less costly on the long term than their current situations, in which 'fear makes us spend'. Visits could end up being globally less numerous if young children are desensitized. Shared costs between the HCS and the patients would be acceptable. Private clinics options do create higher costs, and allergen-safe foods can be expensive.
# Allergists: Not applicable
Other healthcare professionals: Time off work transportation and parking would be the possible costs involved. Finding food containing allergens would be easier than avoiding them, and would reduce parents' time spent preparing the food for the children. ETHICAL ISSUES: The cost associated with avoidance, which are borne by the patients, can be a financial burden for low income families, contributing to inequity in food allergy management. OIT, being the financial responsibility of the healthcare system, would allow reducing inequities.
# C18 -Societal costs
OIT: No data AVOIDANCE
# •
The burden of managing avoidance (or lack of) in schools and daycares is hard to quantify but is very well described in qualitative studies.
# CONSULTATIONS
Patients: Investing in the display of allergies is important, and is perceived to be driven by fear and anxiety, while investment in the OIT is seen as bringing hope for change.
# Acknowledgements
We would like to acknowledge the other members of the deliberative committee. The
# CONSULTATIONS
Patients: Allergies affect lots of people, children being the first concerned, which makes the first objective taking preventive measures. OIT can be seen as an investment in the future, seeking to improve quality of life for all concerned, which could lead to reductions in expenses associated with reactions, and could help society at large since reduced anxiety could allow the patients to become more productive. The insufficient actual investment in allergy treatments could be considered unfair compared to other conditions which impact day to day life and nutrition (i.e. diabetes). Allergists: It might be too costly to offer it on a global scale, but it could be manageable with an age cut-off. However, this would need to be balanced with the needs of older patients with severe persistent disease. It may require a reorganization of the allergists' clinical office with a delegation of less specialized but lucrative interventions to other health professionals. Some say the government could afford providing the resources for administrating OIT.
# Conclusion
These guidelines bring to the forefront the critical importance and value of placing patients at the center of the development of clinical practice guidelines.
Here, this approach was instrumental to developing recommendations for the responsible implementation of OIT in clinical practice, adapted to individual patient needs. The multicriteria approach offers an alternative to technocentric approaches in CPG development by balancing human, ethical and technical considerations in decision making (Fig. 4). Technocentric approaches tend to create a pressure to standardize patient care in order to generate quantitative data, which may not always be in patients' best interest. Rather than adapting patient care to meet methodological needs for quantitative data, the methodology should be adapted to patients' needs for best care. As the saying goes, 'Not everything that counts can be counted, and not everything that can be counted counts [75]. '
# Supplementary information
Supplementary information accompanies this paper at https ://doi. org/10.1186/s1322 3-020-0413-7.
Additional file 1. Supplementary appendices. Leek are members of the OIT CPG working group, in alphabetical order except for the executive team. MSC adapted the EVIDEM framework to transform it into a patient-centered ethical framework. MMG reorganized the criteria of the EVIDEM framework into five dimensions and adapted the framework to a qualitative MCDA approach (no weighting and no scoring) to deepen the reflective aspects of the framework. HK, ESC, PB, MW, MMG were responsible for executive decisions throughout the development of the clinical practice guidelines. MW performed the review of the literature to which all authors contributed, except for the ethical aspects, which was performed by CFG. MSC, MW, MMG and PB performed consultations and chaired consultations panels. MSC organized and analyzed the consultations. MMG performed the data integration. All authors had full access to all of the data collected through the literature review and consultations. MSC, MW, MMG and PB take responsibility for the accuracy of the data synthesis. All authors contributed to the analysis and interpretation of data. MSC, MW, MMG and PB drafted the deliberation guide. MSC, MW and MMG chaired the deliberation committee. All authors drafted the recommendations during the deliberation. MSC, MMG, MW, and PB drafted the manuscript. All authors read and approved the final manuscript.
# Funding
# CSACI.
# Availability of data and materials
Additional data is included in the supplemental repository. Clinical tools for implementation in practice will be made available at http://www.csaci .ca/OIT.
# Ethics approval and consent to participate
The study was performed according to the current practices at INESSS for clinical practice guidelines; patients consulted on their perspectives of the different dimensions of OIT completed an informed consent.
# Consent for publication
Not applicable.
# Competing interests
Direct competing interests related to the topic of the guidelines P. Bégin and J. Upton are non-remunerated investigators on an investigator-instigated trial sponsored by the Canadian Institutes of Health on the use of omalizumab in oral immunotherapy (in-kind contribution of investigative drug product by Novartis worth > $100,000 CAD). They were excluded from the room for the discussion and deliberations on recommendations related to the use of omalizumab in oral immunotherapy. M. Ben-Shoshan was a principal investigator on a trial on the use of pharmaceutical peanut flour preparations in OIT sponsored by Aimmune Therapeutics (> $100,000 CAD in grant support). J. Upton was a non-remunerated sub-investigator on clinical trial sponsored by Aimmune Therapeutics on the use of pharmaceutical peanut flour preparations in OIT. They were excluded from the room for the discussion and deliberations on recommendations related to the use of pharmaceutical food products in OIT. Direct competing interests unrelated to the topic of the guidelines P. Begin A. Haynes is a pediatric allergist currently not offering OIT in clinic. S. Kapur is a pediatric allergist currently offering OIT in clinic. He has previously contributed to a national cohort study published on the topic. G. Parizeault is a pediatrician with a practice focus on allergy in a region without allergist. He is currently offering OIT in clinic. S. Pernice, is a registered dietician practicing in an academic allergy clinic offering OIT. M.N. Primeau is a pediatric allergist currently not offering OIT in clinic. J. Upton is an adult-trained allergists currently not offering OIT outside research. She is a clinician with a research program including clinical trials OIT. She is on the national advisory board of Food Allergy Canada. She has given public and scientific lectures on the topic of OIT. C. Vaillancourt is a family physician with a practice focus on allergy in a region without allergist. He is currently offering OIT in clinic. T. K. Vander Leek is a pediatric allergists currently offering OIT in clinic. He has previously contributed to a national cohort study published on the topic. Other authors and members of the deliberative committee declared no indirect conflicts of interest.
# Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | None | None |
1e6d94dd5745d9d39d1ebc5d1c81e74b667dbe00 | cma | None | The objective of this guideline is to update the existing Canadian recommendations for the medical management of neurologically deceased ("braindead") adult and pediatric potential donors for the purposes of single or multiorgan recovery for transplantation and Ms. Vanya Lang, the donor family member and patient partner, whose experiential perspectives kept this initiative focused on the overarching purpose: providing highquality endoflife care for deceased organ donors and improving outcomes for transplant recip ients. The authors acknowledge the information services support they received to design and execute the search strategies for the sys tematic reviews used to inform this guideline:# D
emand for organs continues to exceed their availability, both in Canada and around the world. 1 Optimizing the medical management of potential organ donors is an important strategy for enhancing organ supply. The explicit goals for management of deceased organ donors in the intensive care unit (ICU) are to stabilize the potential donor and to optimize the number and quality of organs for transplantation.
In 2006, the Canadian Council for Donation and Transplanta tion produced the first Canadian recommendations for organ donor management, 2 the result of a 2004 forum -Medical Man agement to Optimize Donor Organ Potential -in collaboration with the Canadian Critical Care Society, the Canadian Associa tion of Transplantation and the Canadian Society of Transplanta tion. This forum was the first structured, cooperative assembly of health care professionals in the fields of critical care medicine and transplantation and was a landmark event in Canadian organ donation practice. 2 The 2006 guideline had an influence on organ donation recommendations internationally; however, it had not been updated to incorporate emerging evidence in organ donor management and critical care medicine and the many advances in guideline development methodology. 7 The objective of this guideline is to update the existing Can ad ian recommendations for the medical management of neuro logically deceased ("braindead") adult and pediatric potential donors for the purposes of single or multiorgan recovery for transplantation. (The full guideline is available in Appendix 1, at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.190631//DC1.)
# Scope
The scope of this guideline is the management of the potential organ donor, beginning at the time of the neurologic determination of death and ending at the time of transfer to the surgical recovery team. This includes all aspects of medical care in the ICU for adult and pediatric organ donors: monitoring, investigations, somatic sup port, preventive care, drug administration and technical procedures.
Aspects of deceased donation that are not in the scope of this guideline include ICU interventions that precede death by neuro logic criteria, the neurologic determination of death, donation after a circulatory determination of death, donation after med ical assistance in dying, organ allocation procedures, anesthetic and surgical procedures related to organ recovery or transplan tation, and management of the organ recipient.
The clinical practice and ethics of starting donor manage ment interventions before neurologic determination of death are not addressed by this guideline.
The target users of this guideline include organ donation organizations, policymakers, administrators and clinicians who manage neurologically deceased organ donors.
# GUIDELINE CPD
# Management of the neurologically deceased organ donor: A Canadian clinical practice guideline
- We suggest against routine administration of thyroid hormone in neurologically deceased potential donors.
- We suggest against routine coronary angiography in neurologically deceased potential donors being assessed for heart donation.
- We suggest maintaining the body temperature of neurologically deceased potential donors in the range of 34°C to 35°C, unless kidneys will not be used for transplantation.
- We recommend a lungprotective ventilation strategy consisting of low tidal volumes (6-8 mL/kg), high positive endexpiratory pressure (at least 8 cm H 2 0) and recruitment manoeuvres performed after ventilator disconnections in neurologically deceased potential lung donors.
# Recommendations
This clinical practice guideline is intended for use in the care of both neurologically deceased adult and pediatric potential organ donors. We based our recommendations on organ donor man agement literature from both age groups, although we discov ered very little pediatricspecific literature. All recommendations apply to pediatric and adult donors, except for the minimal acceptable blood pressure, which should be age adjusted in pediatric patients.
We make 1 strong recommendation, 30 conditional recom mendations, 1 "good practice" statement and 4 "no recommen dations." Readers will note that the preponderance of donor management literature is limited to lower levels of evidence. The authors acknowledge recent studies (published after this guide line was submitted) in this area, but these do not change the direction and certainty of the recommendations. More informa tion on the evidence supporting each recommendation is avail able in the full guideline document (Appendix 1).
This synopsis provides information on 4 recommendations that the steering committee deemed likely to have the most impact on clinical practice. A complete summary of all recom mendations is available in Table 1.
# Thyroid hormone administration
We suggest against routine thyroid hormone supplementation (conditional recommendation, low-certainty evidence).
We make no recommendation about thyroid hormone supplementation for patients with hemodynamic instability or cardiac dysfunction.
Endogenous catecholamine release is increased during both acute critical illness and neurologic death. Although this causes an increase in systemic vascular resistance, cardiac output is compromised by neurologic death-induced myocardial suppres sion and a decrease in thyroid hormone release owing to pitu itary failure. This state has the potential to compromise trans plantation of the heart itself and other organs as a result of impaired perfusion. There is therefore a theoretical advantage to exogenous thyroid hormone supplementation.
Four randomized controlled trials (RCTs) assessed the effect of thyroid hormone on donor hearts and showed no improvement in the number of hearts eligible for transplanta tion. These studies were included in a 2012 systematic review, 15 which concluded there was no benefit from any form of thyroid hormone for neurologically deceased potential donors. We excluded 3 other RCTs included in the 2012 systematic review from our analysis as they did not report on any of our outcomes of interest (e.g., reported only on biochemical markers). All of these RCTs included several cointerventions administered to both the intervention and control groups.
In addition to the RCTs, we identified 5 observational studies that reported conflicting results regarding the effect of treatment with thyroid hormone on the number of transplanted hearts. In the largest cohort study of 63 593 patients, 21 patients who received thy roid hormone had a 9.23% higher rate of heart recovery. Two addi tional cohort studies described a multivariate model that included thyroid hormone as a covariable associated with an increased chance of heart transplant eligibility. 22,23 Thus, for our primary out come of interest -number of hearts transplanted -the evidence suggests that thyroid hormone is of little benefit, although some larger cohort data suggest increased cardiac recovery.
The guideline panel did consider other outcomes, including cardiac function prerecovery, total number of organs recovered, graft survival and patient survival. Only cardiac function pre recovery was assessed in RCTs and no significant improvement was observed. Cohort data, primarily from the large United Network for Organ Sharing report, 21 suggest that thyroid hor mone replacement is associated with increased cardiac graft and patient survival at 1 and 12 months, and increased number of organs recovered. Although these findings were statistically sig nificant, their interpretation is complicated by the fact that most patients received thyroid replacement as part of a hormone ther apy bundle and the effect of thyroid alone is difficult to assess.
Given the absence of established benefit in RCTs comparing thyroid hormone to no thyroid hormone, and the conflicting observational evidence, we suggest against the routine use of thyroid hormone in all potential donors.
We acknowledge that it is accepted practice in many centres to administer thyroid hormone to patients with cardiac dysfunc tion and that a recommendation against doing so in this sub group would have added acceptability and feasibility issues. We also acknowledge that there is no published evidence of physio logic harm associated with the administration of thyroid hor mone in this context. Given the absence of comparative evidence (RCTs or observational) in this higherrisk population and the potentially substantial acceptability issues, the committee felt the benefits and harms were very closely balanced. As such, we make no recommendation in the subgroup of patients with hemodynamic instability or cardiac dysfunction.
# Coronary angiography
We suggest against routine coronary angiography (conditional recommendation, very low-certainty evidence).
# Coronary angiography should be performed in the presence of risk factors for coronary artery disease as determined according to local criteria (good practice statement).
The evidence addressing the benefits of coronary angiography in potential heart donors is of very low quality. There is only 1 study that directly addresses this question. In this retrospective cohort study, Hauptman and colleagues 24 compared the rates of early graft failure in recipients who received a heart from a donor who underwent coronary angiography versus those who received hearts from donors who did not undergo coronary angiogram. Recipients who received a heart from donors who had an angio gram were less likely to have early graft failure. 24 No adverse effects were reported. This was a retrospective, nonrandomized study with low internal validity. - We suggest intravenous vasopressin as a firstline vasoactive agent for hypotension (conditional recommendation, very lowcertainty evidence).
- We suggest intravenous norepinephrine as a secondline agent for hypotension not responding to vasopressin alone (conditional recommendation, very lowcertainty evidence).
- We suggest against the use of dopamine at any dose (conditional recommendation, lowcertainty evidence).
- We make no recommendation regarding other vasoactive medications and inotropes.
# Antihypertensive medications
- We suggest using shortacting intravenous antihypertensive agents as per standard ICU practice to prevent endorgan damage (conditional recommendation, very lowcertainty evidence).
# Minimal acceptable blood pressure target
- We suggest maintaining mean arterial pressure ≥ 65 mm Hg rather than a lower threshold (conditional recommendation, very lowcertainty evidence).
# Fluid resuscitation
- We suggest infusing crystalloids, rather than colloids, for plasmavolume expansion (conditional recommendation, lowcertainty evidence).
# Protocolized fluid management
- We make no recommendation regarding the use of fluid management protocols.
# Glycemic control and nutrition
# Glucose control
- We suggest maintaining serum glucose levels in the range of 6-10 mmol/L, rather than a lower range of 4-6 mmol/L (conditional recommendation, very lowcertainty evidence).
# Glucose, insulin and potassium administration
- We suggest against the infusion of combined solutions of glucose, insulin and potassium (conditional recommendation, very lowcertainty evidence).
# Nutritional support
- We suggest providing enteral nutrition as compared with no nutritional support (conditional recommendation, very lowcertainty evidence).
# Diabetes insipidus and hypernatremia
# Serum sodium control
- We suggest maintaining serum sodium concentration in the normal range (135-155 mmol/L) (conditional recommendation, very lowcertainty evidence).
# Diabetes insipidus and vasopressin
- We suggest treating diabetes insipidus with desmopressin or vasopressin during hemodynamic stability (conditional recommendation, very lowcertainty evidence).
- We suggest treating diabetes insipidus with vasopressin during hemodynamic instability (conditional recommendation, very lowcertainty evidence).
# Hormonal therapy
# Thyroid hormone
- We suggest against routine thyroid hormone supplementation (conditional recommendation, lowcertainty evidence).
- We make no recommendation about thyroid hormone supplementation for hemodynamic instability or cardiac dysfunction.
# Corticosteroids
- We suggest intravenous corticosteroid therapy for donors requiring vasopressor support (conditional recommendation, lowcertainty evidence).
- We make no recommendation about highdose corticosteroid therapy for potential lung donors.
# Transfusion therapy
# Transfusion threshold
- We suggest withholding red blood cell transfusions unless hemoglobin levels fall below 70 g/L (conditional recommendation, very low certainty in evidence).
# Correction of coagulopathy and thrombocytopenia
- We suggest that in the absence of clinically significant bleeding, transfusions of fresh frozen plasma be withheld altogether, and that platelet transfusions be withheld unless platelet levels fall below 10 × 10 9 /L (conditional recommendation, very low certainty in evidence).
We also considered the logistics of coronary angiography. Coronary angiography requires patient transport outside of the ICU, exposes the donor organs to potentially harmful intra arterial contrast, is not available in all centres where patients who are potential donors are admitted, and is relatively costly and resource intensive.
Considering the limited evidence of benefit and the risks described above, we suggest against using routine coronary
# Bacterial infections
# Antibiotics
- We suggest reserving antibiotic therapy for the treatment of known or suspected infection (conditional recommendation, very lowcertainty evidence).
# Routine cultures
- We suggest that screening cultures of blood, urine and sputum be performed at intervals consistent with general ICU practice and patient clinical status (conditional recommendation, very lowcertainty evidence).
# Organ-specific considerations: heart, lungs and intra-abdominal organs
# Cardiac assessment tools
- We suggest against routine use of pulmonary artery catheters (conditional recommendation, very lowcertainty evidence).
- We suggest serial echocardiography at intervals consistent with general ICU practice (conditional recommendation, very lowcertainty evidence).
# Cardiac biomarkers
- We suggest against the measurement of serum cardiac biomarkers (conditional recommendation, very lowcertainty evidence).
# Coronary angiography
- We suggest against routine coronary angiography (conditional recommendation, very lowcertainty evidence).
- Coronary angiography should be performed in the presence of risk factors for coronary artery disease as determined according to local criteria (good practice statement).
# Lung-protective ventilation
- We recommend a lungprotective ventilation strategy consisting of low tidal volumes (6-8 mL/kg), high positive endexpiratory pressure (at least 8 cm H 2 0) and recruitment manoeuvres after ventilator disconnections in potential lung donors (strong recommendation, moderate certainty evidence).
# Bronchoscopy
- We suggest diagnostic bronchoscopy be performed for potential lung donors (conditional recommendation, lowcertainty evidence).
# Inhaled β-agonist therapy
- We suggest against routine use of inhaled βagonists (conditional recommendation, moderatecertainty evidence).
# Chest radiography and computed tomography scan
- We suggest a single routine diagnostic chest radiograph for lung donors and additional chest imaging as clinically indicated (conditional recommendation, lowcertainty evidence).
# Albumin: creatinine ratio screening
- We suggest using the albumin:creatinine ratio for detecting microalbuminuria when assessing potential kidney donors with type 1 or 2 diabetes mellitus (conditional recommendation, very low certainty in evidence).
# Hemoglobin HbA 1c testing
- We suggest that hemoglobin HbA 1c testing be performed in potential donors being considered for pancreas donation (conditional recommendation, very lowcertainty evidence).
# Abdominal imaging
- We suggest that abdominal CT or ultrasound should be used only in those with age > 50 yr, comorbid conditions, high body mass index, or clinical history of malignancy (conditional recommendation, lowcertainty evidence).
# Other therapeutic interventions
# Therapeutic hypothermia
- We suggest maintaining the core body temperature in the range of 34°C-35°C, unless kidneys will not be used for transplantation, in which case normothermia is appropriate (conditional recommendation, lowcertainty evidence).
# Duration of donor management
- For potential donors with acute organ injury, we make no recommendation regarding timing of organ recovery surgery or optimal duration of ICU donor management (conditional recommendation, very lowcertainty evidence).
Note: CT = computed tomography, HbA1c = glycosylated hemoglobin, ICU = intensive care unit.
angiography. As a good practice statement, however, we suggest that coronary angiography be considered in donors with risk fac tors for coronary artery disease because despite the lack of sup porting evidence for angiography in this clinical situation, it is expected that the benefit of avoiding transplant of a heart with coronary artery disease will outweigh the risk related to logistics and intraarterial contrast.
# Lung-protective ventilation
We recommend a lung-protective ventilation strategy consisting of low tidal volumes (6-8 mL/kg), high positive end-expiratory pressure (PEEP) (at least 8 cm H 2 0) and recruitment manoeuvres after ventilator disconnections in potential lung donors (strong recommendation, moderate-certainty evidence).
Ventilation with low tidal volumes is the standard of care for many ICU patient populations and is supported by experimental evidence and physiologic rationale. Some of the highestquality evidence in organ donor management is in the area of donor ventilation.
We defined a lungprotective ventilatory strategy as low tidal volumes, high PEEP and recruitment manoeuvres. We were unable to identify literature that evaluated any of these 3 com pon ents in isolation. One RCT and 3 observational studies exam ined mechanical ventilation with a lungprotective approach in neurologically deceased potential donors. The RCT com pared a lungprotective approach (tidal volumes of 6-8 mL/kg predicted body weight, PEEP 8-10 cm H 2 O, recruitment manoeu vres after disconnections from the ventilator (and an additional protocol for apnea testing) to conventional ventilation (tidal vol umes > 8 mL/kg predicted body weight, PEEP< 8 cm H 2 O, no pro tocolized recruitment manoeuvres and apnea tests off the venti lator). 25 The protective strategy was continued for a minimum of 6 hours, and potential donors assigned to this strategy were twice as likely to proceed to lung procurement. There was no sig nal of harm among the lung recipients; nor was there any signal of harm from the protective ventilation strategy with respect to the recovery of other organs.
Three observational studies with historical control groups evaluated the effect of a comprehensive lungdonor manage ment strategy. Two of these studies involved the ventilation protocol tested in the RCT. 26,27 The third study involved higher PEEP of 15 cm H 2 O, without the other components of lung protective ventilation. All 3 studies showed an improved lung procurement rate with implementation of their comprehensive lung donor management strategies, and 1 of the 3 studies showed increased recipient survival. 28 The committee considered potential drawbacks not explored in these studies. First, as was the case in all the studies, the criteria for lung donation eligibility frequently involves the ratio of arterial oxygen partial pressure to fractional inspired oxygen (Pao 2 :FiO 2 ratio) as a measure of lung function. However, PEEP is a therapeu tic intervention that may transiently improve the Pao 2 :FiO 2 ratio in some physiologic states. Thus, there is a risk that high PEEP ventilation allows relatively suboptimally functioning lungs to appear numerically viable for transplant at the time of eligibility assessment. In the RCT, lungprotective ventilation was not associ ated with an increase in criterioneligible lungs being declined based on gross inspection or other surgical opinion. 25 Second, increasing mean airway pressure via increased PEEP has the potential to decrease cardiac output. 32 It is possible that the decreased cardiac output outweighs any benefit on graft oxy gen delivery derived from improved arterial oxygenation. In the donation population, this may be best assessed through the viability of other organs in potential donors managed with lung protective ventilation, but this outcome was not reported in the included studies.
Given that the evidence for a benefit from lungprotective ventilation is greatest for lung donation, we considered narrow ing our recommendations to potential lung donors only. How ever, the candidacy of specific organs for donation is often not known in the early stages of donor care, and a delay in initiating lungprotective ventilation will reduce its benefit. We therefore recommend that lungprotective ventilation be started as soon as possible in all potential neurologically deceased donors. Intensivists and respiratory therapists are experienced with lung protective ventilation in the critically ill, and this approach does not incur any additional costs with respect to equipment or human resources. We therefore do not expect major barriers to implementing this recommendation routinely in neurologically deceased donors.
# Therapeutic hypothermia
We suggest maintaining the core body temperature in the range of 34-35°C, unless kidneys will not be used for transplantation, in which case normothermia is appropriate (conditional recommendation, low-certainty evidence).
In the single RCT in this area, 33 the induction of mild therapeutic hypothermia (34°C-35°C) in donors was shown to reduce the occur rence of delayed graft function in kidneys, a benefit that was even more substantial in the extended criteria donor population. There was no evidence of harm in the intervention group and the recovery of other organs was not affected in the hypothermia group. Graft outcome of other transplanted organs was not reported.
A retrospective analysis of mild spontaneous hypothermia (< 36°C) was performed from a data set designed to study dopa mine in the organ donor population. 34 Similarly to the RCT described above, the study showed a reduction in kidney delayed graft function in the hypothermia group. There was no difference in 5year graft survival. The same data set used to study cardiac donors identified a lower 3year graft survival in donors with spontaneous temperature less than 36.2°C. 35 Given the methodological limitations of studying spontaneous hypo thermia, causation versus association for outcomes was an issue; evidence was downgraded to low.
Targeted temperature management is now common practice in most critical care units. Although there are only 3 studies evalu ating this intervention in organ donors, the absence of any identified harm, combined with the fact that the most commonly recovered organ is the kidney, led our guideline committee to suggest mild hypothermia in all organ donors until kidneys have been ruled out for donation.
We acknowledge that there are minimal data on the effect of mild hypothermia on nonrenal organs and that the evidence for cardiac donors is weak. New evidence could change this recom mendation. The considerations for hypothermia are stronger when only kidneys are considered in an extended criteria donor. The 23member guideline panel selected by the steering com mittee included representation from critical care medicine (adult and pediatric), critical care nursing and pharmacy; an infectious disease specialist; organ donation specialist physicians; and peo ple with organspecific expertise in transplant cardiology, cardiac surgery, pulmonology, lung surgery, urology, nephrology and abdominal surgery. We included 2 patient partners, a family mem ber of a deceased multiorgan donor and a heart transplant recipi ent. Other panel members included representatives from specific knowledge user groups: the Canadian Critical Care Society, the Canadian Society of Transplantation, the Canadian Association of Critical Care Nurses and the Canadian Donation and Transplanta tion Research Program. By design, the guideline panel included geographic diversity from 4 provinces (Ontario, Quebec, Alberta and BC), representing the most active donation and transplant programs in Canada. The full participant list and description of the guideline methodology is available in Appendix 1.
# Methods
# Guideline panel composition
Canadian
# Guideline development
We reviewed the results of a systematic review of published organ donor management guidelines 36 before deciding on the scope of our effort. This review of 27 guidelines from 22 countries provided an overview of topics that had been covered by other groups and informed our list of 29 potential PICO (Patient, Inter vention, Comparator, Outcome) questions (Appendix 1).
The guideline panel was divided into 3 smaller working groups that selected outcomes of interest for each question. The overall group explicitly rated these outcomes for their relative importance from "not important" to "critical" according to GRADE guidance. 37 In cases of disagreement, decisions were made by group discussion and consensus. We developed a hier archy of outcomes to inform these discussions: clinical optimiza tion during the interval between death declaration and organ recovery; increased organ acceptance, recovery and transplanta tion; an increase in organ recovery; improved graft function; graft survival; and recipient survival and quality of life.
Within the 3 working groups, panel members were assigned PICO questions in pairs and collaborated with information technologists or medical librarians to design and conduct search strategies for each of the 29 PICO questions. Our population of interest was neurologically deceased organ donors. Primary searches were limited to human studies reported in English, either in full text or abstract. At minimum for each question, we searched MEDLINE (PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL). Primary searches were restricted to human studies reported in English, from 1981 to present, either in full text or abstract (see Appendix 1 for details of the search strategies, including individual end dates). Two panel members independently screened all relevant citations of each PICO question for eligibility. Disagreements were resolved through consensus and discussion. Searches were completed by September 2018. Steering committee members monitored the literature up until January 24, 2020, for recent publications that could affect the direction or certainty of any recommendations.
In situations where little to no direct research evidence was available in the organ donation or transplantation population, we extended our search to indirect evidence. In most cases, this referred to studies in the general ICU population, but in some cases, it included animal studies or trials in other patient populations.
In their assigned pairs, panel members abstracted study char acteristics and outcome data from all eligible studies for each PICO question. In addition to clinical data, we also assessed indi vidual study risk of bias using the Cochrane Risk of Bias tool 38 for RCTs and the Newcastle-Ottawa tool 39 for observational studies. When possible, we pooled outcome data for each PICO question and performed metaanalyses using the Cochrane Collaboration Review Manager 5.2. 40 Once this analysis was completed, we assessed the overall certainty (confidence) in the effect estimate for each outcome of interest following the GRADE approach 41 based on these criteria: risk of bias, precision, consistency, directness of the evidence, risk of publication bias, presence of a dose-effect relationship, magnitude of effect and an assessment of the effect of plausible residual confounding or bias. Consider ing all of these elements, the strength of evidence for each out come was categorized as high, moderate, low or very low. Steer ing committee members with GRADE expertise and experience (B.R. and L.H.) oversaw this process.
Pairs of panel members prepared evidence summaries for each question in collaboration with the methodologist (B.R.), fol lowing the GRADE approach 42 and using the GRADEpro Guideline Development Tool online software. 43 Based on these evidence summaries, the 3 working groups devel oped recommendations for each PICO question. We used the GRADE Evidence to Decision framework to facilitate discussion on each rec ommendation. 44 Recommendation development was based on the certainty of the evidence, the balance of desirable and undesirable consequences of compared management options, assumptions about the values and preferences associated with the decision, implications for resource use and health equity, the acceptability of an intervention to stakeholders, and feasibility of implementation. The guideline panel assessed each recommendation for pediatric specific considerations. The 3 working groups presented their rec ommendations to the entire guideline panel for further review and discussion. Disagreements were resolved by consensus.
In accordance with the GRADE approach, 45 we used the phrasing "we recommend" for strong recommendations and "we suggest" for conditional recommendations. Table 2 pro vides a guide to interpretation of these recommendations for intended stakeholders, including patients, clinicians and health policymakers.
The guideline panel endeavoured to provide recommenda tions for each original PICO question. In the exceptional circum stance where there was insufficient evidence for or against an intervention, or if there was a perceived balance between net benefits and net harms, then the panel made "no recommenda tion." "Good practice statements" were made when there was a high level of certainty about the effect of the therapy, but little direct supporting evidence. 47
# External review
Representatives of the supporting organizations, including the Canadian Critical Care Society, the Canadian Society of Trans plantation and the Canadian Association of Critical Care Nurses, performed external reviews. The lead author (I.B.) incorporated the feedback into the guideline and steering committee mem bers edited it. The entire guideline panel had an opportunity to review the final version of the guideline.
# Management of competing interests
All guideline panel members signed a confidentiality agreement at the inaugural meeting in 2017, where they were also asked to disclose any potential direct and indirect competing interests using a Canadian Blood Services competing interests documen tation form. These were collected again a year later and before publication. Canadian Blood Services personnel and the steering committee reviewed the declarations. Several panel members have professional roles in organ donation administration, with governmental notforprofit entities, or have funded scientific research; however, no steering committee or panel member was judged to have a relevant direct competing interest.
# Implementation
No specific dosing regimens were recommended for either pedi atric or adult patients, and groups planning to use these recom mendations to create bedside treatment protocols or standard ized order sets should consult with critical care pharmacists with experience treating the target population.
Members of our guideline panel have created "evidence bulle tins" (1page, laminated cards explaining key recommendations) for distribution to ICUs in partnership with interested provincial organ donation organizations, and leaders in ICU education (bit. ly/dmevidencebulletins). We have also developed adult and pediatric order sets for use by provincial organ donation organ izations and the hospitals that they service (Appendix 1), as well as a family brochure (bit.ly/dmfamilybrochure).
In some cases, a PICO question addressed whether or not to administer a particular medication in a particular circum stance. We made evidencebased recommendations about the appropriateness of the treatment but did not necessarily survey the literature for the best medication or dose from its class (e.g., corticosteroids). In these cases, the panel identified (but did not formally recommend) commonly prescribed medica tions and their usual doses, in order to help clinicians at the bedside.
Canadian Blood Services personnel regularly monitor the lit erature and an update is triggered when there have been any of the following: - New evidence on the existing benefits and harms of interventions; - Changes in outcomes considered important; - Changes in available interventions;
- Changes in evidence that current practice is optimal;
- Changes in values placed on outcomes; or - Changes in resources available for health care.
# Other guidelines
Members of this group performed a systematic review of pub lished organ donor management guidelines 36 to guide the scope of this guideline document. This review of 27 guidelines from 22 countries provided an overview of topics that had been covered by other groups and informed our initial list of potential PICO questions. In contrast to previous guidelines on organ donor management, this guideline was derived using GRADE methodology. For patients Most individuals in this situation would want the recommended course of action and only a small proportion would not.
The majority of individuals in this situation, if fully informed, would choose the suggested course of action, but some would not.
# For clinicians
Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.
The care needs of individual donors may vary as a result of comorbidities, and the practice of individual clinicians may vary in these circumstances, largely owing to the lack of evidence to address these situations.
# For policymakers
The recommendation can be adapted as policy in most situations
Policymaking will require substantial debate and involvement of various stakeholders.
Modified from Guyatt et al. 46
# Gaps in knowledge
An important limitation of these guidelines is that organ donor man agement research is predominantly observational in design. Many important clinical questions have not been addressed by RCTs. In addition, our guideline committee identified more PICO questions than we were able to process in this iteration. A list of items for gener ation of potential PICO questions and consideration for future guide lines is included in the full guidance document (Appendix 1).
# Conclusion
The multidisciplinary guideline panel reviewed the literature for 29 PICO questions and generated 1 strong recommendation, 33 con ditional recommendations, and 1 good practice statement as part of a comprehensive and evidencebased clinical practice guideline for organ donor management. It is our hope that this work can optimize use of the scarce resource that donated organs continue to be. | The objective of this guideline is to update the existing Canadian recommendations for the medical management of neurologically deceased ("braindead") adult and pediatric potential donors for the purposes of single or multiorgan recovery for transplantation and Ms. Vanya Lang, the donor family member and patient partner, whose experiential perspectives kept this initiative focused on the overarching purpose: providing highquality endoflife care for deceased organ donors and improving outcomes for transplant recip ients. The authors acknowledge the information services support they received to design and execute the search strategies for the sys tematic reviews used to inform this guideline:# D
emand for organs continues to exceed their availability, both in Canada and around the world. 1 Optimizing the medical management of potential organ donors is an important strategy for enhancing organ supply. The explicit goals for management of deceased organ donors in the intensive care unit (ICU) are to stabilize the potential donor and to optimize the number and quality of organs for transplantation.
In 2006, the Canadian Council for Donation and Transplanta tion produced the first Canadian recommendations for organ donor management, 2 the result of a 2004 forum -Medical Man agement to Optimize Donor Organ Potential -in collaboration with the Canadian Critical Care Society, the Canadian Associa tion of Transplantation and the Canadian Society of Transplanta tion. This forum was the first structured, cooperative assembly of health care professionals in the fields of critical care medicine and transplantation and was a landmark event in Canadian organ donation practice. 2 The 2006 guideline had an influence on organ donation recommendations internationally; [3][4][5][6] however, it had not been updated to incorporate emerging evidence in organ donor management and critical care medicine and the many advances in guideline development methodology. 7 The objective of this guideline is to update the existing Can ad ian recommendations for the medical management of neuro logically deceased ("braindead") adult and pediatric potential donors for the purposes of single or multiorgan recovery for transplantation. (The full guideline is available in Appendix 1, at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.190631//DC1.)
# Scope
The scope of this guideline is the management of the potential organ donor, beginning at the time of the neurologic determination of death and ending at the time of transfer to the surgical recovery team. This includes all aspects of medical care in the ICU for adult and pediatric organ donors: monitoring, investigations, somatic sup port, preventive care, drug administration and technical procedures.
Aspects of deceased donation that are not in the scope of this guideline include ICU interventions that precede death by neuro logic criteria, the neurologic determination of death, donation after a circulatory determination of death, donation after med ical assistance in dying, organ allocation procedures, anesthetic and surgical procedures related to organ recovery or transplan tation, and management of the organ recipient.
The clinical practice and ethics of starting donor manage ment interventions before neurologic determination of death are not addressed by this guideline.
The target users of this guideline include organ donation organizations, policymakers, administrators and clinicians who manage neurologically deceased organ donors.
# GUIDELINE CPD
# Management of the neurologically deceased organ donor: A Canadian clinical practice guideline
• We suggest against routine administration of thyroid hormone in neurologically deceased potential donors.
• We suggest against routine coronary angiography in neurologically deceased potential donors being assessed for heart donation.
• We suggest maintaining the body temperature of neurologically deceased potential donors in the range of 34°C to 35°C, unless kidneys will not be used for transplantation.
• We recommend a lungprotective ventilation strategy consisting of low tidal volumes (6-8 mL/kg), high positive endexpiratory pressure (at least 8 cm H 2 0) and recruitment manoeuvres performed after ventilator disconnections in neurologically deceased potential lung donors.
# Recommendations
This clinical practice guideline is intended for use in the care of both neurologically deceased adult and pediatric potential organ donors. We based our recommendations on organ donor man agement literature from both age groups, although we discov ered very little pediatricspecific literature. All recommendations apply to pediatric and adult donors, except for the minimal acceptable blood pressure, which should be age adjusted in pediatric patients.
We make 1 strong recommendation, 30 conditional recom mendations, 1 "good practice" statement and 4 "no recommen dations." Readers will note that the preponderance of donor management literature is limited to lower levels of evidence. The authors acknowledge recent studies (published after this guide line was submitted) in this area, but these do not change the direction and certainty of the recommendations. More informa tion on the evidence supporting each recommendation is avail able in the full guideline document (Appendix 1).
This synopsis provides information on 4 recommendations that the steering committee deemed likely to have the most impact on clinical practice. A complete summary of all recom mendations is available in Table 1.
# Thyroid hormone administration
We suggest against routine thyroid hormone supplementation (conditional recommendation, low-certainty evidence).
We make no recommendation about thyroid hormone supplementation for patients with hemodynamic instability or cardiac dysfunction.
Endogenous catecholamine release is increased during both acute critical illness and neurologic death. Although this causes an increase in systemic vascular resistance, cardiac output is compromised by neurologic death-induced myocardial suppres sion and a decrease in thyroid hormone release owing to pitu itary failure. [8][9][10] This state has the potential to compromise trans plantation of the heart itself and other organs as a result of impaired perfusion. There is therefore a theoretical advantage to exogenous thyroid hormone supplementation.
Four randomized controlled trials (RCTs) [11][12][13][14] assessed the effect of thyroid hormone on donor hearts and showed no improvement in the number of hearts eligible for transplanta tion. These studies were included in a 2012 systematic review, 15 which concluded there was no benefit from any form of thyroid hormone for neurologically deceased potential donors. We excluded 3 other RCTs included in the 2012 systematic review from our analysis as they did not report on any of our outcomes of interest (e.g., reported only on biochemical markers). All of these RCTs included several cointerventions administered to both the intervention and control groups.
In addition to the RCTs, we identified 5 observational studies [16][17][18][19][20] that reported conflicting results regarding the effect of treatment with thyroid hormone on the number of transplanted hearts. In the largest cohort study of 63 593 patients, 21 patients who received thy roid hormone had a 9.23% higher rate of heart recovery. Two addi tional cohort studies described a multivariate model that included thyroid hormone as a covariable associated with an increased chance of heart transplant eligibility. 22,23 Thus, for our primary out come of interest -number of hearts transplanted -the evidence suggests that thyroid hormone is of little benefit, although some larger cohort data suggest increased cardiac recovery.
The guideline panel did consider other outcomes, including cardiac function prerecovery, total number of organs recovered, graft survival and patient survival. Only cardiac function pre recovery was assessed in RCTs and no significant improvement was observed. [11][12][13] Cohort data, primarily from the large United Network for Organ Sharing report, 21 suggest that thyroid hor mone replacement is associated with increased cardiac graft and patient survival at 1 and 12 months, and increased number of organs recovered. Although these findings were statistically sig nificant, their interpretation is complicated by the fact that most patients received thyroid replacement as part of a hormone ther apy bundle and the effect of thyroid alone is difficult to assess.
Given the absence of established benefit in RCTs comparing thyroid hormone to no thyroid hormone, and the conflicting observational evidence, we suggest against the routine use of thyroid hormone in all potential donors.
We acknowledge that it is accepted practice in many centres to administer thyroid hormone to patients with cardiac dysfunc tion and that a recommendation against doing so in this sub group would have added acceptability and feasibility issues. We also acknowledge that there is no published evidence of physio logic harm associated with the administration of thyroid hor mone in this context. Given the absence of comparative evidence (RCTs or observational) in this higherrisk population and the potentially substantial acceptability issues, the committee felt the benefits and harms were very closely balanced. As such, we make no recommendation in the subgroup of patients with hemodynamic instability or cardiac dysfunction.
# Coronary angiography
We suggest against routine coronary angiography (conditional recommendation, very low-certainty evidence).
# Coronary angiography should be performed in the presence of risk factors for coronary artery disease as determined according to local criteria (good practice statement).
The evidence addressing the benefits of coronary angiography in potential heart donors is of very low quality. There is only 1 study that directly addresses this question. In this retrospective cohort study, Hauptman and colleagues 24 compared the rates of early graft failure in recipients who received a heart from a donor who underwent coronary angiography versus those who received hearts from donors who did not undergo coronary angiogram. Recipients who received a heart from donors who had an angio gram were less likely to have early graft failure. 24 No adverse effects were reported. This was a retrospective, nonrandomized study with low internal validity. • We suggest intravenous vasopressin as a firstline vasoactive agent for hypotension (conditional recommendation, very lowcertainty evidence).
• We suggest intravenous norepinephrine as a secondline agent for hypotension not responding to vasopressin alone (conditional recommendation, very lowcertainty evidence).
• We suggest against the use of dopamine at any dose (conditional recommendation, lowcertainty evidence).
• We make no recommendation regarding other vasoactive medications and inotropes.
# Antihypertensive medications
• We suggest using shortacting intravenous antihypertensive agents as per standard ICU practice to prevent endorgan damage (conditional recommendation, very lowcertainty evidence).
# Minimal acceptable blood pressure target
• We suggest maintaining mean arterial pressure ≥ 65 mm Hg rather than a lower threshold (conditional recommendation, very lowcertainty evidence).
# Fluid resuscitation
• We suggest infusing crystalloids, rather than colloids, for plasmavolume expansion (conditional recommendation, lowcertainty evidence).
# Protocolized fluid management
• We make no recommendation regarding the use of fluid management protocols.
# Glycemic control and nutrition
# Glucose control
• We suggest maintaining serum glucose levels in the range of 6-10 mmol/L, rather than a lower range of 4-6 mmol/L (conditional recommendation, very lowcertainty evidence).
# Glucose, insulin and potassium administration
• We suggest against the infusion of combined solutions of glucose, insulin and potassium (conditional recommendation, very lowcertainty evidence).
# Nutritional support
• We suggest providing enteral nutrition as compared with no nutritional support (conditional recommendation, very lowcertainty evidence).
# Diabetes insipidus and hypernatremia
# Serum sodium control
• We suggest maintaining serum sodium concentration in the normal range (135-155 mmol/L) (conditional recommendation, very lowcertainty evidence).
# Diabetes insipidus and vasopressin
• We suggest treating diabetes insipidus with desmopressin or vasopressin during hemodynamic stability (conditional recommendation, very lowcertainty evidence).
• We suggest treating diabetes insipidus with vasopressin during hemodynamic instability (conditional recommendation, very lowcertainty evidence).
# Hormonal therapy
# Thyroid hormone
• We suggest against routine thyroid hormone supplementation (conditional recommendation, lowcertainty evidence).
• We make no recommendation about thyroid hormone supplementation for hemodynamic instability or cardiac dysfunction.
# Corticosteroids
• We suggest intravenous corticosteroid therapy for donors requiring vasopressor support (conditional recommendation, lowcertainty evidence).
• We make no recommendation about highdose corticosteroid therapy for potential lung donors.
# Transfusion therapy
# Transfusion threshold
• We suggest withholding red blood cell transfusions unless hemoglobin levels fall below 70 g/L (conditional recommendation, very low certainty in evidence).
# Correction of coagulopathy and thrombocytopenia
• We suggest that in the absence of clinically significant bleeding, transfusions of fresh frozen plasma be withheld altogether, and that platelet transfusions be withheld unless platelet levels fall below 10 × 10 9 /L (conditional recommendation, very low certainty in evidence).
We also considered the logistics of coronary angiography. Coronary angiography requires patient transport outside of the ICU, exposes the donor organs to potentially harmful intra arterial contrast, is not available in all centres where patients who are potential donors are admitted, and is relatively costly and resource intensive.
Considering the limited evidence of benefit and the risks described above, we suggest against using routine coronary
# Bacterial infections
# Antibiotics
• We suggest reserving antibiotic therapy for the treatment of known or suspected infection (conditional recommendation, very lowcertainty evidence).
# Routine cultures
• We suggest that screening cultures of blood, urine and sputum be performed at intervals consistent with general ICU practice and patient clinical status (conditional recommendation, very lowcertainty evidence).
# Organ-specific considerations: heart, lungs and intra-abdominal organs
# Cardiac assessment tools
• We suggest against routine use of pulmonary artery catheters (conditional recommendation, very lowcertainty evidence).
• We suggest serial echocardiography at intervals consistent with general ICU practice (conditional recommendation, very lowcertainty evidence).
# Cardiac biomarkers
• We suggest against the measurement of serum cardiac biomarkers (conditional recommendation, very lowcertainty evidence).
# Coronary angiography
• We suggest against routine coronary angiography (conditional recommendation, very lowcertainty evidence).
• Coronary angiography should be performed in the presence of risk factors for coronary artery disease as determined according to local criteria (good practice statement).
# Lung-protective ventilation
• We recommend a lungprotective ventilation strategy consisting of low tidal volumes (6-8 mL/kg), high positive endexpiratory pressure (at least 8 cm H 2 0) and recruitment manoeuvres after ventilator disconnections in potential lung donors (strong recommendation, moderate certainty evidence).
# Bronchoscopy
• We suggest diagnostic bronchoscopy be performed for potential lung donors (conditional recommendation, lowcertainty evidence).
# Inhaled β-agonist therapy
• We suggest against routine use of inhaled βagonists (conditional recommendation, moderatecertainty evidence).
# Chest radiography and computed tomography scan
• We suggest a single routine diagnostic chest radiograph for lung donors and additional chest imaging as clinically indicated (conditional recommendation, lowcertainty evidence).
# Albumin: creatinine ratio screening
• We suggest using the albumin:creatinine ratio for detecting microalbuminuria when assessing potential kidney donors with type 1 or 2 diabetes mellitus (conditional recommendation, very low certainty in evidence).
# Hemoglobin HbA 1c testing
• We suggest that hemoglobin HbA 1c testing be performed in potential donors being considered for pancreas donation (conditional recommendation, very lowcertainty evidence).
# Abdominal imaging
• We suggest that abdominal CT or ultrasound should be used only in those with age > 50 yr, comorbid conditions, high body mass index, or clinical history of malignancy (conditional recommendation, lowcertainty evidence).
# Other therapeutic interventions
# Therapeutic hypothermia
• We suggest maintaining the core body temperature in the range of 34°C-35°C, unless kidneys will not be used for transplantation, in which case normothermia is appropriate (conditional recommendation, lowcertainty evidence).
# Duration of donor management
• For potential donors with acute organ injury, we make no recommendation regarding timing of organ recovery surgery or optimal duration of ICU donor management (conditional recommendation, very lowcertainty evidence).
Note: CT = computed tomography, HbA1c = glycosylated hemoglobin, ICU = intensive care unit.
angiography. As a good practice statement, however, we suggest that coronary angiography be considered in donors with risk fac tors for coronary artery disease because despite the lack of sup porting evidence for angiography in this clinical situation, it is expected that the benefit of avoiding transplant of a heart with coronary artery disease will outweigh the risk related to logistics and intraarterial contrast.
# Lung-protective ventilation
We recommend a lung-protective ventilation strategy consisting of low tidal volumes (6-8 mL/kg), high positive end-expiratory pressure (PEEP) (at least 8 cm H 2 0) and recruitment manoeuvres after ventilator disconnections in potential lung donors (strong recommendation, moderate-certainty evidence).
Ventilation with low tidal volumes is the standard of care for many ICU patient populations and is supported by experimental evidence and physiologic rationale. Some of the highestquality evidence in organ donor management is in the area of donor ventilation.
We defined a lungprotective ventilatory strategy as low tidal volumes, high PEEP and recruitment manoeuvres. We were unable to identify literature that evaluated any of these 3 com pon ents in isolation. One RCT and 3 observational studies exam ined mechanical ventilation with a lungprotective approach in neurologically deceased potential donors. [25][26][27][28] The RCT com pared a lungprotective approach (tidal volumes of 6-8 mL/kg predicted body weight, PEEP 8-10 cm H 2 O, recruitment manoeu vres after disconnections from the ventilator (and an additional protocol for apnea testing) to conventional ventilation (tidal vol umes > 8 mL/kg predicted body weight, PEEP< 8 cm H 2 O, no pro tocolized recruitment manoeuvres and apnea tests off the venti lator). 25 The protective strategy was continued for a minimum of 6 hours, and potential donors assigned to this strategy were twice as likely to proceed to lung procurement. There was no sig nal of harm among the lung recipients; nor was there any signal of harm from the protective ventilation strategy with respect to the recovery of other organs.
Three observational studies with historical control groups evaluated the effect of a comprehensive lungdonor manage ment strategy. [26][27][28] Two of these studies involved the ventilation protocol tested in the RCT. 26,27 The third study involved higher PEEP of 15 cm H 2 O, without the other components of lung protective ventilation. All 3 studies showed an improved lung procurement rate with implementation of their comprehensive lung donor management strategies, and 1 of the 3 studies showed increased recipient survival. 28 The committee considered potential drawbacks not explored in these studies. First, as was the case in all the studies, the criteria for lung donation eligibility frequently involves the ratio of arterial oxygen partial pressure to fractional inspired oxygen (Pao 2 :FiO 2 ratio) as a measure of lung function. However, PEEP is a therapeu tic intervention that may transiently improve the Pao 2 :FiO 2 ratio in some physiologic states. [29][30][31] Thus, there is a risk that high PEEP ventilation allows relatively suboptimally functioning lungs to appear numerically viable for transplant at the time of eligibility assessment. In the RCT, lungprotective ventilation was not associ ated with an increase in criterioneligible lungs being declined based on gross inspection or other surgical opinion. 25 Second, increasing mean airway pressure via increased PEEP has the potential to decrease cardiac output. 32 It is possible that the decreased cardiac output outweighs any benefit on graft oxy gen delivery derived from improved arterial oxygenation. In the donation population, this may be best assessed through the viability of other organs in potential donors managed with lung protective ventilation, but this outcome was not reported in the included studies.
Given that the evidence for a benefit from lungprotective ventilation is greatest for lung donation, we considered narrow ing our recommendations to potential lung donors only. How ever, the candidacy of specific organs for donation is often not known in the early stages of donor care, and a delay in initiating lungprotective ventilation will reduce its benefit. We therefore recommend that lungprotective ventilation be started as soon as possible in all potential neurologically deceased donors. Intensivists and respiratory therapists are experienced with lung protective ventilation in the critically ill, and this approach does not incur any additional costs with respect to equipment or human resources. We therefore do not expect major barriers to implementing this recommendation routinely in neurologically deceased donors.
# Therapeutic hypothermia
We suggest maintaining the core body temperature in the range of 34-35°C, unless kidneys will not be used for transplantation, in which case normothermia is appropriate (conditional recommendation, low-certainty evidence).
In the single RCT in this area, 33 the induction of mild therapeutic hypothermia (34°C-35°C) in donors was shown to reduce the occur rence of delayed graft function in kidneys, a benefit that was even more substantial in the extended criteria donor population. There was no evidence of harm in the intervention group and the recovery of other organs was not affected in the hypothermia group. Graft outcome of other transplanted organs was not reported.
A retrospective analysis of mild spontaneous hypothermia (< 36°C) was performed from a data set designed to study dopa mine in the organ donor population. 34 Similarly to the RCT described above, the study showed a reduction in kidney delayed graft function in the hypothermia group. There was no difference in 5year graft survival. The same data set used to study cardiac donors identified a lower 3year graft survival in donors with spontaneous temperature less than 36.2°C. 35 Given the methodological limitations of studying spontaneous hypo thermia, causation versus association for outcomes was an issue; evidence was downgraded to low.
Targeted temperature management is now common practice in most critical care units. Although there are only 3 studies evalu ating this intervention in organ donors, the absence of any identified harm, combined with the fact that the most commonly recovered organ is the kidney, led our guideline committee to suggest mild hypothermia in all organ donors until kidneys have been ruled out for donation.
We acknowledge that there are minimal data on the effect of mild hypothermia on nonrenal organs and that the evidence for cardiac donors is weak. New evidence could change this recom mendation. The considerations for hypothermia are stronger when only kidneys are considered in an extended criteria donor. The 23member guideline panel selected by the steering com mittee included representation from critical care medicine (adult and pediatric), critical care nursing and pharmacy; an infectious disease specialist; organ donation specialist physicians; and peo ple with organspecific expertise in transplant cardiology, cardiac surgery, pulmonology, lung surgery, urology, nephrology and abdominal surgery. We included 2 patient partners, a family mem ber of a deceased multiorgan donor and a heart transplant recipi ent. Other panel members included representatives from specific knowledge user groups: the Canadian Critical Care Society, the Canadian Society of Transplantation, the Canadian Association of Critical Care Nurses and the Canadian Donation and Transplanta tion Research Program. By design, the guideline panel included geographic diversity from 4 provinces (Ontario, Quebec, Alberta and BC), representing the most active donation and transplant programs in Canada. The full participant list and description of the guideline methodology is available in Appendix 1.
# Methods
# Guideline panel composition
Canadian
# Guideline development
We reviewed the results of a systematic review of published organ donor management guidelines 36 before deciding on the scope of our effort. This review of 27 guidelines from 22 countries provided an overview of topics that had been covered by other groups and informed our list of 29 potential PICO (Patient, Inter vention, Comparator, Outcome) questions (Appendix 1).
The guideline panel was divided into 3 smaller working groups that selected outcomes of interest for each question. The overall group explicitly rated these outcomes for their relative importance from "not important" to "critical" according to GRADE guidance. 37 In cases of disagreement, decisions were made by group discussion and consensus. We developed a hier archy of outcomes to inform these discussions: clinical optimiza tion during the interval between death declaration and organ recovery; increased organ acceptance, recovery and transplanta tion; an increase in organ recovery; improved graft function; graft survival; and recipient survival and quality of life.
Within the 3 working groups, panel members were assigned PICO questions in pairs and collaborated with information technologists or medical librarians to design and conduct search strategies for each of the 29 PICO questions. Our population of interest was neurologically deceased organ donors. Primary searches were limited to human studies reported in English, either in full text or abstract. At minimum for each question, we searched MEDLINE (PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL). Primary searches were restricted to human studies reported in English, from 1981 to present, either in full text or abstract (see Appendix 1 for details of the search strategies, including individual end dates). Two panel members independently screened all relevant citations of each PICO question for eligibility. Disagreements were resolved through consensus and discussion. Searches were completed by September 2018. Steering committee members monitored the literature up until January 24, 2020, for recent publications that could affect the direction or certainty of any recommendations.
In situations where little to no direct research evidence was available in the organ donation or transplantation population, we extended our search to indirect evidence. In most cases, this referred to studies in the general ICU population, but in some cases, it included animal studies or trials in other patient populations.
In their assigned pairs, panel members abstracted study char acteristics and outcome data from all eligible studies for each PICO question. In addition to clinical data, we also assessed indi vidual study risk of bias using the Cochrane Risk of Bias tool 38 for RCTs and the Newcastle-Ottawa tool 39 for observational studies. When possible, we pooled outcome data for each PICO question and performed metaanalyses using the Cochrane Collaboration Review Manager 5.2. 40 Once this analysis was completed, we assessed the overall certainty (confidence) in the effect estimate for each outcome of interest following the GRADE approach 41 based on these criteria: risk of bias, precision, consistency, directness of the evidence, risk of publication bias, presence of a dose-effect relationship, magnitude of effect and an assessment of the effect of plausible residual confounding or bias. Consider ing all of these elements, the strength of evidence for each out come was categorized as high, moderate, low or very low. Steer ing committee members with GRADE expertise and experience (B.R. and L.H.) oversaw this process.
Pairs of panel members prepared evidence summaries for each question in collaboration with the methodologist (B.R.), fol lowing the GRADE approach 42 and using the GRADEpro Guideline Development Tool online software. 43 Based on these evidence summaries, the 3 working groups devel oped recommendations for each PICO question. We used the GRADE Evidence to Decision framework to facilitate discussion on each rec ommendation. 44 Recommendation development was based on the certainty of the evidence, the balance of desirable and undesirable consequences of compared management options, assumptions about the values and preferences associated with the decision, implications for resource use and health equity, the acceptability of an intervention to stakeholders, and feasibility of implementation. The guideline panel assessed each recommendation for pediatric specific considerations. The 3 working groups presented their rec ommendations to the entire guideline panel for further review and discussion. Disagreements were resolved by consensus.
In accordance with the GRADE approach, 45 we used the phrasing "we recommend" for strong recommendations and "we suggest" for conditional recommendations. Table 2 pro vides a guide to interpretation of these recommendations for intended stakeholders, including patients, clinicians and health policymakers.
The guideline panel endeavoured to provide recommenda tions for each original PICO question. In the exceptional circum stance where there was insufficient evidence for or against an intervention, or if there was a perceived balance between net benefits and net harms, then the panel made "no recommenda tion." "Good practice statements" were made when there was a high level of certainty about the effect of the therapy, but little direct supporting evidence. 47
# External review
Representatives of the supporting organizations, including the Canadian Critical Care Society, the Canadian Society of Trans plantation and the Canadian Association of Critical Care Nurses, performed external reviews. The lead author (I.B.) incorporated the feedback into the guideline and steering committee mem bers edited it. The entire guideline panel had an opportunity to review the final version of the guideline.
# Management of competing interests
All guideline panel members signed a confidentiality agreement at the inaugural meeting in 2017, where they were also asked to disclose any potential direct and indirect competing interests using a Canadian Blood Services competing interests documen tation form. These were collected again a year later and before publication. Canadian Blood Services personnel and the steering committee reviewed the declarations. Several panel members have professional roles in organ donation administration, with governmental notforprofit entities, or have funded scientific research; however, no steering committee or panel member was judged to have a relevant direct competing interest.
# Implementation
No specific dosing regimens were recommended for either pedi atric or adult patients, and groups planning to use these recom mendations to create bedside treatment protocols or standard ized order sets should consult with critical care pharmacists with experience treating the target population.
Members of our guideline panel have created "evidence bulle tins" (1page, laminated cards explaining key recommendations) for distribution to ICUs in partnership with interested provincial organ donation organizations, and leaders in ICU education (bit. ly/dmevidencebulletins). We have also developed adult and pediatric order sets for use by provincial organ donation organ izations and the hospitals that they service (Appendix 1), as well as a family brochure (bit.ly/dmfamilybrochure).
In some cases, a PICO question addressed whether or not to administer a particular medication in a particular circum stance. We made evidencebased recommendations about the appropriateness of the treatment but did not necessarily survey the literature for the best medication or dose from its class (e.g., corticosteroids). In these cases, the panel identified (but did not formally recommend) commonly prescribed medica tions and their usual doses, in order to help clinicians at the bedside.
Canadian Blood Services personnel regularly monitor the lit erature and an update is triggered when there have been any of the following: • New evidence on the existing benefits and harms of interventions; • Changes in outcomes considered important; • Changes in available interventions;
• Changes in evidence that current practice is optimal;
• Changes in values placed on outcomes; or • Changes in resources available for health care.
# Other guidelines
Members of this group performed a systematic review of pub lished organ donor management guidelines 36 to guide the scope of this guideline document. This review of 27 guidelines from 22 countries provided an overview of topics that had been covered by other groups and informed our initial list of potential PICO questions. In contrast to previous guidelines on organ donor management, this guideline was derived using GRADE methodology. For patients Most individuals in this situation would want the recommended course of action and only a small proportion would not.
The majority of individuals in this situation, if fully informed, would choose the suggested course of action, but some would not.
# For clinicians
Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.
The care needs of individual donors may vary as a result of comorbidities, and the practice of individual clinicians may vary in these circumstances, largely owing to the lack of evidence to address these situations.
# For policymakers
The recommendation can be adapted as policy in most situations
Policymaking will require substantial debate and involvement of various stakeholders.
Modified from Guyatt et al. 46
# Gaps in knowledge
An important limitation of these guidelines is that organ donor man agement research is predominantly observational in design. Many important clinical questions have not been addressed by RCTs. In addition, our guideline committee identified more PICO questions than we were able to process in this iteration. A list of items for gener ation of potential PICO questions and consideration for future guide lines is included in the full guidance document (Appendix 1).
# Conclusion
The multidisciplinary guideline panel reviewed the literature for 29 PICO questions and generated 1 strong recommendation, 33 con ditional recommendations, and 1 good practice statement as part of a comprehensive and evidencebased clinical practice guideline for organ donor management. It is our hope that this work can optimize use of the scarce resource that donated organs continue to be.
# Acknowledgements:
The authors especially thank Ms. Kathryn Ivison
#
Competing interests: John Gordon Boyd reports receiving salary support from the Trillium Gift of Life Network, nonfinancial support from Caster Medical and a grant from Physician Services Incorpor ated, outside the submitted work. Maureen Meade reports receiving a knowledge translation grant from Canadian Blood Services, and sal ary support as a hospital donation physician for Trillium Gift of Life Network. Matthew J Weiss reports receiving ongoing funding from Transplant Québec for his work as medical director of organ dona tion. Karim Soliman reports receiving a stipend to support education in the province from the Trillium Gift of Life Network. Jeffrey Singh re ports receiving a salary as the regional medical lead for donation at | None | None |
bef3c62b6b2ff71c3d2a1ae205d3bfc5bd15c4eb | cma | None | The intent of this guideline (Part 1 and Part 2) is to provide practical, accessible, and B.C. specific guidance. In essence, this is more of a Clinical Guidance Document and not a formal guideline. It's a distillation of many guidelines, expert recommendations, and standards of care. There are few overall pain guidelines for direct comparison. The guideline development working group members were made aware of the Appraisal of Guidelines for Research and Evaluation (AGREE) process that helped inform their appraisal of these guidelines. There is no clear or absolute clinical pathway to managing pain and many controversies persist, especially in the use of opioid and cannabis. The working group recommends reasonable clinical judgement, clear documentation, and frequent reassessment.For many patients with acute, subacute, or chronic pain, pharmacological management is part of overall care. Indeed, it is imperative to get acute pain under control early and effectively but with a clear goal of reassessing its effectiveness and presenting a well-articulated anticipated plan to taper and stop medications. The benefits of long-term medications, especially opioids, are less well understood. For longer term non-cancer pain, ensure that non-opioid and non-pharmacological therapies have been effectively optimized first. 1 The management of cancer and end-of-life pain usually requires a different strategy that may more appropriately include opioids. Managing patients with most types of pain is not necessarily an "either/or" strategy but rather a layering of interventions including non-pharmacological management, self-management, and pharmacological management.Acetaminophen Indications: Consider for initial management of patients with mild to moderate pain. 3 Use the lowest effective dose and stop therapy if minimal or no effect. Cautions: Higher doses, chronic use, increasing age, renal disfunction and alcohol use increase risk of hepatic toxicity.Indications: Consider for patients with mild to moderate musculoskeletal pain and inflammation. Use the lowest effective dose for the shortest duration to reduce adverse events and reassess effectiveness within the first few weeks.- The risk of gastrointestinal (GI) complications is unlikely, but possible, within the first week. The risk increases with longer duration of therapy. Patients at high risk of GI complications may benefit from a COX-2 inhibitor (i.e., celecoxib), and/or the addition of a proton pump inhibitors (PPI) (i.e., rabeprazole) even for short term use. - Patients at high risk or with established cardiovascular disease may be at increased risk of cardiovascular (CV) events with NSAIDs. Risk appears to be dose and duration dependent. - Contraindicated in patients with a Creatinine Clearance (CrCl ≤30 ml/min. NSAIDs may cause further deterioration in renal function in patients with mild-moderate or declining renal function, use with caution. - Older adults have a greater frequency of impaired renal function, existing electrolyte imbalances, comorbid conditions (including CV disease), and multiple medications including over the counter (OTC) products. Take a full history and assess individual patient's appropriateness for NSAIDs.Indications: There is limited evidence comparing the combination of NSAIDs and acetaminophen to opioids, with some small trials suggesting no difference in pain during dental extractions, hip and knee osteoarthritis, and acute extremity pain. 4-7 A 2020 Cochrane review found low-quality evidence comparing an NSAID and acetaminophen to opioids in acute soft tissue injuries and was uncertain of the findings of no difference in pain at day 1, 3 or 7. 8 Other small trials suggest lower opioid doses may be required after surgery when added to NSAIDs and acetaminophen. 6,7 A 2021 systematic review found NSAIDs to be associated with better pain scores at 6 and 12 hours postoperatively when compared to codeine with or without acetaminophen in outpatient surgery. 9 A 2020 Cochrane Review comparing NSAIDs and opioids in acute soft tissue injuries, found moderate quality evidence of no difference in pain at 1 hour, and low certainty evidence of no difference in pain at 4 and 7 days. 8 NSAID participants were more likely to return to function in 7-10 days and experienced less GI and neurological adverse events. 8Indications: Consider for acute conditions such as when patients have sprains, strains and overuse injuries 10 and in some chronic conditions such as osteoarthritis, particularly of the hand or knee. Re-evaluate every 3 months and continue only in responders. 10 Topical formulations with diclofenac (1-4%), ibuprofen (5-10%) or ketoprofen (1-5%) have the best evidence10 and are available OTC (diclofenac 1.16-2.32%) or through a compounding pharmacy (generally in the 5-10% range). These can be expensive and are not a PharmaCare benefit. While increased concentrations are seen in practice, they have not been studied extensively. Cautions: Systemic absorption from topical NSAIDs is low (approximately 6-23%) compared to oral forms. However, systemic adverse events have been reported. Topical NSAIDs are generally well tolerated by all patients, including those over 65 years of age.# Considerations and Controversies of Care
- Many guidelines on pain management exist, including those from national, provincial, regulatory authority, advocacy, and academic institutions. They may not all completely align, and the levels of evidence and evidence review process used to create those guidelines may appear unclear in terms of clinical decision making. However, most have a consistent framework to guide clinicians while allowing for good individualized clinical judgement. - Evidence may include large systematic reviews, randomized control trials, and expert opinion. Evidence may come from high quality studies, but the strength of the evidence may be described as poor, e.g., simply because of small study numbers. While an effect may be described as statistically significant, the magnitude of the clinical impact maybe small. - Guidelines are generally considered to be based on strong clinical evidence, yet some recommendations clearly state the evidence is weak. However, weak evidence may be the only evidence available and is intended to give the clinician an option to consider. - The number needed to treat (NNT), and the number needed to harm (NNH) are important concepts to help weigh the benefit and harm of a drug or treatment. They are used to inform a clinician about a specific condition response. However, an intervention may be used in several conditions but be more effective in one condition than another.
- Pain is a symptom and not a specific condition with clearly defined parameters like blood pressure and spirometry. Clinicians who need to treat patients with pain need information on how to do this as safely and effectively as possible for that patient. - It is important to use medications with caution for any patient who may have reduced renal, hepatic, or cardiac function.
Likewise, patients with reduced lean body mass (i.e., increased fat concentration), malnourishment (e.g., reduced albumin), concomitant disease, and multiple medications, may need dose adjustments. Consult product monographs for specific drugs and refer to Appendix A: Medication Table.
# Skeletal Muscle Relaxants
Indications: For acute musculoskeletal pain only. There is insufficient evidence to support the use of cyclobenzaprine for chronic myofascial pain. 11 Cautions: Due to the risk of long-term dependence and high incidence of adverse effects (e.g., sedation, dizziness, dry mouth), consider short term use only (1-2 weeks). Adverse effects may be more pronounced and may increase the risk of falls in frail older adults.
# Gabapentinoids 12
Indications: Consider for patients with neuropathic pain conditions such as post herpetic neuralgia or painful diabetic neuropathy. Benefits and harms can both often be seen and assessed as early as 1 week after initiation. Higher doses (gabapentin >1800 mg/d; pregabalin >300 mg/d) may not provide significant additional benefit relative to the increased risk of adverse events. 12 A good summary of gabapentinoids is provided by the B.C. Provincial Academic Detailing Service.
Cautions: Due to the risk of severe respiratory depression and sedation, use with caution when combined with opioids and/or other central nervous system (CNS) depressants. 13 Adverse effects (e.g. drowsiness, dizziness, etc.,) may be more pronounced and may increase risk of falls in frail older adults. Gabapentinoids have been identified as drugs of potential misuse. 14 These drugs are renally excreted, therefore use with caution in patients with renal impairment.
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) Indications: Consider for patients with neuropathic pain conditions (e.g. diabetic neuralgia, post herpetic neuralgia). Duloxetine has a larger evidence base for the treatment of neuropathic pain than venlafaxine. Benefits and harms can often be seen and assessed within 1 week. Higher doses (e.g. duloxetine >60 mg/d) do not produce better analgesia. SNRIs are better tolerated than tricyclic antidepressants (TCAs) in frail older adults. 18 Tricyclic Antidepressants (TCAs) Indications: Low quality evidence suggests TCAs may result in a 30% reduction in pain for some patients.
TCAs do not appear to be more effective than placebo in chronic low-back pain. There is a lack of evidence to evaluate the role of TCAs in fibromyalgia. 19 Cautions: Due to high incidence of anticholinergic side effects (e.g., drowsiness, dry mouth, and constipation), consider alternatives in frail older adults. If a TCA is indicated, start with low doses and consider nortriptyline as it may have fewer anticholinergic effects and is often better tolerated.
# Opioid Therapy
This section provides guidance for managing patients who are both opioid-naïve and those already on long-term opioid therapy. Indications for tapering and cessation of opioids are also included.
# Controversies of Care
The use of opioids is one of the more controversial issues for many clinicians.
- There are national guidelines as well as regulatory authority directives that give clear guidance about the use of opioids.
To some clinicians, these appear excessively harsh and restrictive while others may appreciate the specificity of the guidance. Some clinicians are concerned about disciplinary action if they prescribe opioids or exceed the recommended daily maximum. - Virtually all guidelines distinguish between non-cancer and palliative end-of-life care, yet some clinicians fail to properly consider that distinction and restrict appropriate comfort measures. - The 2017 Canadian Guideline for Opioids for Non-Cancer Pain (McMaster Michael G. DeGroote National Pain Centre) is the current standard, yet a follow-up review of those guidelines by the main author suggests that 1/3 of clinicians mistakenly believed the guideline suggested mandatory tapering and that 2/3 of respondents highlighted resistance by patients and lack of access to effective non-opioid treatment. 20 - A 2018 review by the same author looking at 96 clinical trials, concluded "use of opioids was associated with significantly less pain and significantly improved physical functioning…but the magnitude of the association was small". The mean follow up period of the studies was 60 days. 21 - As mentioned in the 2017 Canadian Medical Association Journal (CMAJ) article "No guideline can account for the unique features of patients and their clinical circumstances, and the new (2017) guideline is not meant to replace clinical judgement. Patients, prescribers and other stakeholders, including regulators and insurers, should not view its recommendations as absolute". 22 - Consensual tapers may lead to improved or at least no worse pain management (though in a significant minority of patients this might not be the case), while forced tapers may increase risk of opioid use disorder (OUD), overdose, and suicide. 23 - The 2017 National Pain Centre Guidelines that describe maximum daily doses, also suggest that some patients may benefit from higher doses. - Clinicians may hesitate or avoid prescribing opioids to elderly patients, but age alone is not a reason to avoid opioids.
Considerations for safely prescribing opioids for the elderly are described below. - There are several screening tools available to identify the risk of developing OUD when initiating opioids, but evidence suggests these may not help identify those at low risk. Only the absence of a mood disorder was associated with low risk. Previous OUD, certain mental health conditions (e.g. personality disorder), and the use of certain psychiatric medications such as atypical anti-psychotics were associated with high risk of developing OUD. 24 - The most commonly prescribed opioids in 2018/19, in BC, in order of most to least, are codeine, hydromorphone, tramadol, morphine, and oxycodone. 25 However, the analgesic activity of codeine (and to a lesser extent tramadol) is dependent on genetic polymorphisms, making them more difficult to dose adjust in patients requiring additional dose adjustments due to renal or hepatic impairment. - TRAMADOL: There is a perception that tramadol is a safer opioid as it was not historically considered a Schedule 1 narcotic.
However, effective March 31, 2022, Health Canada has added tramadol to the Controlled Drugs and Substances Act to reflect the fact it is an opioid with the same risks as others. 26 Tramadol's analgesic activity, much like codeine, is dependent on CYP2D6 metabolism which is altered in approximately 28% of patients. 27 In addition, tramadol acts as a serotonin and norepinephrine reuptake inhibitor (SNRI), increasing the risk of drug interactions and side effects (including serotonin syndrome and seizures) over that of other opioids. 28
# Considerations for Initiation of Opioid Therapy for Opioid-Naïve Patients
Indications for Opioid Medications:
- Moderate to severe acute pain (e.g., post-operative, injuries) expected to resolve.
- Palliative and life-limiting conditions (e.g., end-stage heart failure, chronic obstructive pulmonary disease (COPD), cancers) -for these situations, refer to Palliative Care Guideline as the benefits and risks are different in these patients who will need longer and likely escalating doses. Palliative care patients should never be denied opioid medications when required.
Despite previous practice, there is limited or weak evidence for the value of initiating opioids for patients with chronic non cancer pain (CNCP). In many instances, the risks of prescription OUD or adverse effects outweigh the potential benefits. The long-term use of opioids for managing pain has a potentially higher risk of harm and has limited evidence for benefit. A classic example of this type is a young patient with gradually worsening degenerative back or joint pain.
# Prescribing Considerations:
- The initiation of an opioid should always be considered as a "therapeutic trial". Document well the initial discussion and rationale for use of opioids. Encourage patients to self-limit where possible. - Limit prescriptions. Consider a trial for 7 days or less at a time. Increase interval as patient stabilizes on a dose that does not compromise function. An oral dose of morphine 5-10 mg, or hydromorphone 1-2 mg are common adult starting doses, especially in the immediate post-op period. - Start patients, especially those who are opioid naïve, on lowest effective dose and titrate as needed with close monitoring of efficacy and side effects. A particularly useful tool is: Centre for Effective Practice 'Opioid Manager' . The Opioid Manager is a practical tool and checklist for opioid prescribing decisions including opioid therapy trials, maintenance, monitoring, switching, and tapering. Other tools include the Opioid Risk Tool, Current Opioid Misuse Measure (COMM)™.
Opioids are a potent and useful class of medications for the treatment of pain and endof-life symptoms when used appropriately. However, while supporting the patient with pain management, clinicians need to be aware of appropriate prescribing guidelines to mitigate the risks of opioid harms and dependence.
- Consider and minimise drug interactions (e.g., CNS depressants, serotonin concerns with tramadol). See Appendix A: Medication Table for specific drug interactions. - Be aware of the College of Physician and Surgeons of BC (CPSBC) Safe Prescribing Standards. The CPSBC also has a list of prescribing tools and resources on their website. - Fully inform patients of the risks and benefits of using opioids and discuss plans for the possible tapering and/or discontinuation of the medication. Document this discussion. - A patient handout is encouraged.
- Common side effects such as drowsiness and nausea often improve while constipation tends to persist and needs to be actively managed with diet, stool softeners and/or laxatives. - Frail older adults with moderate to severe pain and functional impairment or poor quality of life should not be excluded from consideration of opioid therapy. See Pharmacological Pain Management in the Older Adult below. - Patients on long-term opioids at stable doses (often referred to as legacy patients) may not be able to taper down to the recommended doses, but that doesn't preclude a conversation about their use and the potential to taper down to a lower dose. - An additional resource is a detailed review on Opioid Metabolism by Howard Smith. 29 - For B.C. specific information and coverage, see Appendix A: Medication Table.
# Contraindications and Cautions
# Absolute Contraindications
Relative Contraindications If considering prescribing opioids, assess for active and past substance use disorder (SUD) (including alcohol, opioids, marijuana) and psychiatric disorders. The presence of these disorders is not a reason to not prescribe but suggest a need to proceed with caution and to have a clear discussion with patient about risks. Indeed, the presence of any SUD is not an absolute contraindication to prescribe opioids, though it does increase risk of overdose and addiction to opioids. Thus, more safeguards, including enhanced monitoring, need to be put in place and clear documentation of risks and benefits for that particular patient outlined.
# Use with Caution
- Concurrent use with CYP3A4 inhibitors/inducers (e.g., clarithromycin, diltiazem, "azoles" such as ketoconazole, certain ARV's such as ritonavir, phenobarbital, and phenytoin). See Appendix A: Medication Table . - Codeine is metabolized by CYP2D6 to its active form, morphine. Up to 23% of the population may produce significantly more or less morphine than expected based on the dose. 30 Monitor for increased side effects, decreased efficacy or select alternative drug. - Concurrent use of potentially sedating medications such as gabapentinoids 13 cyclobenzaprine, diphenhydramine and dimenhydrate. - Hepatic and renal impairment may change the pharmacokinetics of medications, reducing elimination and increasing availability of that drug. - Use of alcohol with opioids should be actively discouraged.
- When patients have co-existing mental health conditions such as mood or thought disorders, consider the extent to which they may be exacerbating or coexisting with the pain. Use caution when considering an opioid and reflect on the concomitant need to manage the mental health condition as well. The Canadian National Guideline for Opioids for Chronic Non-Cancer Pain recommends stabilizing an active psychiatric disorder before initiating a trial of opioids (weak recommendation).
# Pandemic Considerations.
During the COVID-19 pandemic and concurrent opioid overdose epidemic, consideration may be needed to reduce the risk of harm from both. In an effort to reduce the spread of COVID-19, the BCCSU Risk Mitigation in the context of dual public health emergencies interim guidance document outlines many related changes in prescribing policy. There are provincial policy changes that reduce risk of exposure such as phone orders and transferring scripts between pharmacies. Longer prescriptions and potentially delaying or slowing tapers may also be strategies to avoid destabilizing already vulnerable patients.
# Considerations for Patients Already on Opioid Therapy
Most primary care practitioners see patients who are already on long-term opioid therapy for chronic pain, regardless of initial indications. These considerations apply whether the patients are long established or new to the practice. Again, it is not appropriate to refuse to accept or continue to care for patients on opioids and it is not appropriate to abruptly stop prescribing.
# Indications for Long-term Use of Opioid Medications:
- Palliative care and end-of-life conditions.
- Conditions not expected to improve and not well managed with non-opioid medications. Some examples may include worsening scoliosis, degenerative disc disease or vertebral fractures not amenable to other interventions. - Some patients with chronic pain already on opioids may be stable and functional with minimal disability and side effects.
Maintaining them on opioids may be appropriate and indicated. A forced taper may worsen pain and reduce stability.
# Ongoing Management
- Reassess regularly to ensure that non-opioid and non-pharmacological therapies have been maximized. Document the reassessment. - Self-Reflection: "If you are feeling pressured to prescribe opioids, ask yourself where this pressure is coming from and how you might respond". - There is not a defined target morphine equivalent daily dose (MEDD), but clinicians should prescribe the lowest effective dose.
- The CPSBC Safe Prescribing Standards, suggests that doses above 90 MEDD require "substantive evidence of exceptional need and benefit". The standards do not say that higher doses cannot or should not be prescribed, just that the evidence and need for a higher dose must be documented. In addition, the guidelines do not suggest mandatory tapering. 20,31 Clinical examples may include patients with severe pain for which higher doses of opioids are needed and patients who present with existing prescription doses which exceed 90 MEDD for whom abrupt tapering or cessation would cause harm. Documentation is critical. - Consider using long-acting opioids after stabilizing the patient on immediate release opioid. Even in this situation, be aware that there is poor evidence supporting long-term use of opioids and discuss and document the risk of long-acting opioids in advance. - For anticipated longer term prescriptions, a written treatment agreement is encouraged. Sample agreement available at CPSBC Prescribing tools and resources. - Divergence from the treatment agreement may suggest a need to re-evaluate the clinical situation and consider the biopsychosocial stressors that may be present. Agreements are not meant to be punitive so it does not necessarily indicate that opioids must be tapered or stopped. Breach of agreements should not be used as a method to justify termination of opioid therapy, nor should they be used to support discharging a patient from a practice. Instead, they should be used to support opening a conversation about appropriate and safe opioid use. Consider discussion with an addiction medicine specialist or pain specialist with experience in addictions. - However, if there is clear evidence of prescription forgery or confirmed diversion (with a supportive urine drug test (UDT), you no longer have an obligation to prescribe. - All patients on opioids for chronic pain could be considered for random UDT. However, there is uncertain evidence about the effect of urine drug screening on the risk of opioid overdose. 1 A urine drug test may be used in the context of patient education and safety to identify additional drugs (sometimes taken unknowingly) that may put patients at higher risk. Absence of the prescribed opioid in random urine testing should be a red flag for possible diversion. A respectful discussion of results may be useful before any action is taken. Refer to BCCSU's Opioid Use Disorder. See Urine Drug Testing for more information, but please note this is a document specific to the use of UDT in the management of OUD.
- Ideally, patients should be prescribed opioids by their primary care provider only. Where possible, only one consistent provider or team should be providing the prescriptions. However, the current reality in B.C. is that some patients may see multiple providers; therefore, make good use of documentation and electronic medical record (EMR) functions including ready access to patient agreements, current medications and any "cautions" or "flags" that are attached. - PharmaNet provides an up-to-date list of filled prescriptions and should be used prior to every opioid prescription and refill.
CareConnect provides recent clinical encounters including ER visits and prescriptions written. - Consider blister-packs and controlled dispensing strategies if there is concern about use other than prescribed.
- Consider offering a naloxone kit and education to patient and family on how to administer and respond to overdose. Refer to towardtheheart.com produced by the BC Centre for Disease Control (BCCDC) for naloxone kit guidance. - For safety of children, pets and opioid-naïve adults and prevention of theft, educate patients on safe storage and disposal of opioid medications. - Reassess regularly and be vigilant for incipient or existing prescription OUD (e.g., escalating dosages, increasing pain complaints, multi-doctoring). Ask about alternate routes of use, including snorting, chewing, smoking, or injecting.
# When to Taper and/or Stop Opioids
- For patients prescribed opioids for short-term, acute pain (e.g., post-operative or injuries), recommend a tapering and discontinuation plan including dosage, frequency and duration. Confirm the follow-up plan with the patient. - Opioid tapering and discontinuation may be difficult for the patient who fears worsening of the pain and withdrawal symptoms. Patients should be actively engaged in a discussion about the merits of gradual dose reduction, including the potential for equivalent or better pain control with less opioid-associated risks (e.g., reduced risk of myocardial infarction , motor vehicle accident (MVA), sleep apnea, sexual dysfunction, falls, depression, addiction, unintended overdose). However, a percentage of people will not experience these benefits and the taper may not be appropriate. - Comments such as 'I think we can work towards giving you just as much pain control with less medication risks' are a good start to conversations about the possibility of a dose reduction.
Indications for Tapering and/or Stopping When there is a loss of therapeutic effect on pain and function.
When there are intolerable side effects such as sedation. Patient request. When there is non-adherence to the agreed plan or clear evidence of diversion. This is considered a breach of the opioid agreement and mitigation steps need to be taken such as daily witnessed dispensing or lowering the dose. With evidence of diversion and a supportive UDT confirming none of the prescribed opioid present, then you have no obligation to continue prescribing. When clear evidence of OUD is present or worsening it is appropriate to refer to addiction specialist instead of attempting to taper. - Many guidelines suggest that a taper be considered for patients whose MEDD is above 90. This is not a strict limit and clinical judgement is always warranted. This does not apply to cancer/palliative patients. - Patients on long-term opioids at stable doses may not be able to taper down to the recommended dose range. Again, it is never inappropriate to have a conversation about the continued use of these medications and the potential to slowly taper down to a lower dose. - Opioid-induced hyperalgesia is an adverse effect that is characterized by decreasing efficacy that is not improved by increasing the dose of the opioid. 32 It is dose dependent and worse at higher doses but occurs at any opioid dose in patients with chronic non-cancer pain. 33 Symptoms include spreading or burning pain and allodynia (i.e. pain due to a stimulus such as light touch that does not usually provoke pain). It may also be accompanied by other signs of opioid toxicity such as myoclonus, delirium, and seizures. Symptoms improve by reducing or eliminating the drug. Consider opioid rotation in cases of opioid toxicity. See Opioid Switching section below.
# Tapering Strategies
There is no evidence for any specific tapering strategy. However, a commonly described strategy is:
- A reduction of 5-10% of the daily dose.
- A dose reduction every 2-4 weeks.
- Tapering in the older adult may be slower (e.g., 5% every 2-8 weeks) and include rest periods. See the Canadian Guideline on OUD among older adults. - Beginning with just a 2-3% drop can build confidence and allow the person to gain insight into any anticipatory anxietyrelated pain symptoms. - Patients habituated to high-dose, long-term opioids may need longer intervals between drops in dose (e.g., 5% every 1-3 months). - Monitor the patient for withdrawal symptoms and consider withdrawal management medications such as clonidine, Imodium and NSAIDs. - A good Canadian opioid reduction guide is Centre for Effective Practice 'Opioid' Manager-Opioid Tapering Template.
# Cautions While Tapering / Discontinuing Long-Term Opioids:
- Never abruptly stop opioids with patients on chronic opioid therapy, especially if pregnant.
- Tapering (especially rapidly) can paradoxically increase the risk of overdose, OUD, and suicide if underlying pain is not well managed. Consider switching to an alternative opioid including methadone or partial agonist such as buprenorphine. - A clinician needs to differentiate between worsening or non-responsive chronic pain, and untreated or unmasked OUD. The concomitant existence of OUD and chronic pain may require a referral to an addiction's specialist, whereas worsening chronic pain should prompt an overall evaluation of the pharmacologic and non-pharmacologic strategy.
# Opioid Switching
For patients on opioids who have significant side effects or reduced effectiveness, consider switching to another opioid. See Appendix A: Medication
# Opioid Use Disorder (OUD)
Prescribing opioids for pain is associated with a risk for developing prescription opioid use disorder. 34 Despite a number of screening tools available to identify patients at increased risk, there are few validated ways to identify those who can be safely prescribed opioid analgesics. 24 This guideline is not intended to provide guidance on diagnosing and managing OUD. For full guidance, see BC Guidelines: Opioid Use Disorder and the British Columbia Centre on Substance Use (BCCSU).
Providing opioids for analgesia for patients with OUD is complex. Patients on opioid agonist therapy (OAT) may be prescribed opioids for severe acute pain but generally not for CNCP. Refer or request guidance from an addiction medicine specialist with pain experience.
- For patients already on long-acting opioids for years, consider whether they may have a prescription OUD, and, if evidence of OUD (versus increasing opioid tolerance), consider opioid agonist/partial agonist treatment (e.g., buprenorphine/naloxone or methadone).
# Cannabis
Cannabis and cannabinoid use for medical purposes can be another controversial topic. As with opioids, views and authorization practices may be influenced by media, social justice issues, personal experience and at times conflicting evidence. Complicating its use in a medical setting is the proportion of Canadians who indicated they had consumed cannabis within the last 12 months rose from 9.4% to 14.8% between 2004 and 2017, and in the year following legalization (2018-2019) that number increased to 17.5%. 35 Statistics Canada reported in 2018 that 45% of Canadians had tried cannabis at least once in the lifetime and that 50% of the people who self-reported using cannabis for medical reasons, did so for pain management.
The challenge for clinicians is weighing the evidence for medical use, managing the potential biases (including their own) from all sides of the debate, and being aware that many of their patients are and will be using it for managing pain. Be aware of simply switching one dependency (e.g. opioids) for another (e.g. cannabis) and be aware that evidence regarding cannabis use is still evolving.
The Canadian Public Health Association (CPHA) has produced Cannabasics, a document describing the basics of the plant and products but does not give treatment recommendations.
# Cannabis for Chronic Pain
Recent guidance intended for the Canadian clinician highlights that more research is needed to determine the role of cannabis in managing chronic pain. However, the Simplified Guideline for Prescribing Medical Cannabinoids in Primary Care 36 suggests that cannabinoids may be useful for chronic neuropathic pain, chemotherapy induced nausea and vomiting, and spasticity of multiple sclerosis and spinal cord injury, but not as a first line therapy.
In contrast, a recent review by the National Academies of Sciences, Engineering and Medicine found there was conclusive or substantial evidence that cannabis or cannabinoids are effective for the treatment of chronic pain in adults. 37 The Canadian National Guideline for Opioids for Chronic Non-Cancer Pain notes that nabilone may have similar effects on pain relief when compared to opioids, NSAIDs, or tricyclic antidepressants 34 (Low Quality Evidence). Evidence comparing opioids to nabilone was from a single study. 38 Saskatchewan's Rx Files: Cannabinoids Overview provides a succinct overview of medical cannabis.
A recent 2021 BMJ review offered a "weak recommendation to offer a trial of non-inhaled medical cannabis … in addition to the standard care and management (if not sufficient), for people living with cancer and non-cancer pain". The review also describes the recommendation as "weak because of the close balance between benefits and harms … for chronic pain". Harms or adverse events in some cases are described as "mostly self-limited and transient" such as drowsiness and impaired attention, but that some patients place a high value on small to very small improvements in pain and physical functioning. 39 More significant harms including risk of MI, stroke and atrial fibrillation have also been described. 40 Health effects of marijuana use is described by the Centers for Disease Control and Prevention (USA). It also warns that anxiety and depression may be aggravated and there are reports of interactions with blood thinners. 40 Absolute risk is harder to quantify and there continues to be discussion about the effects of smoking cannabis verses edible forms, and what effect the THC:CBD ratio has on harms and adverse effects.
In summary, while cannabis is now legal, consumed by many patients and may prove effective for some conditions, it is difficult to provide broader evidence informed indications for its use. More clarity is needed for specific therapeutic products and dosing schedules.
The Lower-Risk Cannabis Use Guideline 41 provides 10 recommendations of modifiable behaviours to reduce the risk of adverse effects of cannabis use, including avoiding early age initiation, using lower potency THC products, avoiding synthetic cannabinoids, and preferring non-smoking methods.
# Health care providers need to be knowledgeable and non-judgmental when informing patients about cannabis and cannabinoids.
The UBC Faculty of Medicine's Continuing Professional Development (CPD) eLearning has a free on-line module Cannabis Education for Health Care Providers as well as a Cannabis Education Toolkit.
# Pharmacological Pain Management in the Older Adult
Managing 'older adults' with pain, especially the frail older adult, often requires modifications and adjustments in both approach and dosages. Many experts suggest that age greater than 70 and/or frailty require awareness of additional factors when assessing and managing pain. Frailty is a medical syndrome with multiple causes and contributors, characterized by diminished strength and endurance and reduced physiological function, leading to increased adverse health outcomes such as functional decline and early mortality. However, frailty is not inevitable in ageing and can be prevented or reversed. For more information see BCGuidelines: Frailty in Older Adults -Early Identification and Management. Information about Healthy Aging and Preventing Frailty, can also be found in the updated provincial healthy aging strategy.
# The medication table found in Appendix A is provided for otherwise healthy adult patients. Dose adjustments for special populations (e.g., children, elderly, pregnancy, renal or hepatic dysfunction, polypharmacy) may be necessary. Please consult other resources for specific cases such as the product monograph, a pharmacist, primary literature and/or an interaction checker (e.g., Lexicomp) before prescribing.
Guiding principles when prescribing for frail/older patients: - In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - Persistent pain in frail older adults increases morbidity and poor health outcomes, making treatment a priority. - As cognition worsens, pain is less likely to be reported and may manifest as other distress behaviours (e.g., agitation, resisting care, insomnia, poor appetite). - Risk of falls is elevated. However, pain, decreased attention or poor sleep due to chronic pain can also increase the risk of falls. For more information on preventing falls see BCGuidelines: Fall Prevention: Risk Assessment and Management for Community-Dwelling Older Adults. - Multiple morbidity, cognitive impairment and altered pharmacokinetics mandate an individualized approach. Bloodwork as needed (e.g., renal function) in the initial assessment phase and intermittently if the use of medication persists. - Opioid naive patients should be started at the lowest recommended dose and titrated as needed.
- Constipation is one of the most common side effects and may need to be actively managed, starting with diet and stool softeners.
# Choices of Opioid for Frail Older Adults.
- The use of opioids is not contraindicated in frail older adults but starting doses should be at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Ongoing dosing, when needed, should be titrated slowly based on efficacy and adverse effects. Please consult product monographs for more information. - The most commonly prescribed opioids in 2018/19, in BC, in order of most to least, are codeine, hydromorphone, tramadol, morphine, and oxycodone. 25 - The analgesic activity of codeine (and to a lesser extent tramadol) is dependent on genetic polymorphisms, making them more difficult to dose adjust in patients requiring additional dose adjustments due to renal or hepatic impairment. See the cautionary note regarding Tramadol in the Opioid Therapy: Controversies of Care section above. - In addition to starting at the low end of the dosing range for hydromorphone, morphine and oxycodone for all older adults, additional dose adjustments are needed for patients with impaired hepatic or renal function. Please consult product monographs for more information. - Methadone, fentanyl, and buprenorphine are also used in managing pain, but less frequently and may require more experience or expert guidance. - Gabapentinoids may have a higher rate of side effects including respiratory depression and sedation, and therefore should be used with caution in the older adult, especially in those with reduced renal function.
# Practitioner Resources
- Pathways: An online resource that allows GPs, nurse practitioners and their office staff to quickly access current and accurate referral information for specialists and specialty clinics, including wait times and areas of expertise. In addition, Pathways makes available hundreds of patient and physician resources that are categorized and searchable. Pain Management resource video at Pathways is available at vimeo.com/528999461. - Pain BC: has several resources to support patients and caregivers, education for health professionals caring for those with pain. Some resources include Pain BC's Live Plan Be, Chronic Pain Road Map, support line. For treatment of Acute Pain: maximum duration of 7 days is recommended Use the lowest dose for the shortest duration to reduce risk of serious adverse effects (i.e., GI complications, CV events, renal toxicity)
To reduce GI complications, use a COX-2 inhibitor or add a PPI even for short term use. Studies show CV risk is similar between naproxen (≤ 750 mg/d), ibuprofen (≤1200mg/d), and celecoxib (≤ 200 mg/d) 5,6 ibuprofen Advil, Motrin, G Caps/tabs: 200, 400, 600, 800 mg Advil XR XR tabs: 600 mg Anti-inflammatory: 400-600 mg TID Low back pain: 300-600 mg TID-QID Mild-moderate pain: 200-800 mg every 6-8 hours Dysmenorrhea: 200-600 mg q6h Headache: 400-800 mg q6h x1-2 doses Gout: 800 mg TID for 5-7 days Maximum: 2400mg per day GI: dyspepsia, epigastric pain, nausea/vomiting, diarrhea, gastric and duodenal ulcers, GI bleeding. Available without a prescription: These products are Schedule 2 products which may be sold by a pharmacist on a non-prescription basis, and which must be retained within the Professional Service Area of the pharmacy where there is no public access and no opportunity for patient self-selection.
The principles of the Guidelines and Protocols Advisory Committee are to:
- encourage appropriate responses to common medical situations - recommend actions that are sufficient and efficient, neither excessive nor deficient - permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: [email protected] Website: www.BCGuidelines.ca | The intent of this guideline (Part 1 and Part 2) is to provide practical, accessible, and B.C. specific guidance. In essence, this is more of a Clinical Guidance Document and not a formal guideline. It's a distillation of many guidelines, expert recommendations, and standards of care. There are few overall pain guidelines for direct comparison. The guideline development working group members were made aware of the Appraisal of Guidelines for Research and Evaluation (AGREE) process that helped inform their appraisal of these guidelines. There is no clear or absolute clinical pathway to managing pain and many controversies persist, especially in the use of opioid and cannabis. The working group recommends reasonable clinical judgement, clear documentation, and frequent reassessment.For many patients with acute, subacute, or chronic pain, pharmacological management is part of overall care. Indeed, it is imperative to get acute pain under control early and effectively but with a clear goal of reassessing its effectiveness and presenting a well-articulated anticipated plan to taper and stop medications. The benefits of long-term medications, especially opioids, are less well understood. For longer term non-cancer pain, ensure that non-opioid and non-pharmacological therapies have been effectively optimized first. 1 The management of cancer and end-of-life pain usually requires a different strategy that may more appropriately include opioids. Managing patients with most types of pain is not necessarily an "either/or" strategy but rather a layering of interventions including non-pharmacological management, self-management, and pharmacological management.Acetaminophen Indications: Consider for initial management of patients with mild to moderate pain. 3 Use the lowest effective dose and stop therapy if minimal or no effect. Cautions: Higher doses, chronic use, increasing age, renal disfunction and alcohol use increase risk of hepatic toxicity.Indications: Consider for patients with mild to moderate musculoskeletal pain and inflammation. Use the lowest effective dose for the shortest duration to reduce adverse events and reassess effectiveness within the first few weeks.• The risk of gastrointestinal (GI) complications is unlikely, but possible, within the first week. The risk increases with longer duration of therapy. Patients at high risk of GI complications may benefit from a COX-2 inhibitor (i.e., celecoxib), and/or the addition of a proton pump inhibitors (PPI) (i.e., rabeprazole) even for short term use. • Patients at high risk or with established cardiovascular disease may be at increased risk of cardiovascular (CV) events with NSAIDs. Risk appears to be dose and duration dependent. • Contraindicated in patients with a Creatinine Clearance (CrCl ≤30 ml/min. NSAIDs may cause further deterioration in renal function in patients with mild-moderate or declining renal function, use with caution. • Older adults have a greater frequency of impaired renal function, existing electrolyte imbalances, comorbid conditions (including CV disease), and multiple medications including over the counter (OTC) products. Take a full history and assess individual patient's appropriateness for NSAIDs.Indications: There is limited evidence comparing the combination of NSAIDs and acetaminophen to opioids, with some small trials suggesting no difference in pain during dental extractions, hip and knee osteoarthritis, and acute extremity pain. 4-7 A 2020 Cochrane review found low-quality evidence comparing an NSAID and acetaminophen to opioids in acute soft tissue injuries and was uncertain of the findings of no difference in pain at day 1, 3 or 7. 8 Other small trials suggest lower opioid doses may be required after surgery when added to NSAIDs and acetaminophen. 6,7 A 2021 systematic review found NSAIDs to be associated with better pain scores at 6 and 12 hours postoperatively when compared to codeine with or without acetaminophen in outpatient surgery. 9 A 2020 Cochrane Review comparing NSAIDs and opioids in acute soft tissue injuries, found moderate quality evidence of no difference in pain at 1 hour, and low certainty evidence of no difference in pain at 4 and 7 days. 8 NSAID participants were more likely to return to function in 7-10 days and experienced less GI and neurological adverse events. 8Indications: Consider for acute conditions such as when patients have sprains, strains and overuse injuries 10 and in some chronic conditions such as osteoarthritis, particularly of the hand or knee. Re-evaluate every 3 months and continue only in responders. 10 Topical formulations with diclofenac (1-4%), ibuprofen (5-10%) or ketoprofen (1-5%) have the best evidence10 and are available OTC (diclofenac 1.16-2.32%) or through a compounding pharmacy (generally in the 5-10% range). These can be expensive and are not a PharmaCare benefit. While increased concentrations are seen in practice, they have not been studied extensively. Cautions: Systemic absorption from topical NSAIDs is low (approximately 6-23%) compared to oral forms. However, systemic adverse events have been reported. Topical NSAIDs are generally well tolerated by all patients, including those over 65 years of age.# Considerations and Controversies of Care
• Many guidelines on pain management exist, including those from national, provincial, regulatory authority, advocacy, and academic institutions. They may not all completely align, and the levels of evidence and evidence review process used to create those guidelines may appear unclear in terms of clinical decision making. However, most have a consistent framework to guide clinicians while allowing for good individualized clinical judgement. • Evidence may include large systematic reviews, randomized control trials, and expert opinion. Evidence may come from high quality studies, but the strength of the evidence may be described as poor, e.g., simply because of small study numbers. While an effect may be described as statistically significant, the magnitude of the clinical impact maybe small. • Guidelines are generally considered to be based on strong clinical evidence, yet some recommendations clearly state the evidence is weak. However, weak evidence may be the only evidence available and is intended to give the clinician an option to consider. • The number needed to treat (NNT), and the number needed to harm (NNH) are important concepts to help weigh the benefit and harm of a drug or treatment. They are used to inform a clinician about a specific condition response. However, an intervention may be used in several conditions but be more effective in one condition than another.
• Pain is a symptom and not a specific condition with clearly defined parameters like blood pressure and spirometry. Clinicians who need to treat patients with pain need information on how to do this as safely and effectively as possible for that patient. • It is important to use medications with caution for any patient who may have reduced renal, hepatic, or cardiac function.
Likewise, patients with reduced lean body mass (i.e., increased fat concentration), malnourishment (e.g., reduced albumin), concomitant disease, and multiple medications, may need dose adjustments. Consult product monographs for specific drugs and refer to Appendix A: Medication Table.
# Skeletal Muscle Relaxants
Indications: For acute musculoskeletal pain only. There is insufficient evidence to support the use of cyclobenzaprine for chronic myofascial pain. 11 Cautions: Due to the risk of long-term dependence and high incidence of adverse effects (e.g., sedation, dizziness, dry mouth), consider short term use only (1-2 weeks). Adverse effects may be more pronounced and may increase the risk of falls in frail older adults.
# Gabapentinoids 12
Indications: Consider for patients with neuropathic pain conditions such as post herpetic neuralgia or painful diabetic neuropathy. Benefits and harms can both often be seen and assessed as early as 1 week after initiation. Higher doses (gabapentin >1800 mg/d; pregabalin >300 mg/d) may not provide significant additional benefit relative to the increased risk of adverse events. 12 A good summary of gabapentinoids is provided by the B.C. Provincial Academic Detailing Service.
Cautions: Due to the risk of severe respiratory depression and sedation, use with caution when combined with opioids and/or other central nervous system (CNS) depressants. 13 Adverse effects (e.g. drowsiness, dizziness, etc.,) may be more pronounced and may increase risk of falls in frail older adults. Gabapentinoids have been identified as drugs of potential misuse. 14 These drugs are renally excreted, therefore use with caution in patients with renal impairment.
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) Indications: Consider for patients with neuropathic pain conditions (e.g. diabetic neuralgia, post herpetic neuralgia). Duloxetine has a larger evidence base for the treatment of neuropathic pain than venlafaxine. [15][16][17] Benefits and harms can often be seen and assessed within 1 week. Higher doses (e.g. duloxetine >60 mg/d) do not produce better analgesia. SNRIs are better tolerated than tricyclic antidepressants (TCAs) in frail older adults. 18 Tricyclic Antidepressants (TCAs) Indications: Low quality evidence suggests TCAs may result in a 30% reduction in pain for some patients.
TCAs do not appear to be more effective than placebo in chronic low-back pain. There is a lack of evidence to evaluate the role of TCAs in fibromyalgia. 19 Cautions: Due to high incidence of anticholinergic side effects (e.g., drowsiness, dry mouth, and constipation), consider alternatives in frail older adults. If a TCA is indicated, start with low doses and consider nortriptyline as it may have fewer anticholinergic effects and is often better tolerated.
# Opioid Therapy
This section provides guidance for managing patients who are both opioid-naïve and those already on long-term opioid therapy. Indications for tapering and cessation of opioids are also included.
# Controversies of Care
The use of opioids is one of the more controversial issues for many clinicians.
• There are national guidelines as well as regulatory authority directives that give clear guidance about the use of opioids.
To some clinicians, these appear excessively harsh and restrictive while others may appreciate the specificity of the guidance. Some clinicians are concerned about disciplinary action if they prescribe opioids or exceed the recommended daily maximum. • Virtually all guidelines distinguish between non-cancer and palliative end-of-life care, yet some clinicians fail to properly consider that distinction and restrict appropriate comfort measures. • The 2017 Canadian Guideline for Opioids for Non-Cancer Pain (McMaster Michael G. DeGroote National Pain Centre) is the current standard, yet a follow-up review of those guidelines by the main author suggests that 1/3 of clinicians mistakenly believed the guideline suggested mandatory tapering and that 2/3 of respondents highlighted resistance by patients and lack of access to effective non-opioid treatment. 20 • A 2018 review by the same author looking at 96 clinical trials, concluded "use of opioids was associated with significantly less pain and significantly improved physical functioning…but the magnitude of the association was small". The mean follow up period of the studies was 60 days. 21 • As mentioned in the 2017 Canadian Medical Association Journal (CMAJ) article "No guideline can account for the unique features of patients and their clinical circumstances, and the new (2017) guideline is not meant to replace clinical judgement. Patients, prescribers and other stakeholders, including regulators and insurers, should not view its recommendations as absolute". 22 • Consensual tapers may lead to improved or at least no worse pain management (though in a significant minority of patients this might not be the case), while forced tapers may increase risk of opioid use disorder (OUD), overdose, and suicide. 23 • The 2017 National Pain Centre Guidelines that describe maximum daily doses, also suggest that some patients may benefit from higher doses. • Clinicians may hesitate or avoid prescribing opioids to elderly patients, but age alone is not a reason to avoid opioids.
Considerations for safely prescribing opioids for the elderly are described below. • There are several screening tools available to identify the risk of developing OUD when initiating opioids, but evidence suggests these may not help identify those at low risk. Only the absence of a mood disorder was associated with low risk. Previous OUD, certain mental health conditions (e.g. personality disorder), and the use of certain psychiatric medications such as atypical anti-psychotics were associated with high risk of developing OUD. 24 • The most commonly prescribed opioids in 2018/19, in BC, in order of most to least, are codeine, hydromorphone, tramadol, morphine, and oxycodone. 25 However, the analgesic activity of codeine (and to a lesser extent tramadol) is dependent on genetic polymorphisms, making them more difficult to dose adjust in patients requiring additional dose adjustments due to renal or hepatic impairment. • TRAMADOL: There is a perception that tramadol is a safer opioid as it was not historically considered a Schedule 1 narcotic.
However, effective March 31, 2022, Health Canada has added tramadol to the Controlled Drugs and Substances Act to reflect the fact it is an opioid with the same risks as others. 26 Tramadol's analgesic activity, much like codeine, is dependent on CYP2D6 metabolism which is altered in approximately 28% of patients. 27 In addition, tramadol acts as a serotonin and norepinephrine reuptake inhibitor (SNRI), increasing the risk of drug interactions and side effects (including serotonin syndrome and seizures) over that of other opioids. 28
# Considerations for Initiation of Opioid Therapy for Opioid-Naïve Patients
Indications for Opioid Medications:
• Moderate to severe acute pain (e.g., post-operative, injuries) expected to resolve.
• Palliative and life-limiting conditions (e.g., end-stage heart failure, chronic obstructive pulmonary disease (COPD), cancers) -for these situations, refer to Palliative Care Guideline as the benefits and risks are different in these patients who will need longer and likely escalating doses. Palliative care patients should never be denied opioid medications when required.
Despite previous practice, there is limited or weak evidence for the value of initiating opioids for patients with chronic non cancer pain (CNCP). In many instances, the risks of prescription OUD or adverse effects outweigh the potential benefits. The long-term use of opioids for managing pain has a potentially higher risk of harm and has limited evidence for benefit. A classic example of this type is a young patient with gradually worsening degenerative back or joint pain.
# Prescribing Considerations:
• The initiation of an opioid should always be considered as a "therapeutic trial". Document well the initial discussion and rationale for use of opioids. Encourage patients to self-limit where possible. • Limit prescriptions. Consider a trial for 7 days or less at a time. Increase interval as patient stabilizes on a dose that does not compromise function. An oral dose of morphine 5-10 mg, or hydromorphone 1-2 mg are common adult starting doses, especially in the immediate post-op period. • Start patients, especially those who are opioid naïve, on lowest effective dose and titrate as needed with close monitoring of efficacy and side effects. A particularly useful tool is: Centre for Effective Practice 'Opioid Manager' . The Opioid Manager is a practical tool and checklist for opioid prescribing decisions including opioid therapy trials, maintenance, monitoring, switching, and tapering. Other tools include the Opioid Risk Tool, Current Opioid Misuse Measure (COMM)™.
Opioids are a potent and useful class of medications for the treatment of pain and endof-life symptoms when used appropriately. However, while supporting the patient with pain management, clinicians need to be aware of appropriate prescribing guidelines to mitigate the risks of opioid harms and dependence.
• Consider and minimise drug interactions (e.g., CNS depressants, serotonin concerns with tramadol). See Appendix A: Medication Table for specific drug interactions. • Be aware of the College of Physician and Surgeons of BC (CPSBC) Safe Prescribing Standards. The CPSBC also has a list of prescribing tools and resources on their website. • Fully inform patients of the risks and benefits of using opioids and discuss plans for the possible tapering and/or discontinuation of the medication. Document this discussion. • A patient handout is encouraged.
• Common side effects such as drowsiness and nausea often improve while constipation tends to persist and needs to be actively managed with diet, stool softeners and/or laxatives. • Frail older adults with moderate to severe pain and functional impairment or poor quality of life should not be excluded from consideration of opioid therapy. See Pharmacological Pain Management in the Older Adult below. • Patients on long-term opioids at stable doses (often referred to as legacy patients) may not be able to taper down to the recommended doses, but that doesn't preclude a conversation about their use and the potential to taper down to a lower dose. • An additional resource is a detailed review on Opioid Metabolism by Howard Smith. 29 • For B.C. specific information and coverage, see Appendix A: Medication Table.
# Contraindications and Cautions
# Absolute Contraindications
Relative Contraindications If considering prescribing opioids, assess for active and past substance use disorder (SUD) (including alcohol, opioids, marijuana) and psychiatric disorders. The presence of these disorders is not a reason to not prescribe but suggest a need to proceed with caution and to have a clear discussion with patient about risks. Indeed, the presence of any SUD is not an absolute contraindication to prescribe opioids, though it does increase risk of overdose and addiction to opioids. Thus, more safeguards, including enhanced monitoring, need to be put in place and clear documentation of risks and benefits for that particular patient outlined.
# Use with Caution
• Concurrent use with CYP3A4 inhibitors/inducers (e.g., clarithromycin, diltiazem, "azoles" such as ketoconazole, certain ARV's such as ritonavir, phenobarbital, and phenytoin). See Appendix A: Medication Table . • Codeine is metabolized by CYP2D6 to its active form, morphine. Up to 23% of the population may produce significantly more or less morphine than expected based on the dose. 30 Monitor for increased side effects, decreased efficacy or select alternative drug. • Concurrent use of potentially sedating medications such as gabapentinoids 13 cyclobenzaprine, diphenhydramine and dimenhydrate. • Hepatic and renal impairment may change the pharmacokinetics of medications, reducing elimination and increasing availability of that drug. • Use of alcohol with opioids should be actively discouraged.
• When patients have co-existing mental health conditions such as mood or thought disorders, consider the extent to which they may be exacerbating or coexisting with the pain. Use caution when considering an opioid and reflect on the concomitant need to manage the mental health condition as well. The Canadian National Guideline for Opioids for Chronic Non-Cancer Pain recommends stabilizing an active psychiatric disorder before initiating a trial of opioids (weak recommendation).
# Pandemic Considerations.
During the COVID-19 pandemic and concurrent opioid overdose epidemic, consideration may be needed to reduce the risk of harm from both. In an effort to reduce the spread of COVID-19, the BCCSU Risk Mitigation in the context of dual public health emergencies interim guidance document outlines many related changes in prescribing policy. There are provincial policy changes that reduce risk of exposure such as phone orders and transferring scripts between pharmacies. Longer prescriptions and potentially delaying or slowing tapers may also be strategies to avoid destabilizing already vulnerable patients.
# Considerations for Patients Already on Opioid Therapy
Most primary care practitioners see patients who are already on long-term opioid therapy for chronic pain, regardless of initial indications. These considerations apply whether the patients are long established or new to the practice. Again, it is not appropriate to refuse to accept or continue to care for patients on opioids and it is not appropriate to abruptly stop prescribing.
# Indications for Long-term Use of Opioid Medications:
• Palliative care and end-of-life conditions.
• Conditions not expected to improve and not well managed with non-opioid medications. Some examples may include worsening scoliosis, degenerative disc disease or vertebral fractures not amenable to other interventions. • Some patients with chronic pain already on opioids may be stable and functional with minimal disability and side effects.
Maintaining them on opioids may be appropriate and indicated. A forced taper may worsen pain and reduce stability.
# Ongoing Management
• Reassess regularly to ensure that non-opioid and non-pharmacological therapies have been maximized. Document the reassessment. • Self-Reflection: "If you are feeling pressured to prescribe opioids, ask yourself where this pressure is coming from and how you might respond". • There is not a defined target morphine equivalent daily dose (MEDD), but clinicians should prescribe the lowest effective dose.
• The CPSBC Safe Prescribing Standards, suggests that doses above 90 MEDD require "substantive evidence of exceptional need and benefit". The standards do not say that higher doses cannot or should not be prescribed, just that the evidence and need for a higher dose must be documented. In addition, the guidelines do not suggest mandatory tapering. 20,31 Clinical examples may include patients with severe pain for which higher doses of opioids are needed and patients who present with existing prescription doses which exceed 90 MEDD for whom abrupt tapering or cessation would cause harm. Documentation is critical. • Consider using long-acting opioids after stabilizing the patient on immediate release opioid. Even in this situation, be aware that there is poor evidence supporting long-term use of opioids and discuss and document the risk of long-acting opioids in advance. • For anticipated longer term prescriptions, a written treatment agreement is encouraged. Sample agreement available at CPSBC Prescribing tools and resources. • Divergence from the treatment agreement may suggest a need to re-evaluate the clinical situation and consider the biopsychosocial stressors that may be present. Agreements are not meant to be punitive so it does not necessarily indicate that opioids must be tapered or stopped. Breach of agreements should not be used as a method to justify termination of opioid therapy, nor should they be used to support discharging a patient from a practice. Instead, they should be used to support opening a conversation about appropriate and safe opioid use. Consider discussion with an addiction medicine specialist or pain specialist with experience in addictions. • However, if there is clear evidence of prescription forgery or confirmed diversion (with a supportive urine drug test (UDT), you no longer have an obligation to prescribe. • All patients on opioids for chronic pain could be considered for random UDT. However, there is uncertain evidence about the effect of urine drug screening on the risk of opioid overdose. 1 A urine drug test may be used in the context of patient education and safety to identify additional drugs (sometimes taken unknowingly) that may put patients at higher risk. Absence of the prescribed opioid in random urine testing should be a red flag for possible diversion. A respectful discussion of results may be useful before any action is taken. Refer to BCCSU's Opioid Use Disorder. See Urine Drug Testing for more information, but please note this is a document specific to the use of UDT in the management of OUD.
• Ideally, patients should be prescribed opioids by their primary care provider only. Where possible, only one consistent provider or team should be providing the prescriptions. However, the current reality in B.C. is that some patients may see multiple providers; therefore, make good use of documentation and electronic medical record (EMR) functions including ready access to patient agreements, current medications and any "cautions" or "flags" that are attached. • PharmaNet provides an up-to-date list of filled prescriptions and should be used prior to every opioid prescription and refill.
CareConnect provides recent clinical encounters including ER visits and prescriptions written. • Consider blister-packs and controlled dispensing strategies if there is concern about use other than prescribed.
• Consider offering a naloxone kit and education to patient and family on how to administer and respond to overdose. Refer to towardtheheart.com produced by the BC Centre for Disease Control (BCCDC) for naloxone kit guidance. • For safety of children, pets and opioid-naïve adults and prevention of theft, educate patients on safe storage and disposal of opioid medications. • Reassess regularly and be vigilant for incipient or existing prescription OUD (e.g., escalating dosages, increasing pain complaints, multi-doctoring). Ask about alternate routes of use, including snorting, chewing, smoking, or injecting.
# When to Taper and/or Stop Opioids
• For patients prescribed opioids for short-term, acute pain (e.g., post-operative or injuries), recommend a tapering and discontinuation plan including dosage, frequency and duration. Confirm the follow-up plan with the patient. • Opioid tapering and discontinuation may be difficult for the patient who fears worsening of the pain and withdrawal symptoms. Patients should be actively engaged in a discussion about the merits of gradual dose reduction, including the potential for equivalent or better pain control with less opioid-associated risks (e.g., reduced risk of myocardial infarction [MI], motor vehicle accident (MVA), sleep apnea, sexual dysfunction, falls, depression, addiction, unintended overdose). However, a percentage of people will not experience these benefits and the taper may not be appropriate. • Comments such as 'I think we can work towards giving you just as much pain control with less medication risks' are a good start to conversations about the possibility of a dose reduction.
Indications for Tapering and/or Stopping When there is a loss of therapeutic effect on pain and function.
When there are intolerable side effects such as sedation. Patient request. When there is non-adherence to the agreed plan or clear evidence of diversion. This is considered a breach of the opioid agreement and mitigation steps need to be taken such as daily witnessed dispensing or lowering the dose. With evidence of diversion and a supportive UDT confirming none of the prescribed opioid present, then you have no obligation to continue prescribing. When clear evidence of OUD is present or worsening it is appropriate to refer to addiction specialist instead of attempting to taper. • Many guidelines suggest that a taper be considered for patients whose MEDD is above 90. This is not a strict limit and clinical judgement is always warranted. This does not apply to cancer/palliative patients. • Patients on long-term opioids at stable doses may not be able to taper down to the recommended dose range. Again, it is never inappropriate to have a conversation about the continued use of these medications and the potential to slowly taper down to a lower dose. • Opioid-induced hyperalgesia is an adverse effect that is characterized by decreasing efficacy that is not improved by increasing the dose of the opioid. 32 It is dose dependent and worse at higher doses but occurs at any opioid dose in patients with chronic non-cancer pain. 33 Symptoms include spreading or burning pain and allodynia (i.e. pain due to a stimulus such as light touch that does not usually provoke pain). It may also be accompanied by other signs of opioid toxicity such as myoclonus, delirium, and seizures. Symptoms improve by reducing or eliminating the drug. Consider opioid rotation in cases of opioid toxicity. See Opioid Switching section below.
# Tapering Strategies
There is no evidence for any specific tapering strategy. However, a commonly described strategy is:
• A reduction of 5-10% of the daily dose.
• A dose reduction every 2-4 weeks.
• Tapering in the older adult may be slower (e.g., 5% every 2-8 weeks) and include rest periods. See the Canadian Guideline on OUD among older adults. • Beginning with just a 2-3% drop can build confidence and allow the person to gain insight into any anticipatory anxietyrelated pain symptoms. • Patients habituated to high-dose, long-term opioids may need longer intervals between drops in dose (e.g., 5% every 1-3 months). • Monitor the patient for withdrawal symptoms and consider withdrawal management medications such as clonidine, Imodium and NSAIDs. • A good Canadian opioid reduction guide is Centre for Effective Practice 'Opioid' Manager-Opioid Tapering Template.
# Cautions While Tapering / Discontinuing Long-Term Opioids:
• Never abruptly stop opioids with patients on chronic opioid therapy, especially if pregnant.
• Tapering (especially rapidly) can paradoxically increase the risk of overdose, OUD, and suicide if underlying pain is not well managed. Consider switching to an alternative opioid including methadone or partial agonist such as buprenorphine. • A clinician needs to differentiate between worsening or non-responsive chronic pain, and untreated or unmasked OUD. The concomitant existence of OUD and chronic pain may require a referral to an addiction's specialist, whereas worsening chronic pain should prompt an overall evaluation of the pharmacologic and non-pharmacologic strategy.
# Opioid Switching
For patients on opioids who have significant side effects or reduced effectiveness, consider switching to another opioid. See Appendix A: Medication
# Opioid Use Disorder (OUD)
Prescribing opioids for pain is associated with a risk for developing prescription opioid use disorder. 34 Despite a number of screening tools available to identify patients at increased risk, there are few validated ways to identify those who can be safely prescribed opioid analgesics. 24 This guideline is not intended to provide guidance on diagnosing and managing OUD. For full guidance, see BC Guidelines: Opioid Use Disorder and the British Columbia Centre on Substance Use (BCCSU).
Providing opioids for analgesia for patients with OUD is complex. Patients on opioid agonist therapy (OAT) may be prescribed opioids for severe acute pain but generally not for CNCP. Refer or request guidance from an addiction medicine specialist with pain experience.
• For patients already on long-acting opioids for years, consider whether they may have a prescription OUD, and, if evidence of OUD (versus increasing opioid tolerance), consider opioid agonist/partial agonist treatment (e.g., buprenorphine/naloxone or methadone).
# Cannabis
Cannabis and cannabinoid use for medical purposes can be another controversial topic. As with opioids, views and authorization practices may be influenced by media, social justice issues, personal experience and at times conflicting evidence. Complicating its use in a medical setting is the proportion of Canadians who indicated they had consumed cannabis within the last 12 months rose from 9.4% to 14.8% between 2004 and 2017, and in the year following legalization (2018-2019) that number increased to 17.5%. 35 Statistics Canada reported in 2018 that 45% of Canadians had tried cannabis at least once in the lifetime and that 50% of the people who self-reported using cannabis for medical reasons, did so for pain management.
The challenge for clinicians is weighing the evidence for medical use, managing the potential biases (including their own) from all sides of the debate, and being aware that many of their patients are and will be using it for managing pain. Be aware of simply switching one dependency (e.g. opioids) for another (e.g. cannabis) and be aware that evidence regarding cannabis use is still evolving.
The Canadian Public Health Association (CPHA) has produced Cannabasics, a document describing the basics of the plant and products but does not give treatment recommendations.
# Cannabis for Chronic Pain
Recent guidance intended for the Canadian clinician highlights that more research is needed to determine the role of cannabis in managing chronic pain. However, the Simplified Guideline for Prescribing Medical Cannabinoids in Primary Care 36 suggests that cannabinoids may be useful for chronic neuropathic pain, chemotherapy induced nausea and vomiting, and spasticity of multiple sclerosis and spinal cord injury, but not as a first line therapy.
In contrast, a recent review by the National Academies of Sciences, Engineering and Medicine found there was conclusive or substantial evidence that cannabis or cannabinoids are effective for the treatment of chronic pain in adults. 37 The Canadian National Guideline for Opioids for Chronic Non-Cancer Pain notes that nabilone may have similar effects on pain relief when compared to opioids, NSAIDs, or tricyclic antidepressants 34 (Low Quality Evidence). Evidence comparing opioids to nabilone was from a single study. 38 Saskatchewan's Rx Files: Cannabinoids Overview provides a succinct overview of medical cannabis.
A recent 2021 BMJ review offered a "weak recommendation to offer a trial of non-inhaled medical cannabis … in addition to the standard care and management (if not sufficient), for people living with cancer and non-cancer pain". The review also describes the recommendation as "weak because of the close balance between benefits and harms … for chronic pain". Harms or adverse events in some cases are described as "mostly self-limited and transient" such as drowsiness and impaired attention, but that some patients place a high value on small to very small improvements in pain and physical functioning. 39 More significant harms including risk of MI, stroke and atrial fibrillation have also been described. 40 Health effects of marijuana use is described by the Centers for Disease Control and Prevention (USA). It also warns that anxiety and depression may be aggravated and there are reports of interactions with blood thinners. 40 Absolute risk is harder to quantify and there continues to be discussion about the effects of smoking cannabis verses edible forms, and what effect the THC:CBD ratio has on harms and adverse effects.
In summary, while cannabis is now legal, consumed by many patients and may prove effective for some conditions, it is difficult to provide broader evidence informed indications for its use. More clarity is needed for specific therapeutic products and dosing schedules.
The Lower-Risk Cannabis Use Guideline 41 provides 10 recommendations of modifiable behaviours to reduce the risk of adverse effects of cannabis use, including avoiding early age initiation, using lower potency THC products, avoiding synthetic cannabinoids, and preferring non-smoking methods.
# Health care providers need to be knowledgeable and non-judgmental when informing patients about cannabis and cannabinoids.
The UBC Faculty of Medicine's Continuing Professional Development (CPD) eLearning has a free on-line module Cannabis Education for Health Care Providers as well as a Cannabis Education Toolkit.
# Pharmacological Pain Management in the Older Adult
Managing 'older adults' with pain, especially the frail older adult, often requires modifications and adjustments in both approach and dosages. Many experts suggest that age greater than 70 and/or frailty require awareness of additional factors when assessing and managing pain. Frailty is a medical syndrome with multiple causes and contributors, characterized by diminished strength and endurance and reduced physiological function, leading to increased adverse health outcomes such as functional decline and early mortality. However, frailty is not inevitable in ageing and can be prevented or reversed. For more information see BCGuidelines: Frailty in Older Adults -Early Identification and Management. Information about Healthy Aging and Preventing Frailty, can also be found in the updated provincial healthy aging strategy.
# The medication table found in Appendix A is provided for otherwise healthy adult patients. Dose adjustments for special populations (e.g., children, elderly, pregnancy, renal or hepatic dysfunction, polypharmacy) may be necessary. Please consult other resources for specific cases such as the product monograph, a pharmacist, primary literature and/or an interaction checker (e.g., Lexicomp) before prescribing.
Guiding principles when prescribing for frail/older patients: • In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. • Persistent pain in frail older adults increases morbidity and poor health outcomes, making treatment a priority. • As cognition worsens, pain is less likely to be reported and may manifest as other distress behaviours (e.g., agitation, resisting care, insomnia, poor appetite). • Risk of falls is elevated. However, pain, decreased attention or poor sleep due to chronic pain can also increase the risk of falls. For more information on preventing falls see BCGuidelines: Fall Prevention: Risk Assessment and Management for Community-Dwelling Older Adults. • Multiple morbidity, cognitive impairment and altered pharmacokinetics mandate an individualized approach. Bloodwork as needed (e.g., renal function) in the initial assessment phase and intermittently if the use of medication persists. • Opioid naive patients should be started at the lowest recommended dose and titrated as needed.
• Constipation is one of the most common side effects and may need to be actively managed, starting with diet and stool softeners.
# Choices of Opioid for Frail Older Adults.
• The use of opioids is not contraindicated in frail older adults but starting doses should be at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Ongoing dosing, when needed, should be titrated slowly based on efficacy and adverse effects. Please consult product monographs for more information. • The most commonly prescribed opioids in 2018/19, in BC, in order of most to least, are codeine, hydromorphone, tramadol, morphine, and oxycodone. 25 • The analgesic activity of codeine (and to a lesser extent tramadol) is dependent on genetic polymorphisms, making them more difficult to dose adjust in patients requiring additional dose adjustments due to renal or hepatic impairment. See the cautionary note regarding Tramadol in the Opioid Therapy: Controversies of Care section above. • In addition to starting at the low end of the dosing range for hydromorphone, morphine and oxycodone for all older adults, additional dose adjustments are needed for patients with impaired hepatic or renal function. Please consult product monographs for more information. • Methadone, fentanyl, and buprenorphine are also used in managing pain, but less frequently and may require more experience or expert guidance. • Gabapentinoids may have a higher rate of side effects including respiratory depression and sedation, and therefore should be used with caution in the older adult, especially in those with reduced renal function.
# Practitioner Resources
• Pathways: An online resource that allows GPs, nurse practitioners and their office staff to quickly access current and accurate referral information for specialists and specialty clinics, including wait times and areas of expertise. In addition, Pathways makes available hundreds of patient and physician resources that are categorized and searchable. Pain Management resource video at Pathways is available at vimeo.com/528999461. • Pain BC: has several resources to support patients and caregivers, education for health professionals caring for those with pain. Some resources include Pain BC's Live Plan Be, Chronic Pain Road Map, support line. For treatment of Acute Pain: maximum duration of 7 days is recommended Use the lowest dose for the shortest duration to reduce risk of serious adverse effects (i.e., GI complications, CV events, renal toxicity)
To reduce GI complications, use a COX-2 inhibitor or add a PPI even for short term use. Studies show CV risk is similar between naproxen (≤ 750 mg/d), ibuprofen (≤1200mg/d), and celecoxib (≤ 200 mg/d) 5,6 ibuprofen Advil, Motrin, G Caps/tabs: 200, 400, 600, 800 mg Advil XR XR tabs: 600 mg Anti-inflammatory: 400-600 mg TID Low back pain: 300-600 mg TID-QID Mild-moderate pain: 200-800 mg every 6-8 hours Dysmenorrhea: 200-600 mg q6h Headache: 400-800 mg q6h x1-2 doses Gout: 800 mg TID for 5-7 days Maximum: 2400mg per day GI: dyspepsia, epigastric pain, nausea/vomiting, diarrhea, gastric and duodenal ulcers, GI bleeding. Available without a prescription: These products are Schedule 2 products which may be sold by a pharmacist on a non-prescription basis, and which must be retained within the Professional Service Area of the pharmacy where there is no public access and no opportunity for patient self-selection.
#
The principles of the Guidelines and Protocols Advisory Committee are to:
• encourage appropriate responses to common medical situations • recommend actions that are sufficient and efficient, neither excessive nor deficient • permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: [email protected] Website: www.BCGuidelines.ca
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This guideline is based on scientific evidence current as of the effective date.
The guideline was developed by the Guidelines and Protocols Advisory Committee and adopted by the Medical Services Commission.
For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook.
Appendix A: Medication Table [1][2][3][4] This drug list includes examples of treatment options (commonly used drugs and/or a PharmaCare benefit) and is not a comprehensive list.
Information in this table is provided for otherwise healthy adult patients. Dose adjustments for special populations (e.g. children, elderly, pregnancy, renal or hepatic dysfunction, polypharmacy) may be necessary. Please consult other resources for specific cases such as the product monograph, a pharmacist, primary literature and/or an interaction checker (e.g., Lexicomp) before prescribing. | None | None |
843b9294e1722908833b6110a3bba586b8838185 | cma | None | On June 29, 2022, NACI published interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada. The statement outlined recommendations for booster doses in specific populations ahead of the uncertain trajectory of the COVID-19 pandemic in the coming months. Since that time: On September 1 2022, Health Canada authorized the use of Moderna Spikevax Bivalent (50 mcg) COVID-19 vaccine as a booster dose in adults ≥18 years of age. The Moderna Spikevax Bivalent (50 mcg) COVID-19 vaccine is the first bivalent Omicron BA.1containing mRNA COVID-19 vaccine authorized for use in Canada. The epidemiology of COVID-19 continues to change and there is still considerable uncertainty with regard to the likelihood, timing, and severity of any potential future COVID-19 waves. It is possible that, consistent with other respiratory viruses, the incidence of COVID-19 may increase in the later fall and winter seasons and that new variants of concern (VOCs) may emerge. The emergence of Omicron subvariants BA.4 and BA.5 have led to a resurgence in COVID-19 cases nationally, and these subvariants currently make up the majority of new COVID-19 cases in Canada (previous Omicron subvariants, including Omicron BA.1 make up <5% of new COVID-19 cases in Canada). Nationally, indicators of disease severity, including hospitalizations and deaths, have also increased during the summer wave (1) . Although Omicron and its subvariants have largely been associated with less severe illness compared to previous VOCs, the severity of Omicron subvariants BA.4 and BA.5 in comparison to other Omicron subvariants is currently unclear and data are still emerging at this time (2)(3)(4) . The Omicron variant has demonstrated it is partially evasive of immunity conferred by original COVID-19 vaccines or by a previous infection with a SARS-CoV-2 variant that emerged prior to Omicron. The immune evasion exhibited by Omicron subvariants BA.4 and BA.5 may be greater than that exhibited by previous Omicron subvariants, although evidence is still emerging at this time. Available evidence to date suggests three doses of an authorized, original mRNA COVID-19 vaccine continues to provide strong and sustained protection against severe outcomes from COVID-19. While the proportion of Canadians vaccinated with a primary series is high, the proportion who have received at least one additional dose has plateaued at a much lower level, especially in younger age groups. NACI continues to recommend a primary series with an authorized mRNA vaccine in all authorized age groups. NACI has also provided recommendations for a booster dose with an authorized COVID-19 vaccine for all adults, adolescents, and children 5 to 11 years of age. Immunization of those who are eligible for vaccination but have n ot yet received their recommended doses (primary or booster) remains a top priority in Canada. As with previous COVID-19 booster programs, a fall booster dose with any authorized COVID-19 vaccine will be most important for older adults and other populations at increased risk of severe COVID-19 disease, regardless of the number of booster doses previously received.# PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in -depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict o f interest. 4 | RECOMMENDATIONS ON THE USE OF BIVALENT OMICRON-CONTAINING MRNA COVID-19 VACCINES NACI continues to monitor the rapidly evolving scientific data while recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed. NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were updated on February 14, 2022: To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19
# METHODS
NACI's recommendations on booster doses are based on the decision-making framework outlined in the published statement Interim guidance on booster COVID-19 vaccine doses in Canada. This framework has been updated with evolving evidence (e.g., including considerations of population level cumulative immunity and vaccine coverage) as outlined in the published statement Interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada. Recommendations are based on evidence of the need for (e.g., increased risk of severe illness from COVID-19 and/or increased risk of decreased protection, and waning protection due to increased time since last dose or infection) and benefit of (e.g., safety and effectiveness) booster doses in the Canadian context.
On August 18, 2022, NACI reviewed available evidence on the burden of illness in the Canadian population, as well as booster dose acceptability in the Canadian population. NACI also reviewed the available evidence on the use of the Moderna Spikevax Bivalen t COVID-19 vaccine in adults ≥18 years of age (including manufacturer's clinical data in the regulatory submission to Health Canada and published scientific literature). Additionally, NACI reviewed evidence of post-market safety on mRNA vaccines pertaining to myocarditis and/or pericarditis. For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to NACI's: Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
Further information on NACI's process and procedures is available elsewhere (5,6) . driven primarily by the Omicron BA.4 and BA.5 subvariants. Although signs of stabilization are being observed, significant regional variability remains, and test positivity remains elevated compared to historical trends. It is also possible that, consistent with other respiratory viruses, the incidence of COVID-19 will increase again in the later fall and winter seasons, thus posing a risk for individuals/communities and increasing pressure on health systems. For the most up-to-date epidemiology of COVID-19 in Canada, please refer to the Government of Canada's COVID-19 daily epidemiology update. Indicators of disease severity (i.e., hospitalizations and intensive care unit admissions) increased during the summer wave; however, signs of stabilization are being observed. The incidence of severe outcomes remains significantly higher in adults ≥80 years of age compared to younger age groups, and hospitalization rates in this age group are higher than pandemic averages. Even though Omicron and its subvariants have largely been associated with a smaller proportion of severe disease compared to the previous variants, there is still uncertainty regarding the disease severity of Omicron BA.4/BA.5 relative to previous Omicron subvariants. In addition, the surge in SARS-CoV-2 infections caused in part by the increased transmissibility of Omicron BA.4/BA.5, has had a substantial impact on health system infrastructure. NACI continues to monitor emerging data on additional Omicron subvariants of interest, such as BA.2.75. To date, there have been only a very small number of Omicron BA.2.75 sequences detected in Canada.
# Hybrid immunity & seroprevalence
- Available evidence to date shows that hybrid immunity (i.e., protection conferred from both vaccination and infection) is more robust than immunity due to infection or vaccination alone. However, the duration of protection from hybrid immunity has yet to be fully characterized, and evidence is still emerging with regard to hybrid immunity and protection against Omicron subvariants BA.4 and BA.5, the current predominately circulating variants in Canada. In fully-vaccinated individuals, a previous SARS-CoV-2 infection with the Omicron VOC confers significant protection from reinfection with Omicron BA.4 and/or BA.5, although the durability of this protection has yet to be established (3,4,(7)(8)(9)(10) . However, preliminary evidence also suggests that in fully-vaccinated individuals, protection against reinfection is lower against Omicron BA.5, compared to earlier Omicron subvariants (i.e., BA.2), highlighting the potential immune-escape capability of Omicron BA.5. Emerging Canadian evidence suggests that a large proportion of older adults are protected by vaccination, but may not have acquired hybrid immunity. In Canada, older adults have higher vaccination rates (both with a primary series and with additional doses) compared to younger adults (11) , and according to recent seroprevalence data, are less likely to have been infected during the Omicron wave compared to younger adults and adolescents (12) . It is expected that individuals who have been infected with SARS-CoV-2 may optimize their benefit from future vaccine doses by timing them according to the interval since infection, using similar immunological principles to those informing intervals between vaccine doses. Emerging evidence indicates that a longer interval between SARS-CoV-2 infection and vaccination is associated with improved immune responses to COVID-19 vaccines (13,14) .
Vaccine effectiveness of original COVID-19 booster vaccines Evidence has shown a reduced vaccine effectiveness (VE) of currently-available COVID-19 vaccines against Omicron compared to the effectiveness observed with previous VOCs. VE against Omicron infection after a first booster dose of an original mRNA COVID-19 vaccine is approximately 60% shortly after receipt of the booster dose, an d decreases over time in most studies (15)(16)(17)(18)(19)(20)(21)(22) . However, current data suggest that original mRNA COVID-19 vaccines continue to provide significant protection against hospitalization and severe disease. Initial VE against severe disease is approximately 90% following a first booster dose, and remains above 75% up to 26 weeks from the first booster in most studies (23)(24)(25)(26)(27) ; duration of protection against severe disease is not yet known. Evidence on VE of a second COVID-19 booster dose is currently limited. Recent data from the US have shown that during a period of Omicron BA.2 dominance, among adults at least 50 years of age, a second booster dose of an original mRNA COVID-19 vaccine provided additional protection against emergency department and/or urgent care visits due to COVID-19, as well as hospitalization, compared to those who received one booster dose of an original mRNA COVID-19 vaccine (23) . VE studies from Canada and Israel have also demonstrated additional protection compared to a first booster, inclu ding against severe disease (28)(29)(30)(31)(32) . However, the duration of this increased protection from a second booster dose is currently unknown. (33) showed that Moderna Spikevax Bivalent (50 mcg) administered as a second booster dose to individuals ≥18 years of age had a similar reactogenicity profile to that of Moderna Spikevax original (50 mcg) given as a second booster dose. Also, the frequency of adverse events following Moderna Spikevax Bivalent (50 mcg) given as a second booster dose was similar or lower compared to that of a first booster dose of Moderna Spikevax original (50 mcg), and of the second dose of the Moderna Spikevax original primary series (100 mcg). There were no vaccine-related cases of myocarditis,
# Potential benefits of bivalent vaccines
- Omicron and its subvariants are antigenically distinct from the original SARS-CoV-2 virus, as well as earlier SARS-CoV-2 VOCs, with BA.1 emerging as one of the most antigenically distinct subvariants (34) . Given the potential for substantial virus evolution and uncertainty about the emergence of future variants, modification of the strain composition of COVID-19 vaccines may broaden immune protection against divergent SARS-CoV-2 spike protein antigens. Available data, including clinical data on immune responses against BA.4 and BA.5 with a BA.1-targeted, bivalent mRNA vaccine, suggest that inclusion of Omicron in an updated booster vaccine composition may have immediate benefits in the form of increased protection against variants such as Omicron BA.4 and BA.5 (35) . The BA.1targeted, bivalent mRNA vaccines may also elicit a greater breadth of immune response, potentially providing additional protection against future variants of concern , although given the unpredictable nature of the ongoing evolution of SARS-CoV-2, this is uncertain at this time (34) . In individuals previously exposed to SARS-CoV-2 (either through infection or vaccination), infection with Omicron elicits a robust and broadly cross-reactive antibody response (36) . This includes an elevated antibody response against Omicron BA.4 and BA.5 (37) . In a clinical trial, individuals who received a second booster dose with Moderna Spikevax Bivalent (50 mcg), and who had no evidence of prior SARS-CoV-2 infection, had larger relative increases in neutralizing antibody titres from pre-to post-booster when compared to those who had evidence of prior SARS-CoV-2 infection. Individuals who received a second booster dose with Moderna Spikevax Bivalent (50 mcg) who had evidence of prior SARS-CoV-2 infection, had significantly higher levels of neutralizing antibody titres at both time points (pre-and post-booster) compared to individuals without evidence of prior infection, however with a smaller relative increase from pre-booster levels. It is possible individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant. Additionally, individuals who were previously infected may experience a Post-market safety of mRNA booster doses Available surveillance data to date from Canada and international jurisdictions indicate that the risk of myocarditis and/or pericarditis following a first booster dose of an original mRNA COVID-19 vaccine using manufacturer-authorized booster dosage appears to be lower than the risk following the second dose of the primary series (38)(39)(40)(41)(42)(43)(44) . o This trend is observed for both Pfizer-BioNTech Comirnaty (30 mcg) and Moderna Spikevax (50 mcg) original vaccine products and across all age groups (including individuals under 30 years of age, for whom the risks are highest). However, a limited number of Moderna Spikevax (50 mcg) original booster doses have been administered to individuals under the age of 30 given the vaccine recommendations/authorizations in each country for this age group. o Preliminary post-marketing surveillance data from the US (38) and France (40) have shown similar rates of myocarditis following administration of the Mod erna Spikevax (50 mcg) original or Pfizer-BioNTech Comirnaty (30 mcg) booster doses.
Of note, during the period of surveillance, in the US, Moderna Spikevax original (50 mcg) was authorized for use among individuals aged ≥18 years and, in France, Moderna Spikevax original (50 mcg) was recommended for use among individuals aged ≥30 years. o No product-specific differences between Pfizer-BioNTech Comirnaty (30 mcg) and Moderna Spikevax (50 mcg) original have been identified with respect to the risk of myocarditis after administration of a booster dose. In addition, preliminary safety data indicate that the risk of myocarditis and/or pericarditis associated with a second booster dose of an original mRNA COVID-19 vaccine is lower than the risk following the second dose of the primary series (44,45) . NACI will also continue to monitor post-market safety and surveillance data and update its recommendations as needed.
Ethics, equity, feasibility, and acceptability Given the considerable uncertainty regarding the trajectory of the COVID-19 pandemic, NACI based its recommendations on an evidence-informed framework and recommends booster doses focus on those at greatest risk of severe illness from COVID-19. Intentions to accept a booster dose of a COVID- 19
# Other considerations
- As an immunological correlate of protection has not been determined for COVID-19 at this time, it is unknown how the neutralizing antibody responses that have been reported from the Moderna Spikevax Bivalent clinical trial are related to the prevention of severe outcomes from COVID-19. No participants in the Moderna Spikevax Bivalent clinical trial were concurrently administered other vaccines. Data with regard to the safety and immunogenicity of other authorized COVID-19 vaccines (including original mRNA COVID-19 vaccines) when given concurrently with other vaccines, are currently limited. However, no specific safety concerns have been identified to date (46)(47)(48)(49)(50)(51)(52) . Studies to assess the safety and immunogenicity of concurrent administration of COVID-19 vaccines with other vaccines are ongoing. Currently, there are no data available on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as a primary series, first booster dose or in a mixed series with vaccines other than Moderna Spikevax original. All participants in the Moderna Spikevax Bivalent clinical trial were administered Moderna Spikevax Bivalent (50 mcg) as a second booster dose after a two-dose primary series (100 mcg doses) and a first booster dose of Moderna Spikevax original (50 mcg) (35) . It is likely that the immunological benefits and safety profile will be similar in individuals receiving a bivalent Omicron-containing mRNA COVID-19 vaccine as a first booster. NACI will continue to monitor new evidence as it becomes available. Although the authorized 50 mcg dose of Moderna Spikevax Bivalent is half of the authorized 100 mcg dose of Moderna Spikevax original administered as part of a primary series, if Moderna Spikevax Bivalent (50 mcg) is administered in error as part of a primary series, this dose should be considered valid as part of the primary series.
# Considerations for the use of a bivalent Omicron-containing mRNA COVID-19 vaccine
- Individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant. There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions, with a focus on protecting those at highest risk for serious outcomes from COVID-19. There are currently no data on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as part of a primary series. NACI continues to recommend a primary series with an original mRNA vaccine in all authorized age groups. NACI Individuals in this cohort can receive any available, authorized, mRNA COVID-19 vaccine as a booster dose, as any option is expected to provide strong protection against severe outcomes from COVID-19. Maximizing the benefit of protection of a booster dose may be affected by the interval between doses. A longer time between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength. A longer interval may, however, also increase the chance of a period with waning (lower) protection while awaiting a next dose.
a For a first or second booster dose for adults 18 years of age and older who are not able or willing to receive an mRNA COVID -19 vaccine, a protein subunit COVID-19 vaccine (Novavax Nuvaxovid) may be offered to adults with out contraindications to the vaccine. Novavax Nuvaxovid is not currently authorized for use as a booster dose in Canada. Medicago Covifenz is not currently authorized for use as a booster dose in Canada. Janssen Jcovden COVID-19 vaccine may be offered as a first booster to individuals 18 years of age and older without contraindications to the vaccine only when all other COVID-19 vaccines are contraindicated.
NACI RESEARCH PRIORITIES
# Immunogenicity
In this study, the primary immunogenicity analysis was based on the primary immunogenicity set which includes participants with no evidence of SARS-CoV-2 infection at baseline (pre-booster). For the pre-specified primary objectives, there were four corresponding endpoints: Individuals with prior SARS-CoV-2 infection In addition to the primary analysis, a pre-planned subgroup analysis was also performed to assess the consistency of results in participants with evidence of prior SARS-CoV-2 infection. Based on this analysis, results in individuals with evidence of prior SARS-CoV-2 infection were consistent with results in those without evidence of prior SARS-CoV-2 infection, with regards to meeting the primary and secondary immunogenicity endpoints. Individuals with evidence of prior SARS-CoV-2 infection had considerably higher GMTs pre-booster against both Omicron and the original SARS-CoV-2, compared to those without evidence of prior SARS-CoV-2 infection. Consequently, at Day 29 post-booster GMTs were considerably higher in those with evidence of prior SARS-CoV-2 infection, compared to those without (against both Omicron and original SARS-CoV-2). However, the GMFR from pre-booster levels was larger in those without evidence of prior SARS-CoV-2 infection compared to those with previous infection, by roughly 1.7-fold against Omicron and 1.8-fold against original SARS-CoV-2 in the Moderna Spikevax Bivalent group and 1.8-fold against Omicron and 1.9 fold in the Moderna Spikevax original group. A consistent result was observed for neutralizing antibody activity against Omicron BA.4 and BA.5 specifically. Of note, participants with a confirmed SARS-CoV-2 infection within 3 months of enrollment were not eligible for inclusion in the trial. With an enrollment period of Feb 18 -Mar 8 2022, the majority of individuals with evidence of prior SARS-CoV-2 infection enrolled in the trial were likely not infected with the Omicron VOC.
# APPENDIX A: MODERNA SPIKEVAX BIVALENT CLINICAL TRIAL DATA Vaccine characteristics
For complete prescribing information for Moderna Spikevax Bivalent, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the Drug Product Database.
# Safety
The safety and reactogenicity of Moderna Spikevax Bivalent (50 mcg) administered as a second booster dose was similar to that of Moderna Spikevax original (50 mcg), given as a second booster dose (33,53) . Also, the frequency of adverse events following immunization with Moderna Spikevax Bivalent (33,35,53) was similar or lower relative to that of a first booster dose of Moderna Spikevax original (50 mcg) (54) , and of the second dose of the Moderna Spikevax original primary series (100 mcg) (55) . No new safety signals were identified. There were no vaccine related cases of death, myocarditis and/or pericarditis reported during the study period (33,53) . Given the trial was limited to 814 participants receiving the Moderna Spikevax Bivalent (n=437) and Moderna Spikevax original (n=377) vaccines (33,53) , it is unlikely that any rare adverse event would be detected. NACI will monitor post-market safety surveillance data as it emerges and update the recommendations as needed. | On June 29, 2022, NACI published interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada. The statement outlined recommendations for booster doses in specific populations ahead of the uncertain trajectory of the COVID-19 pandemic in the coming months. Since that time: On September 1 2022, Health Canada authorized the use of Moderna Spikevax Bivalent (50 mcg) COVID-19 vaccine as a booster dose in adults ≥18 years of age. The Moderna Spikevax Bivalent (50 mcg) COVID-19 vaccine is the first bivalent Omicron BA.1containing mRNA COVID-19 vaccine authorized for use in Canada. The epidemiology of COVID-19 continues to change and there is still considerable uncertainty with regard to the likelihood, timing, and severity of any potential future COVID-19 waves. It is possible that, consistent with other respiratory viruses, the incidence of COVID-19 may increase in the later fall and winter seasons and that new variants of concern (VOCs) may emerge. The emergence of Omicron subvariants BA.4 and BA.5 have led to a resurgence in COVID-19 cases nationally, and these subvariants currently make up the majority of new COVID-19 cases in Canada (previous Omicron subvariants, including Omicron BA.1 make up <5% of new COVID-19 cases in Canada). Nationally, indicators of disease severity, including hospitalizations and deaths, have also increased during the summer wave (1) . Although Omicron and its subvariants have largely been associated with less severe illness compared to previous VOCs, the severity of Omicron subvariants BA.4 and BA.5 in comparison to other Omicron subvariants is currently unclear and data are still emerging at this time (2)(3)(4) . The Omicron variant has demonstrated it is partially evasive of immunity conferred by original COVID-19 vaccines or by a previous infection with a SARS-CoV-2 variant that emerged prior to Omicron. The immune evasion exhibited by Omicron subvariants BA.4 and BA.5 may be greater than that exhibited by previous Omicron subvariants, although evidence is still emerging at this time. Available evidence to date suggests three doses of an authorized, original mRNA COVID-19 vaccine continues to provide strong and sustained protection against severe outcomes from COVID-19. While the proportion of Canadians vaccinated with a primary series is high, the proportion who have received at least one additional dose has plateaued at a much lower level, especially in younger age groups. NACI continues to recommend a primary series with an authorized mRNA vaccine in all authorized age groups. NACI has also provided recommendations for a booster dose with an authorized COVID-19 vaccine for all adults, adolescents, and children 5 to 11 years of age. Immunization of those who are eligible for vaccination but have n ot yet received their recommended doses (primary or booster) remains a top priority in Canada. As with previous COVID-19 booster programs, a fall booster dose with any authorized COVID-19 vaccine will be most important for older adults and other populations at increased risk of severe COVID-19 disease, regardless of the number of booster doses previously received.# PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in -depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict o f interest. 4 | RECOMMENDATIONS ON THE USE OF BIVALENT OMICRON-CONTAINING MRNA COVID-19 VACCINES NACI continues to monitor the rapidly evolving scientific data while recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed. NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were updated on February 14, 2022: To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19
# METHODS
NACI's recommendations on booster doses are based on the decision-making framework outlined in the published statement Interim guidance on booster COVID-19 vaccine doses in Canada. This framework has been updated with evolving evidence (e.g., including considerations of population level cumulative immunity and vaccine coverage) as outlined in the published statement Interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada. Recommendations are based on evidence of the need for (e.g., increased risk of severe illness from COVID-19 and/or increased risk of decreased protection, and waning protection due to increased time since last dose or infection) and benefit of (e.g., safety and effectiveness) booster doses in the Canadian context.
On August 18, 2022, NACI reviewed available evidence on the burden of illness in the Canadian population, as well as booster dose acceptability in the Canadian population. NACI also reviewed the available evidence on the use of the Moderna Spikevax Bivalen t COVID-19 vaccine in adults ≥18 years of age (including manufacturer's clinical data in the regulatory submission to Health Canada and published scientific literature). Additionally, NACI reviewed evidence of post-market safety on mRNA vaccines pertaining to myocarditis and/or pericarditis. For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to NACI's: Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
Further information on NACI's process and procedures is available elsewhere (5,6) . driven primarily by the Omicron BA.4 and BA.5 subvariants. Although signs of stabilization are being observed, significant regional variability remains, and test positivity remains elevated compared to historical trends. It is also possible that, consistent with other respiratory viruses, the incidence of COVID-19 will increase again in the later fall and winter seasons, thus posing a risk for individuals/communities and increasing pressure on health systems. For the most up-to-date epidemiology of COVID-19 in Canada, please refer to the Government of Canada's COVID-19 daily epidemiology update. Indicators of disease severity (i.e., hospitalizations and intensive care unit [ICU] admissions) increased during the summer wave; however, signs of stabilization are being observed. The incidence of severe outcomes remains significantly higher in adults ≥80 years of age compared to younger age groups, and hospitalization rates in this age group are higher than pandemic averages. Even though Omicron and its subvariants have largely been associated with a smaller proportion of severe disease compared to the previous variants, there is still uncertainty regarding the disease severity of Omicron BA.4/BA.5 relative to previous Omicron subvariants. In addition, the surge in SARS-CoV-2 infections caused in part by the increased transmissibility of Omicron BA.4/BA.5, has had a substantial impact on health system infrastructure. NACI continues to monitor emerging data on additional Omicron subvariants of interest, such as BA.2.75. To date, there have been only a very small number of Omicron BA.2.75 sequences detected in Canada.
5
# Hybrid immunity & seroprevalence
Available evidence to date shows that hybrid immunity (i.e., protection conferred from both vaccination and infection) is more robust than immunity due to infection or vaccination alone. However, the duration of protection from hybrid immunity has yet to be fully characterized, and evidence is still emerging with regard to hybrid immunity and protection against Omicron subvariants BA.4 and BA.5, the current predominately circulating variants in Canada. In fully-vaccinated individuals, a previous SARS-CoV-2 infection with the Omicron VOC confers significant protection from reinfection with Omicron BA.4 and/or BA.5, although the durability of this protection has yet to be established (3,4,(7)(8)(9)(10) . However, preliminary evidence also suggests that in fully-vaccinated individuals, protection against reinfection is lower against Omicron BA.5, compared to earlier Omicron subvariants (i.e., BA.2), highlighting the potential immune-escape capability of Omicron BA.5. Emerging Canadian evidence suggests that a large proportion of older adults are protected by vaccination, but may not have acquired hybrid immunity. In Canada, older adults have higher vaccination rates (both with a primary series and with additional doses) compared to younger adults (11) , and according to recent seroprevalence data, are less likely to have been infected during the Omicron wave compared to younger adults and adolescents (12) . It is expected that individuals who have been infected with SARS-CoV-2 may optimize their benefit from future vaccine doses by timing them according to the interval since infection, using similar immunological principles to those informing intervals between vaccine doses. Emerging evidence indicates that a longer interval between SARS-CoV-2 infection and vaccination is associated with improved immune responses to COVID-19 vaccines (13,14) .
Vaccine effectiveness of original COVID-19 booster vaccines Evidence has shown a reduced vaccine effectiveness (VE) of currently-available COVID-19 vaccines against Omicron compared to the effectiveness observed with previous VOCs. VE against Omicron infection after a first booster dose of an original mRNA COVID-19 vaccine is approximately 60% shortly after receipt of the booster dose, an d decreases over time in most studies (15)(16)(17)(18)(19)(20)(21)(22) . However, current data suggest that original mRNA COVID-19 vaccines continue to provide significant protection against hospitalization and severe disease. Initial VE against severe disease is approximately 90% following a first booster dose, and remains above 75% up to 26 weeks from the first booster in most studies (23)(24)(25)(26)(27) ; duration of protection against severe disease is not yet known. Evidence on VE of a second COVID-19 booster dose is currently limited. Recent data from the US have shown that during a period of Omicron BA.2 dominance, among adults at least 50 years of age, a second booster dose of an original mRNA COVID-19 vaccine provided additional protection against emergency department and/or urgent care visits due to COVID-19, as well as hospitalization, compared to those who received one booster dose of an original mRNA COVID-19 vaccine (23) . VE studies from Canada and Israel have also demonstrated additional protection compared to a first booster, inclu ding against severe disease (28)(29)(30)(31)(32) . However, the duration of this increased protection from a second booster dose is currently unknown. (33) showed that Moderna Spikevax Bivalent (50 mcg) administered as a second booster dose to individuals ≥18 years of age had a similar reactogenicity profile to that of Moderna Spikevax original (50 mcg) given as a second booster dose. Also, the frequency of adverse events following Moderna Spikevax Bivalent (50 mcg) given as a second booster dose was similar or lower compared to that of a first booster dose of Moderna Spikevax original (50 mcg), and of the second dose of the Moderna Spikevax original primary series (100 mcg). There were no vaccine-related cases of myocarditis,
# Potential benefits of bivalent vaccines
Omicron and its subvariants are antigenically distinct from the original SARS-CoV-2 virus, as well as earlier SARS-CoV-2 VOCs, with BA.1 emerging as one of the most antigenically distinct subvariants (34) . Given the potential for substantial virus evolution and uncertainty about the emergence of future variants, modification of the strain composition of COVID-19 vaccines may broaden immune protection against divergent SARS-CoV-2 spike protein antigens. Available data, including clinical data on immune responses against BA.4 and BA.5 with a BA.1-targeted, bivalent mRNA vaccine, suggest that inclusion of Omicron in an updated booster vaccine composition may have immediate benefits in the form of increased protection against variants such as Omicron BA.4 and BA.5 (35) . The BA.1targeted, bivalent mRNA vaccines may also elicit a greater breadth of immune response, potentially providing additional protection against future variants of concern , although given the unpredictable nature of the ongoing evolution of SARS-CoV-2, this is uncertain at this time (34) . In individuals previously exposed to SARS-CoV-2 (either through infection or vaccination), infection with Omicron elicits a robust and broadly cross-reactive antibody response (36) . This includes an elevated antibody response against Omicron BA.4 and BA.5 (37) . In a clinical trial, individuals who received a second booster dose with Moderna Spikevax Bivalent (50 mcg), and who had no evidence of prior SARS-CoV-2 infection, had larger relative increases in neutralizing antibody titres from pre-to post-booster when compared to those who had evidence of prior SARS-CoV-2 infection. Individuals who received a second booster dose with Moderna Spikevax Bivalent (50 mcg) who had evidence of prior SARS-CoV-2 infection, had significantly higher levels of neutralizing antibody titres at both time points (pre-and post-booster) compared to individuals without evidence of prior infection, however with a smaller relative increase from pre-booster levels. It is possible individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant. Additionally, individuals who were previously infected may experience a Post-market safety of mRNA booster doses Available surveillance data to date from Canada and international jurisdictions indicate that the risk of myocarditis and/or pericarditis following a first booster dose of an original mRNA COVID-19 vaccine using manufacturer-authorized booster dosage appears to be lower than the risk following the second dose of the primary series (38)(39)(40)(41)(42)(43)(44) . o This trend is observed for both Pfizer-BioNTech Comirnaty (30 mcg) and Moderna Spikevax (50 mcg) original vaccine products and across all age groups (including individuals under 30 years of age, for whom the risks are highest). However, a limited number of Moderna Spikevax (50 mcg) original booster doses have been administered to individuals under the age of 30 given the vaccine recommendations/authorizations in each country for this age group. o Preliminary post-marketing surveillance data from the US (38) and France (40) have shown similar rates of myocarditis following administration of the Mod erna Spikevax (50 mcg) original or Pfizer-BioNTech Comirnaty (30 mcg) booster doses.
Of note, during the period of surveillance, in the US, Moderna Spikevax original (50 mcg) was authorized for use among individuals aged ≥18 years and, in France, Moderna Spikevax original (50 mcg) was recommended for use among individuals aged ≥30 years. o No product-specific differences between Pfizer-BioNTech Comirnaty (30 mcg) and Moderna Spikevax (50 mcg) original have been identified with respect to the risk of myocarditis after administration of a booster dose. In addition, preliminary safety data indicate that the risk of myocarditis and/or pericarditis associated with a second booster dose of an original mRNA COVID-19 vaccine is lower than the risk following the second dose of the primary series (44,45) . NACI will also continue to monitor post-market safety and surveillance data and update its recommendations as needed.
Ethics, equity, feasibility, and acceptability Given the considerable uncertainty regarding the trajectory of the COVID-19 pandemic, NACI based its recommendations on an evidence-informed framework and recommends booster doses focus on those at greatest risk of severe illness from COVID-19. Intentions to accept a booster dose of a COVID- 19
# Other considerations
As an immunological correlate of protection has not been determined for COVID-19 at this time, it is unknown how the neutralizing antibody responses that have been reported from the Moderna Spikevax Bivalent clinical trial are related to the prevention of severe outcomes from COVID-19. No participants in the Moderna Spikevax Bivalent clinical trial were concurrently administered other vaccines. Data with regard to the safety and immunogenicity of other authorized COVID-19 vaccines (including original mRNA COVID-19 vaccines) when given concurrently with other vaccines, are currently limited. However, no specific safety concerns have been identified to date (46)(47)(48)(49)(50)(51)(52) . Studies to assess the safety and immunogenicity of concurrent administration of COVID-19 vaccines with other vaccines are ongoing. Currently, there are no data available on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as a primary series, first booster dose or in a mixed series with vaccines other than Moderna Spikevax original. All participants in the Moderna Spikevax Bivalent clinical trial were administered Moderna Spikevax Bivalent (50 mcg) as a second booster dose after a two-dose primary series (100 mcg doses) and a first booster dose of Moderna Spikevax original (50 mcg) (35) . It is likely that the immunological benefits and safety profile will be similar in individuals receiving a bivalent Omicron-containing mRNA COVID-19 vaccine as a first booster. NACI will continue to monitor new evidence as it becomes available. Although the authorized 50 mcg dose of Moderna Spikevax Bivalent is half of the authorized 100 mcg dose of Moderna Spikevax original administered as part of a primary series, if Moderna Spikevax Bivalent (50 mcg) is administered in error as part of a primary series, this dose should be considered valid as part of the primary series.
# Considerations for the use of a bivalent Omicron-containing mRNA COVID-19 vaccine
Individuals who are less likely to have been infected during Omicron waves (particularly older adults) may realize additional benefits from a bivalent Omicroncontaining mRNA COVID-19 vaccine over time, by priming the immune response to the Omicron variant. There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions, with a focus on protecting those at highest risk for serious outcomes from COVID-19. There are currently no data on the use of bivalent Omicron -containing mRNA COVID-19 vaccines as part of a primary series. NACI continues to recommend a primary series with an original mRNA vaccine in all authorized age groups. NACI Individuals in this cohort can receive any available, authorized, mRNA COVID-19 vaccine as a booster dose, as any option is expected to provide strong protection against severe outcomes from COVID-19. Maximizing the benefit of protection of a booster dose may be affected by the interval between doses. A longer time between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength. A longer interval may, however, also increase the chance of a period with waning (lower) protection while awaiting a next dose.
a For a first or second booster dose for adults 18 years of age and older who are not able or willing to receive an mRNA COVID -19 vaccine, a protein subunit COVID-19 vaccine (Novavax Nuvaxovid) may be offered to adults with out contraindications to the vaccine. Novavax Nuvaxovid is not currently authorized for use as a booster dose in Canada. Medicago Covifenz is not currently authorized for use as a booster dose in Canada. Janssen Jcovden COVID-19 vaccine may be offered as a first booster to individuals 18 years of age and older without contraindications to the vaccine only when all other COVID-19 vaccines are contraindicated.
NACI RESEARCH PRIORITIES
# Immunogenicity
In this study, the primary immunogenicity analysis was based on the primary immunogenicity set which includes participants with no evidence of SARS-CoV-2 infection at baseline (pre-booster). For the pre-specified primary objectives, there were four corresponding endpoints: Individuals with prior SARS-CoV-2 infection In addition to the primary analysis, a pre-planned subgroup analysis was also performed to assess the consistency of results in participants with evidence of prior SARS-CoV-2 infection. Based on this analysis, results in individuals with evidence of prior SARS-CoV-2 infection were consistent with results in those without evidence of prior SARS-CoV-2 infection, with regards to meeting the primary and secondary immunogenicity endpoints. Individuals with evidence of prior SARS-CoV-2 infection had considerably higher GMTs pre-booster against both Omicron and the original SARS-CoV-2, compared to those without evidence of prior SARS-CoV-2 infection. Consequently, at Day 29 post-booster GMTs were considerably higher in those with evidence of prior SARS-CoV-2 infection, compared to those without (against both Omicron and original SARS-CoV-2). However, the GMFR from pre-booster levels was larger in those without evidence of prior SARS-CoV-2 infection compared to those with previous infection, by roughly 1.7-fold against Omicron and 1.8-fold against original SARS-CoV-2 in the Moderna Spikevax Bivalent group and 1.8-fold against Omicron and 1.9 fold in the Moderna Spikevax original group. A consistent result was observed for neutralizing antibody activity against Omicron BA.4 and BA.5 specifically. Of note, participants with a confirmed SARS-CoV-2 infection within 3 months of enrollment were not eligible for inclusion in the trial. With an enrollment period of Feb 18 -Mar 8 2022, the majority of individuals with evidence of prior SARS-CoV-2 infection enrolled in the trial were likely not infected with the Omicron VOC.
# APPENDIX A: MODERNA SPIKEVAX BIVALENT CLINICAL TRIAL DATA Vaccine characteristics
For complete prescribing information for Moderna Spikevax Bivalent, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the Drug Product Database.
# Safety
The safety and reactogenicity of Moderna Spikevax Bivalent (50 mcg) administered as a second booster dose was similar to that of Moderna Spikevax original (50 mcg), given as a second booster dose (33,53) . Also, the frequency of adverse events following immunization with Moderna Spikevax Bivalent (33,35,53) was similar or lower relative to that of a first booster dose of Moderna Spikevax original (50 mcg) (54) , and of the second dose of the Moderna Spikevax original primary series (100 mcg) (55) . No new safety signals were identified. There were no vaccine related cases of death, myocarditis and/or pericarditis reported during the study period (33,53) . Given the trial was limited to 814 participants receiving the Moderna Spikevax Bivalent (n=437) and Moderna Spikevax original (n=377) vaccines (33,53) , it is unlikely that any rare adverse event would be detected. NACI will monitor post-market safety surveillance data as it emerges and update the recommendations as needed. | None | None |
e06ff7bc041c8afd92684b7f5e79545ca28d4a38 | cma | None | To provide an overview of the mechanism of action, licensed indications, dosing regimens, and sideeffects of rivaroxaban.Rivaroxaban (Xarelto ) is an oral factor Xa inhibitor. By binding reversibly to the active site of factor Xa, rivaroxaban attenuates thrombin generation and reduces fibrin formation.# INDICATIONS:
Rivaroxaban is currently licensed in Canada for:
- Thromboprophylaxis after elective hip or knee replacement surgery - Treatment of patients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and prevention of recurrent DVT and PE - Stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation - Prevention of stroke, myocardial infarction and cardiovascular death, and for the prevention of acute limb ischemia and mortality in patients with coronary artery disease (CAD), with or without peripheral artery disease (PAD), in combination with acetylsalicylic acid (ASA) 75-100 mg daily
# DOSING:
- Prevention of stroke and systemic embolism in atrial fibrillation: 20 mg once daily (OD) in patients with CrCl >50 mL/min or 15 mg OD for those with CrCl 15 -<50 mL/min. Physicians must use caution when prescribing the 15 mg OD dose for those with CrCl 15 -<30 mL/min. Use is not recommended with CrCl <15 mL/min.
- Acute treatment of DVT and PE: 15 mg twice daily (BID) for 3 weeks and 20 mg OD thereafter.
No dosing adjustment is recommended in those with CrCl 15 -<50 mL/min, however, caution is recommended for those with CrCl 15 -<30 mL/min. Use is not recommended with CrCl <15 mL/min.
# Continued prevention of recurrent DVT and PE:
For extended therapy beyond 6 months, consideration may be given to reducing the dose to 10 mg OD. No dosing adjustment is recommended in those with CrCl 15 -<50 mL/min, however, caution is recommended for those with CrCl 15 -<30 mL/min. Use is not recommended with CrCl <15 mL/min. 4. Thromboprophylaxis after arthroplasty: 10 mg OD starting at least 6-8 h after surgery and continuing for 14 to 35 days after knee or hip replacement surgery, respectively. No dosing adjustment is recommended in those with CrCl 15 -<50 mL/min, however, caution is recommended for those with CrCl 15 -<30 mL/min. Use is not recommended with CrCl <15 mL/min.
- Prevention of stroke, myocardial infarction and cardiovascular death, and for the prevention of acute limb ischemia and mortality in patients with coronary artery disease (CAD) with or without peripheral artery disease (PAD): 2.5 mg BID in combination with ASA 75-100 mg OD. This regimen is only appropriate for patients without atrial fibrillation. In patients with CAD, PAD, or both, rivaroxaban 2.5 mg BID is not indicated in combination with dual antiplatelet therapy.
# MONITORING:
Routine laboratory monitoring is not necessary. Although the prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT) do not provide reliable measures of rivaroxaban's anticoagulant activity, the prothrombin time is more responsive to the presence of rivaroxaban. Anti-factor Xa assays using rivaroxaban calibrators, where available, can be used to determine the plasma rivaroxaban concentration. For more details about specific testing, see the Clinical Guide NOACs/DOACs: Coagulation Tests.
Although no routine coagulation laboratory monitoring is required for long-term rivaroxaban use, periodic clinical assessment is important to determine and reinforce compliance, review comorbidity and medication changes, including an assessment for possible interacting agents, and provide education. Furthermore, for most patients, at least yearly assessment of creatinine clearance is recommended. The creatinine should be measured more frequently in patients with an abnormal value at baseline or at risk of worsening renal function.
# ADVERSE EFFECTS:
The major adverse effect of rivaroxaban is bleeding; concomitant use of antiplatelet drugs or strong inhibitors of both CYP 3A4 and P-glycoprotein (P-gp) (see below under Special Considerations: Drug Interactions) increases this risk. Rivaroxaban should be avoided in patients with indwelling epidural catheters or with a history of recent spinal puncture, in order to reduce the risk of post-operative epidural hematoma.
A small number of patients may experience dyspepsia. Taking rivaroxaban with food will reduce dyspepsia and improve absorption.
# PERI-PROCEDURE MANAGEMENT:
See the Clinical Guide NOACs/DOACs: Perioperative Management and the Tool: Perioperative Anticoagulant Management Algorithm.
# SPECIAL CONSIDERATIONS:
Administration: Rivaroxaban 2.5 mg and 10 mg doses may be taken with or without food. At doses higher than 10 mg OD, rivaroxaban should be administered with food to maximize absorption.
Pregnancy and breast feeding: Rivaroxaban crosses the placenta and should not be used in pregnancy. It has been shown that rivaroxaban appears in breast milk; therefore, this drug should also be avoided in nursing mothers.
Renal and hepatic dysfunction: There is limited information on rivaroxaban in patients with CrCl <15 mL/min and in those with moderate or severe hepatic impairment (Child-Pugh class B or C).
Rivaroxaban should be avoided in such patients. Treatment of cancer-associated thrombosis: Rivaroxaban does not currently have a licensed indication in Canada specifically for use in this patient population but a recent small randomized pilot trial comparing rivaroxaban with low molecular weight heparin (LMWH) showed that in this study population, rivaroxaban may be a reasonable alternative to LMWH when the risk of gastrointestinal (GI) bleeding is low and in patients with non-GI solid tumor malignancies, provided that drug-drug interactions and significant thrombocytopenia are not a concern. This study showed fewer episodes of recurrent VTE but a 2-to 3-fold higher risk of major or clinically relevant bleeding (particularly GI bleeding) with rivaroxaban over LMWH. A thorough review of the relative risks and benefits of both anticoagulant options, in addition to potential drug interactions and patient preference and values, is prudent prior to prescribing anticoagulant therapy in patients with cancer-associated VTE. See the Clinical Guide Cancer and Thrombosis.
# Primary thrombosis prophylaxis in ambulatory cancer patients:
In a randomized trial comparing rivaroxaban 10 mg OD with placebo in ambulatory cancer patients judged to be at high risk for venous thromboembolism according to their Khorana score (≥2), benefit of treatment was not established as rivaroxaban was not associated with significant reduction in the risk of symptomatic or asymptomatic venous thromboembolism or death compared to placebo in the prespecified primary efficacy analysis of up to day 180 (6.0% in the rivaroxaban group versus 8.8% in the placebo group; hazard ratio : 0.66; 95% CI, 0.40-1.09); although a pre-specified analysis restricted to the period of intervention (first receipt of study drug to last dose plus 2 days), did result in a statistically significant reduction in the risk of venous thromboembolism. There was no increase in major bleeding with rivaroxaban therapy (2.0% of patients receiving rivaroxaban versus 1.0% of those receiving placebo; HR: 1.96; 95% CI, 0.59-6.49). Rivaroxaban is not currently licensed for this indication in Canada. See the Clinical Guide Cancer and Thrombosis.
# Stable cardiovascular disease:
The COMPASS trial compared aspirin 100 mg daily alone, rivaroxaban 5 mg twice daily alone and rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily in patients with stable cardiovascular disease (including PAD) and without atrial fibrillation. Those assigned to the combination of aspirin with rivaroxaban 2.5 mg twice daily had better cardiovascular outcomes and lower mortality but more major bleeding than those assigned to aspirin alone; however, the net clinical benefit favored combination therapy. Rivaroxaban 5 mg twice daily alone did not result in better outcomes than aspirin and was associated with more bleeding events. It is yet to be determined which patients with stable cardiovascular disease will benefit most from the combination of rivaroxaban 2.5 mg twice daily and low-dose aspirin.
# Atrial fibrillation patients receiving P2Y12 inhibitor for recent acute coronary artery syndrome (ACS) or percutaneous coronary intervention (PCI):
The PIONEER AF trial randomized patients to one of three groups: (1) rivaroxaban 15 mg daily (10 mg daily if CrCl 30-50mL/min) with a P2Y12 inhibitor; (2) rivaroxaban 2.5 mg twice daily with a P2Y12 inhibitor plus ASA; or (3) warfarin (INR 2-3) with a P2Y12 inhibitor plus ASA. The most common P2Y12 inhibitor used was clopidogrel. The trial found that low dose rivaroxaban (10-15 mg daily) plus a P2Y12 inhibitor or very low dose rivaroxaban (2.5 mg twice daily) plus dual antiplatelet therapy resulted in less bleeding and fewer hospitalizations than regimens including dual antiplatelet therapy plus warfarin. There were no observed differences in the incidence of ischemic events between the arms, but the trial was not powered to detect such differences.
Pragmatically speaking when rivaroxaban is used in this situation it is typically 15 mg daily (10 mg daily for CrCl 30-50mL/min) with clopidogrel. Rivaroxaban dose should be increased once clopidogrel is discontinued.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES, RESOURCES AND TOOLS:
# Date of version: 23November2020
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide an overview of the mechanism of action, licensed indications, dosing regimens, and sideeffects of rivaroxaban.Rivaroxaban (Xarelto ) is an oral factor Xa inhibitor. By binding reversibly to the active site of factor Xa, rivaroxaban attenuates thrombin generation and reduces fibrin formation.# INDICATIONS:
Rivaroxaban is currently licensed in Canada for:
• Thromboprophylaxis after elective hip or knee replacement surgery • Treatment of patients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and prevention of recurrent DVT and PE • Stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation • Prevention of stroke, myocardial infarction and cardiovascular death, and for the prevention of acute limb ischemia and mortality in patients with coronary artery disease (CAD), with or without peripheral artery disease (PAD), in combination with acetylsalicylic acid (ASA) 75-100 mg daily
# DOSING:
1. Prevention of stroke and systemic embolism in atrial fibrillation: 20 mg once daily (OD) in patients with CrCl >50 mL/min or 15 mg OD for those with CrCl 15 -<50 mL/min. Physicians must use caution when prescribing the 15 mg OD dose for those with CrCl 15 -<30 mL/min. Use is not recommended with CrCl <15 mL/min.
2. Acute treatment of DVT and PE: 15 mg twice daily (BID) for 3 weeks and 20 mg OD thereafter.
No dosing adjustment is recommended in those with CrCl 15 -<50 mL/min, however, caution is recommended for those with CrCl 15 -<30 mL/min. Use is not recommended with CrCl <15 mL/min.
# Continued prevention of recurrent DVT and PE:
For extended therapy beyond 6 months, consideration may be given to reducing the dose to 10 mg OD. No dosing adjustment is recommended in those with CrCl 15 -<50 mL/min, however, caution is recommended for those with CrCl 15 -<30 mL/min. Use is not recommended with CrCl <15 mL/min. 4. Thromboprophylaxis after arthroplasty: 10 mg OD starting at least 6-8 h after surgery and continuing for 14 to 35 days after knee or hip replacement surgery, respectively. No dosing adjustment is recommended in those with CrCl 15 -<50 mL/min, however, caution is recommended for those with CrCl 15 -<30 mL/min. Use is not recommended with CrCl <15 mL/min.
5. Prevention of stroke, myocardial infarction and cardiovascular death, and for the prevention of acute limb ischemia and mortality in patients with coronary artery disease (CAD) with or without peripheral artery disease (PAD): 2.5 mg BID in combination with ASA 75-100 mg OD. This regimen is only appropriate for patients without atrial fibrillation. In patients with CAD, PAD, or both, rivaroxaban 2.5 mg BID is not indicated in combination with dual antiplatelet therapy.
# MONITORING:
Routine laboratory monitoring is not necessary. Although the prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT) do not provide reliable measures of rivaroxaban's anticoagulant activity, the prothrombin time is more responsive to the presence of rivaroxaban. Anti-factor Xa assays using rivaroxaban calibrators, where available, can be used to determine the plasma rivaroxaban concentration. For more details about specific testing, see the Clinical Guide NOACs/DOACs: Coagulation Tests.
Although no routine coagulation laboratory monitoring is required for long-term rivaroxaban use, periodic clinical assessment is important to determine and reinforce compliance, review comorbidity and medication changes, including an assessment for possible interacting agents, and provide education. Furthermore, for most patients, at least yearly assessment of creatinine clearance is recommended. The creatinine should be measured more frequently in patients with an abnormal value at baseline or at risk of worsening renal function.
# ADVERSE EFFECTS:
The major adverse effect of rivaroxaban is bleeding; concomitant use of antiplatelet drugs or strong inhibitors of both CYP 3A4 and P-glycoprotein (P-gp) (see below under Special Considerations: Drug Interactions) increases this risk. Rivaroxaban should be avoided in patients with indwelling epidural catheters or with a history of recent spinal puncture, in order to reduce the risk of post-operative epidural hematoma.
A small number of patients may experience dyspepsia. Taking rivaroxaban with food will reduce dyspepsia and improve absorption.
# PERI-PROCEDURE MANAGEMENT:
See the Clinical Guide NOACs/DOACs: Perioperative Management and the Tool: Perioperative Anticoagulant Management Algorithm.
# SPECIAL CONSIDERATIONS:
Administration: Rivaroxaban 2.5 mg and 10 mg doses may be taken with or without food. At doses higher than 10 mg OD, rivaroxaban should be administered with food to maximize absorption.
Pregnancy and breast feeding: Rivaroxaban crosses the placenta and should not be used in pregnancy. It has been shown that rivaroxaban appears in breast milk; therefore, this drug should also be avoided in nursing mothers.
Renal and hepatic dysfunction: There is limited information on rivaroxaban in patients with CrCl <15 mL/min and in those with moderate or severe hepatic impairment (Child-Pugh class B or C).
Rivaroxaban should be avoided in such patients. Treatment of cancer-associated thrombosis: Rivaroxaban does not currently have a licensed indication in Canada specifically for use in this patient population but a recent small randomized pilot trial comparing rivaroxaban with low molecular weight heparin (LMWH) showed that in this study population, rivaroxaban may be a reasonable alternative to LMWH when the risk of gastrointestinal (GI) bleeding is low and in patients with non-GI solid tumor malignancies, provided that drug-drug interactions and significant thrombocytopenia are not a concern. This study showed fewer episodes of recurrent VTE but a 2-to 3-fold higher risk of major or clinically relevant bleeding (particularly GI bleeding) with rivaroxaban over LMWH. A thorough review of the relative risks and benefits of both anticoagulant options, in addition to potential drug interactions and patient preference and values, is prudent prior to prescribing anticoagulant therapy in patients with cancer-associated VTE. See the Clinical Guide Cancer and Thrombosis.
# Primary thrombosis prophylaxis in ambulatory cancer patients:
In a randomized trial comparing rivaroxaban 10 mg OD with placebo in ambulatory cancer patients judged to be at high risk for venous thromboembolism according to their Khorana score (≥2), benefit of treatment was not established as rivaroxaban was not associated with significant reduction in the risk of symptomatic or asymptomatic venous thromboembolism or death compared to placebo in the prespecified primary efficacy analysis of up to day 180 (6.0% in the rivaroxaban group versus 8.8% in the placebo group; hazard ratio [HR]: 0.66; 95% CI, 0.40-1.09); although a pre-specified analysis restricted to the period of intervention (first receipt of study drug to last dose plus 2 days), did result in a statistically significant reduction in the risk of venous thromboembolism. There was no increase in major bleeding with rivaroxaban therapy (2.0% of patients receiving rivaroxaban versus 1.0% of those receiving placebo; HR: 1.96; 95% CI, 0.59-6.49). Rivaroxaban is not currently licensed for this indication in Canada. See the Clinical Guide Cancer and Thrombosis.
# Stable cardiovascular disease:
The COMPASS trial compared aspirin 100 mg daily alone, rivaroxaban 5 mg twice daily alone and rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily in patients with stable cardiovascular disease (including PAD) and without atrial fibrillation. Those assigned to the combination of aspirin with rivaroxaban 2.5 mg twice daily had better cardiovascular outcomes and lower mortality but more major bleeding than those assigned to aspirin alone; however, the net clinical benefit favored combination therapy. Rivaroxaban 5 mg twice daily alone did not result in better outcomes than aspirin and was associated with more bleeding events. It is yet to be determined which patients with stable cardiovascular disease will benefit most from the combination of rivaroxaban 2.5 mg twice daily and low-dose aspirin.
# Atrial fibrillation patients receiving P2Y12 inhibitor for recent acute coronary artery syndrome (ACS) or percutaneous coronary intervention (PCI):
The PIONEER AF trial randomized patients to one of three groups: (1) rivaroxaban 15 mg daily (10 mg daily if CrCl 30-50mL/min) with a P2Y12 inhibitor; (2) rivaroxaban 2.5 mg twice daily with a P2Y12 inhibitor plus ASA; or (3) warfarin (INR 2-3) with a P2Y12 inhibitor plus ASA. The most common P2Y12 inhibitor used was clopidogrel. The trial found that low dose rivaroxaban (10-15 mg daily) plus a P2Y12 inhibitor or very low dose rivaroxaban (2.5 mg twice daily) plus dual antiplatelet therapy resulted in less bleeding and fewer hospitalizations than regimens including dual antiplatelet therapy plus warfarin. There were no observed differences in the incidence of ischemic events between the arms, but the trial was not powered to detect such differences.
Pragmatically speaking when rivaroxaban is used in this situation it is typically 15 mg daily (10 mg daily for CrCl 30-50mL/min) with clopidogrel. Rivaroxaban dose should be increased once clopidogrel is discontinued.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES, RESOURCES AND TOOLS:
•
# Date of version: 23November2020
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
6673324fac4daaa333b5e87cd95c432cf3d14673 | cma | None | This guideline provides recommendations on the primary prevention of atherosclerotic cardiovascular disease (ASCVD/CVD) in adults aged ≥19 years without clinical CVD. It does not apply to patients with a known history of CVD or who currently have signs or symptoms of CVD, as this would require treatment and secondary prevention. The recommendations include how to assess a patient's risk of CVD and how to manage their CVD risk factors. Familial hypercholesterolemia (FH) and other genetic dyslipidaemias are out of scope of this guideline. Practitioners are recommended to access Canadian Cardiovascular Society guidelines that address this condition. 1 For updated guidance on secondary prevention practitioners are recommended to access the 2021 Canadian Cardiovascular Society guidelines. 2 Key Recommendations - Assess CVD risk in all asymptomatic adults ≥40 years of age . 2-5 - Health behaviour change (e.g., smoking cessation, healthy diet) is recommended as the first-line intervention for all risk groups in CVD primary prevention. Pharmacological management is recommended for high risk groups . 2,4,5 - Initiate statin therapy only after objectively evaluating the person's individual risks, benefits and preferences, and by having an individualized discussion with the patient. Initiate pharmaceutical management after considering the patient's overall individual risk. Treatment with a statin is expected to result in a significant reduction (30 -50%) in the elevated baseline lipid levels . 5-8 - Reducing LDL-C using statin and/or non-pharmacological management is recommended as each 1 mmol/L decrease in LDL-C results in a 20-22% relative risk reduction of major vascular events . 2,9 - The use of aspirin to reduce risk of morbidity or mortality may only be beneficial to certain individuals. . 5,10,11 - Recommendation against the use of over-the-counter omega-3 PUFA to reduce CVD risk. .# Assessment of Risk Who to Assess
Consider assessing CVD risk in: - all asymptomatic men and women ≥40 years to establish a baseline 4,5 (Note: Lifetime Prevention Schedule, Ministry of Health, BC, recommends screening men ≥40 years and women ≥50 years); - all patients with pre-existing risk-related conditions (e.g., HTN, DM, CKD); and - all patients with a known family history of premature CVD (defined as men aged <55 years and women aged <65 years in first degree relatives). - A patient may be reassessed in 1 to 5 years depending on their initial risk assessment or if their risk factors change significantly. For further details, refer to Appendix A: Primary Prevention of Cardiovascular Disease Algorithm.
# Risk Assessment a. Risk assessment tool:
The Framingham Risk Score (FRS) is recommended. † The FRS, or any CVD risk assessment tool, is a risk estimation only of a patient's CVD risk. Since these scores are plus or minus several percentage points, it is important to consider modifying the risk estimation based on other known risk factors (e.g., family history, ethnicity) and a practitioner's clinical judgement. For example, the Canadian Cardiovascular Society (CCS) suggests that among individuals 30 -59 years of age without diabetes, the presence of a positive history of premature CVD in first degree relatives increases a patient's FRS by approximately 2-fold. 4 b. In addition to the FRS, other risk assessment tools include Absolute CVD Risk/Benefit Calculator from James McCormack (for patients ≤80 years), the University of Edinburgh Cardiovascular Risk Calculator, the United Kingdom Prospective Diabetes Study (UKPDS) risk calculator that estimates the 10-year CHD and stroke risk for adults with type 2 diabetes and QRISK3 risk calculator (for patients ≤84 years). For additional details on the risk assessment tools, refer to Associated Document: Resource Guide for Physicians -Tools for Primary Prevention of Cardiovascular Disease. Paper-based scores use groups of measurements for the risk factors to assign points; and online calculators use the exact measurements for the risk factors.
A risk score from an online calculator allows for a more individualized estimate of risk .
- Non-modifiable risk factors include: age -chronological and biological age, biological sex (men) family history of CVD or familial hyperlipidemia (1st degree relative with ASCVD -men <55 years and women <65 years) ethnicity (First Nations, 12 South Asians (defined as Indian, Pakistani, Bangladeshi or Sri Lankan origin)) 13 For any individual, it is imperative that the health needs of that individual as it relates to their racial/ethnic background (e.g., South Asians) is critically examined to ensure culturally appropriate medical and health decisions. 14 chronic kidney disease, chronic inflammatory diseases (e.g., rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, vasculitis (polyarteritis nodosa)), HIV infection, hypertensive diseases of pregnancy, Polycystic Ovarian Syndrome, gestational diabetes. - The modifiable risk factors are listed in
# Modifiable Risk Factors Mitigation Strategy Resources
# Smoking
Smoking cessation is probably the most important health behaviour intervention for the prevention of CVD. 15,16 A linear relation exists between number of cigarettes smoked per day and CVD risk. 17
# QuitNow BC Smoking Cessation Program
HealthLinkBC: Quitting Smoking Unhealthy diet A diet rich in vegetables, fruits, legumes, nuts, whole grains, fish and lean proteins with inherent soluble and insoluble vegetable fiber has been consistently shown to be associated with lower all cause mortality. HealthLinkBC: Heart Healthy Eating
# DASH diet
Canada's Food Guide
# Low physical activity/sedentary behaviour
Engaging in at least 150 minutes per week of accumulated moderate to vigorous-intensity aerobic physical activity is associated with reduced ASCVD. HealthLinkBC: Physical Activity
# Reduction in alcohol consumption
Reduction in alcohol intake may lower blood pressure. 29 HealthlinkBC: Low-risk drinking guidelines Canada's Low-Risk Alcohol Drinking Guidelines BCGuidelines: Problem Drinking Hypertension High blood pressure has been shown to increase cardiovascular risk. Adapt health behaviours to reduce blood pressure levels. Pharmacological management may be needed for some patients along with healthy behaviour changes.
# BCGuidelines: Hypertension -Diagnosis and Management
HealthlinkBC: Lifestyle Steps to Lower Your High Blood Pressure Hypertension Canada: Hypertension and You
# Diabetes Mellitus
Diabetes Mellitus is associated with 2-4 fold increase in CVD. 33,34 Adherence to a healthier behaviours in those with type 2 diabetes is associated with lower CVD risk. 35 BCGuidelines: Socio-economic factors may confer a risk equivalent to traditional risk factors. 39,42 Health education, community-based programs, and behavioural counselling have all been suggested to address the impact of these factors on CVD risk.
Diabetes
Links to some clinical practice tools that can help practitioners improve their performance in identifying and taking action on the root causes of poor health. 43 Prescribed medications 44 Some medications, including thiazide diuretics, beta blockers, and oral estrogens can cause modest changes in serum lipid concentrations. Some of the atypical antipsychotic agents, in particular clozapine and olanzapine, have been associated with weight gain, obesity, hypertriglyceridemia, and development of diabetes mellitus.
# h. Assessment Stratification
The patient can be classified as low, intermediate, or high risk for CVD based on the risk assessment. Any patient that is considered very high risk or is symptomatic (defined as secondary prevention -out of the scope of this guideline) should be treated accordingly. The FRS defines low risk as <10%, intermediate risk as 10 -19% and high risk as ≥20%. These groupings are an arbitrary convenience, not a scientifically validated stratification.
A patient in the intermediate risk group may warrant a secondary assessment to raise or lower their risk stratification. However, further investigations may not be appropriate if the results would not influence the decision of how to manage the risk or treat the patient.
Secondary assessment should be done on patients for whom treatment decisions are uncertain. These assessments may include carotid ultrasound, hsCRP, or coronary artery calcium (CAC) scoring. Updated guidance on the use of CAC is recommended by the CCS 2021 guidelines. 2 Conduct a shared decision-making conversation regarding healthy behaviour modifications and if necessary pharmacological interventions. Consider using cardiovascular age during the discussion. Cardiovascular (CV) age using the Cardiovascular Life Expectancy Model (CLEM) is calculated as the patient's age minus the difference between his or her estimated remaining life expectancy (adjusted for coronary and stroke risk) and the average remaining life expectancy of Canadians of the same age and sex (chiprehab.com/index.html). 4,48
# Management of Risk Healthy Behaviour
Healthy behaviour modifications need to be strongly advocated as the first-line intervention for all risk groups. Adequate explanations and support should be provided to patients, so they clearly understand the nature and significance of CVD, and that they have the primary responsibility for adopting the healthy behaviour changes required for reducing their risk.
# Use the prevention visit code -14066 for discussions related to management of modifiable risks. Diagnostics codes that require a prevention focused advice include smoking (786), unhealthy eating and medical obesity (783), physically inactive (785).
a. Smoking: Promote smoking cessation and avoidance of second-hand smoke. Behavioral and pharmacotherapy interventions, alone or in combination, have been shown to improve rates of smoking cessation among the general adult population. 49,50 Use a Screening, Brief Intervention and Referral to Treatment (SBIRT) approach. 51 When talking to a patient about smoking: 1) Screen for use 2) Conduct a Brief Intervention by providing risks of behaviour 3) Assess for willingness to quit 4) Support behaviour change by connecting to resources or treatment.
- For support to quit, refer patients to: QuitNow at www.quitnow.ca/ HealthLinkBC Quitting Smoking -Patients can call 8-1-1 or visit the website www.healthlinkbc.ca/mental-healthsubstance-use/quitting-smoking. BC Smoking Cessation Program at www.gov.bc.ca/bcsmokingcessation Smokers' Helpline at 1-866-366-3667 or online at SmokersHelpline.ca - For more information on effective pharmacological aids for smoking cessation, refer to BC Smoking Cessation program.
- Electronic cigarettes, also known as e-cigarettes, vaping (available with or without nicotine), may play a role as an aid in smoking cessation. At present time, their risk and benefits have not been clearly established and are not included as a pharmacological aid.
b. Physical Activity: Support patient working towards 30 minutes or more of moderate to vigorous intensity physical activity on most days of the week (weekly total ≥150 minutes). 25,55 Behavioural interventions for healthful diet and physical activity have been shown to generally improve participants' dietary intake and physical activity levels at 6 to 12 months of followup. 56 Techniques such as motivational interviewing and brief action planning, that promote collaborative engagement with the patient, are more effective than exercise prescription alone for patients to achieve their physical activity goals.
- Exercise stress test may be warranted for previously sedentary people with additional risk factors for CVD who wish to undertake exercise more vigorous than brisk walking. 4 - For patients who are sedentary, consider a graduated exercise program using Brief Action Planning (BAP).
- Engage the patients in completing a Physical Activity Readiness Questionnaire for Everyone (PAR-Q+) and electronic Physical Activity Readiness Medical Examination (ePARmed-X+) to help them determine their readiness. Refer them to an accessible exercise program (such as healthy heart programs). - For assistance with personalized physical activity advice, refer patient to a physical activity expert at HealthLinkBC or by telephone at 8-1-1.
c. Diet: Encourage a well-balanced diet. There are many dietary pathways to achieve CV risk reduction such as the Mediterranean diet (which emphasizes fruits, vegetables, legumes, whole grains and olive oil, with moderate consumption of fish, dairy products, poultry and minimizing meats and sweets) or the Dietary Approaches to Stop Hypertension (DASH) diet. 4 - For assistance with personalized diet advice, refer patient to a dietitian at HealthLinkBC by telephone 8-1-1 or website: www.healthlinkbc.ca.
# d. Alcohol Consumption:
Screen for alcohol abuse. Use a Screening, Brief Intervention, and Referral for Treatment (SBIRT) approach.
# Follow-up to Healthy Behaviour Modifications
- Assess success of healthy behaviour intervention change at first follow-up.
- Assess cardiovascular risk using lipid profile (non-fasting)
- For those with elevated lipids from their initial risk assessment, they may be followed up with a lipid profile in 3 -6 months. If elevated lipids are still a concern, consider pharmaceutical management. - Studies consistently demonstrate a 20-22% relative risk reduction for each 1 mmol/L reduction in low-density lipoprotein cholesterol (LDL-C). 9 The absolute risk reduction is thus dependent upon the baseline risk and the baseline LDL-C, as statin treatment will provide a greater absolute LDL-C lowering in those with higher baseline values. 2 Both non-HDL-C and ApoB appear to be stronger predictors than LDL-C for major future cardiovascular events. 2,57,58 Non-HDL-C may also be a better indicator of residual risk after statin therapy than LDL-C. 59 ApoB is not available with lipid profiles unless diagnosis of complex dyslipidemia is indicated.
# Pharmaceutical Management
Acetylsalicylic Acid (ASA) Therapy ASA therapy in Primary Prevention: Evidence does not support the use of aspirin in low and intermediate risk patients. The evidence for use of aspirin in high risk patients is currently uncertain. 5,60 Use of aspirin in people >75 may further heighten the risk of clinical significant bleeding. 61
# Statin Therapy
For those patients with DM, CKD, or Familial Hyperdyslipidemia, statin therapy is indicated along with healthy behaviour interventions. Prior to the initiation of statin therapy:
- inform the patient of adverse effects -effects may include muscle pain/myopathy/weakness, rhabdomyolysis, cataracts, elevated blood glucose and diabetes, acute renal failure, and liver injury; - educate the patient about any possible drug interactions with other prescribed medication, over-the-counter remedies and non-pharmaceuticals -consult a pharmacist or product monograph for a complete list; and - emphasize the importance of long-term compliance -it is estimated that 75% of primary prevention patients aged >65 years old started on statins stop their therapy within 2 years. 66 Follow-up to Statin Therapy Within 3 -6 months of the initiation of statin therapy, follow-up with the patient. This may include:
- Measure lipids with a non-HDL-C or an ApoB to assess patient adherence to statin therapy and any response to statin therapy (see Controversies in Care). A full lipid profile is not indicated. If both healthy behaviour intervention and a statin intervention have not been successful and lipids are still above target in the follow-up investigation, consider any other causes of elevated lipids (e.g., hypothyroidism, non-adherence). - Inquire about any adverse effects. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is 5X). 63 - Measure liver transaminase enzyme (alanine aminotransferase (ALT)) only once within the first 3 months of starting statin. If a patient has elevated liver transaminase enzymes, (greater than 3X the normal) consider secondary causes. 65 Further follow-ups as clinically needed. After the initial follow-up, routine monitoring of CK and ALT is not indicated for asymptomatic patients. More frequent routine monitoring with a full lipid profile, non-HDL-C or an ApoB is not considered necessary for the sole purpose of treat-to-target.
# When to Refer Patients to a Specialist
Consider referral to a specialist when there is:
- Difficulty reaching treatment targets despite maximum-tolerated lipid-lowering therapy.
- Intolerance to or adverse effects of statin treatment. Statin intolerance needs to be well documented prior to referral. 63
# Controversies in Care Statin Therapy in Primary Prevention
Both the Canadian Cardiovascular Society (CCS) 4 and the American Heart Association (ACC/AHA)5 acknowledge that there is high interindividual variability in LDL-C levels attained with statin therapy. They agree that recent studies have demonstrated lower CVD event rates with moderate-intensity and high-intensity statin therapy that outweighed the observable risks. 4,5,67 The 2016 USPSTF systematic review of statin therapy in primary prevention showed a reduced risk of all-cause and cardiovascular mortality and ASCVD events and noted greater absolute benefits in those at greater baseline risk. 68 both the CCS and ACC/AHA have recommended a more aggressive approach for statin use (see
# CKD or high risk HTN Treat with statins.
No specific recommendation.
# Statin Use for Primary Prevention in the Elderly Population
The CCS and the ACC/AHA guidelines both recommend discussion of statin use with elderly patients who are believed to be at higher risk. 2,4,5,69 There are randomized controlled trials currently underway specifically assessing statins in primary prevention in this population.
# Treatment Goals
- Both the CCS 4 and the ACC/AHA 5 acknowledge there is controversy regarding the use of lipid treatment targets. This guideline is aligned with the current CCS (2021) recommendations in that treatment with maximally tolerated statins is recommended. If thresholds are not achieved, add-on therapy should be considered.
# Management of Other Clinical Conditions §
A number of clinical conditions contribute significantly to the risk of developing CVD.
# Blood Pressure Control
Support healthy behaviour modifications, followed by the use of antihypertensive medications when appropriate, with consideration for the presence of other CVD risk factors.
# For more information, refer to BCGuidelines.ca -Hypertension -Diagnosis and Management.
Diabetes Care Support healthy behaviour modifications followed by the use of medications when appropriate to control blood glucose. DM is a major risk factor for CVD, but a patient with DM does not need to be automatically considered high risk for CVD. CCS defines a patient with DM high risk for CVD with age ≥40 years, >15-year duration for age ≥30 years (type 1 diabetes mellitus), or with the presence of microvascular disease. While the current FRS now includes diabetic status to individualize a type 2 DM patient's risk, use the United Kingdom Prospective Diabetes (UKPDS) risk calculator or table, website: www.dtu.ox.ac.uk/riskengine. For more information, refer to BCGuidelines.ca -Diabetes Care.
# CKD Management
In patients with CKD, the combination of simvastatin plus ezetimibe has shown benefit in reducing major atherosclerotic events when compared to placebo; however, no benefit on all-cause mortality has been demonstrated. 70 For more information, refer to BCGuidelines.ca -Chronic Kidney Disease -Identification, Evaluation and Management of Adult Patients.
# Methodology
These guideline recommendations are tailored to support practice in British Columbia and are based on guidance by the Canadian Cardiovascular Society (CCS) 2,4 , American Cardiology/American Heart Association (ACC/AHA) 5 , and the European of Cardiology 6 . The guideline development working group used the AGREE II tool to assess the 6 domains and the overall guideline assessment. The working group looked at the three guidelines mentioned above carefully to identify the Scope of Purpose, Stakeholder Involvement, Rigor of Development, Clarity of Presentation, Applicability, Editorial Independence and made an assessment of the overall guideline quality. The AGREE II scores of the guidelines from the working group members showed some variation in domain scoring by individual members but overall agreement of the variation in the quality of these guidelines. The team gained a significant appreciation of both the methodology behind the three guidelines as well as the content and were able to use information from all of them in the GPAC guideline development. The working group started with the draft of the previous version of the GPAC guideline and studied the recommendations from the other three groups to inform this updated version. Where available, key references are provided. In situations where there is a lack of rigorous evidence, we provide best clinical opinion to support decision making and high-quality patient care. The guideline development process included significant engagement and consultation with primary care providers, specialists and key stakeholders, including the Provincial Laboratory Medicine Services. For more information about GPAC guideline development processes, refer to the GPAC handbook available at BCGuidelines.ca.
# Resources
# Health Data Coalition -hdcbc.ca
An online, physician-led data sharing platform that can assist you in assessing your own practice in areas such as chronic disease management or medication prescribing. HDC data can graphically represent patients in your practice with chronic kidney disease in a clear and simple fashion, allowing for reflection on practice and tracking improvements over time.
HealthLinkBC -healthlinkbc.ca HealthLinkBC provides reliable non-emergency health information and advice to patients in BC. Information and advice on managing Diabetes in several languages is available by telephone, website, a mobile app and a collection of print resources.
People can speak to a health services navigator, registered dietitian, registered nurse, qualified exercise professional, or a pharmacist by calling 8-1-1 toll-free in B.C, or 7-1-1 for the deaf and hard of hearing.
# Diagnostic Codes
Prevention visit code -14066
# Smoking -786
Unhealthy eating and medical obesity -783
Physically inactive -785
# Appendices
Undertake a patient-specific discussion regarding the potential risks and benefits of statin use Confirm adherence and barriers to use Follow-up 3-6 months: LDL-C 50% reduction or ApoB < 0.8 g/L or non-HDL-C < 2.6mmol/L
# Consider Statin Treatment
Evaluate CVD risk vs. additional side effects and cost
# Discuss add-on therapy
# Target achieved on maximally tolerated dose
Calculate risk in all adults ≥ 40 using the Framingham risk Score (FRS) or another tool of choice. Statins are associated with a dose-dependent risk of elevated liver enzymes (NNH of 96).4 Investigations are warranted if ALT >3 times the upper limit of normal.
Statin therapy was not associated with cognitive impairment in a meta-analysis of RCTs involving cognitively normal and cognitively impaired patients. 10 Management options for the above adverse effects include statin discontinuation, switching to an alternative statin, dose decreases, and alternate day dosing. 4,5 Data on efficacy of these management options is limited or missing.
Abbreviations: BID = twice daily; CrCl = creatinine clearance in milliliters per minute; G = generics available; mg = milligram; RDP = reference drug program; Tabs = tablets;
Footnotes: a Not an exhaustive list; b Consult product monograph for detailed dosing instructions, dose adjustments for unique patient populations, and drug interactions. Product monographs available from Government of Canada: Drug Product Database, Health Canada advisories, warnings and recalls available from Government of Canada: Recalls and Safety Alerts, and drug interaction software such a Lexicomp. c For normal renal and hepatic function. Consult product monograph for detailed dosing instructions and dose adjustments for unique patient populations. d Pricing is approximate as of Dec 2021 and does not include dispensing fees or additional markups. Note: Information on which products PharmaCare covers can be obtained using the B.C. PharmaCare Formulary Search *Reimbursement is subject to the rules of a patient's PharmaCare plan, including any deductibles. In all cases, coverage is subject to drug price limits set by PharmaCare: Drug Coverage.
PharmaCare
# Associated Documents
Resource Guide for Physicians -Tools for Primary Prevention of Cardiovascular Disease
The principles of the Guidelines and Protocols Advisory Committee are to: | This guideline provides recommendations on the primary prevention of atherosclerotic cardiovascular disease (ASCVD/CVD) in adults aged ≥19 years without clinical CVD. It does not apply to patients with a known history of CVD or who currently have signs or symptoms of CVD, as this would require treatment and secondary prevention. The recommendations include how to assess a patient's risk of CVD and how to manage their CVD risk factors. Familial hypercholesterolemia (FH) and other genetic dyslipidaemias are out of scope of this guideline. Practitioners are recommended to access Canadian Cardiovascular Society guidelines that address this condition. 1 For updated guidance on secondary prevention practitioners are recommended to access the 2021 Canadian Cardiovascular Society guidelines. 2 Key Recommendations • Assess CVD risk in all asymptomatic adults ≥40 years of age [Strong Recommendation, Strong Evidence]. 2-5 • Health behaviour change (e.g., smoking cessation, healthy diet) is recommended as the first-line intervention for all risk groups in CVD primary prevention. Pharmacological management is recommended for high risk groups [Strong Recommendation, Strong Evidence]. 2,4,5 • Initiate statin therapy only after objectively evaluating the person's individual risks, benefits and preferences, and by having an individualized discussion with the patient. Initiate pharmaceutical management after considering the patient's overall individual risk. Treatment with a statin is expected to result in a significant reduction (30 -50%) in the elevated baseline lipid levels [Strong Recommendation, Strong Evidence]. 5-8 • Reducing LDL-C using statin and/or non-pharmacological management is recommended as each 1 mmol/L decrease in LDL-C results in a 20-22% relative risk reduction of major vascular events [Strong Recommendation, Strong Evidence]. 2,9 • The use of aspirin to reduce risk of morbidity or mortality may only be beneficial to certain individuals. [Strong Recommendation, Strong Evidence]. 5,10,11 • Recommendation against the use of over-the-counter omega-3 PUFA to reduce CVD risk. [Strong Recommendation, Strong Evidence].# Assessment of Risk Who to Assess
Consider assessing CVD risk in: • all asymptomatic men and women ≥40 years to establish a baseline 4,5 (Note: Lifetime Prevention Schedule, Ministry of Health, BC, recommends screening men ≥40 years and women ≥50 years); • all patients with pre-existing risk-related conditions (e.g., HTN, DM, CKD); and • all patients with a known family history of premature CVD (defined as men aged <55 years and women aged <65 years in first degree relatives). * A patient may be reassessed in 1 to 5 years depending on their initial risk assessment or if their risk factors change significantly. For further details, refer to Appendix A: Primary Prevention of Cardiovascular Disease Algorithm.
# Risk Assessment a. Risk assessment tool:
The Framingham Risk Score (FRS) is recommended. † The FRS, or any CVD risk assessment tool, is a risk estimation only of a patient's CVD risk. Since these scores are plus or minus several percentage points, it is important to consider modifying the risk estimation based on other known risk factors (e.g., family history, ethnicity) and a practitioner's clinical judgement. For example, the Canadian Cardiovascular Society (CCS) suggests that among individuals 30 -59 years of age without diabetes, the presence of a positive history of premature CVD in first degree relatives increases a patient's FRS by approximately 2-fold. 4 b. In addition to the FRS, other risk assessment tools include Absolute CVD Risk/Benefit Calculator from James McCormack (for patients ≤80 years), the University of Edinburgh Cardiovascular Risk Calculator, the United Kingdom Prospective Diabetes Study (UKPDS) risk calculator that estimates the 10-year CHD and stroke risk for adults with type 2 diabetes and QRISK3 risk calculator (for patients ≤84 years). For additional details on the risk assessment tools, refer to Associated Document: Resource Guide for Physicians -Tools for Primary Prevention of Cardiovascular Disease. Paper-based scores use groups of measurements for the risk factors to assign points; and online calculators use the exact measurements for the risk factors.
A risk score from an online calculator allows for a more individualized estimate of risk .
• Non-modifiable risk factors include: [4][5][6] age -chronological and biological age, biological sex (men) family history of CVD or familial hyperlipidemia (1st degree relative with ASCVD -men <55 years and women <65 years) ethnicity (First Nations, 12 South Asians (defined as Indian, Pakistani, Bangladeshi or Sri Lankan origin)) 13 For any individual, it is imperative that the health needs of that individual as it relates to their racial/ethnic background (e.g., South Asians) is critically examined to ensure culturally appropriate medical and health decisions. 14 chronic kidney disease, chronic inflammatory diseases (e.g., rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, vasculitis (polyarteritis nodosa)), HIV infection, hypertensive diseases of pregnancy, Polycystic Ovarian Syndrome, gestational diabetes. • The modifiable risk factors are listed in
# Modifiable Risk Factors Mitigation Strategy Resources
# Smoking
Smoking cessation is probably the most important health behaviour intervention for the prevention of CVD. 15,16 A linear relation exists between number of cigarettes smoked per day and CVD risk. 17
# QuitNow BC Smoking Cessation Program
HealthLinkBC: Quitting Smoking Unhealthy diet A diet rich in vegetables, fruits, legumes, nuts, whole grains, fish and lean proteins with inherent soluble and insoluble vegetable fiber has been consistently shown to be associated with lower all cause mortality. [18][19][20][21] HealthLinkBC: Heart Healthy Eating
# DASH diet
Canada's Food Guide
# Low physical activity/sedentary behaviour
Engaging in at least 150 minutes per week of accumulated moderate to vigorous-intensity aerobic physical activity is associated with reduced ASCVD. [22][23][24][25][26] HealthLinkBC: Physical Activity
# Reduction in alcohol consumption
Reduction in alcohol intake may lower blood pressure. 29 HealthlinkBC: Low-risk drinking guidelines Canada's Low-Risk Alcohol Drinking Guidelines BCGuidelines: Problem Drinking Hypertension High blood pressure has been shown to increase cardiovascular risk. [30][31][32] Adapt health behaviours to reduce blood pressure levels. Pharmacological management may be needed for some patients along with healthy behaviour changes.
# BCGuidelines: Hypertension -Diagnosis and Management
HealthlinkBC: Lifestyle Steps to Lower Your High Blood Pressure Hypertension Canada: Hypertension and You
# Diabetes Mellitus
Diabetes Mellitus is associated with 2-4 fold increase in CVD. 33,34 Adherence to a healthier behaviours in those with type 2 diabetes is associated with lower CVD risk. 35 BCGuidelines: Socio-economic factors may confer a risk equivalent to traditional risk factors. 39,42 Health education, community-based programs, and behavioural counselling have all been suggested to address the impact of these factors on CVD risk.
Diabetes
Links to some clinical practice tools that can help practitioners improve their performance in identifying and taking action on the root causes of poor health. 43 Prescribed medications 44 Some medications, including thiazide diuretics, beta blockers, and oral estrogens can cause modest changes in serum lipid concentrations. Some of the atypical antipsychotic agents, in particular clozapine and olanzapine, have been associated with weight gain, obesity, hypertriglyceridemia, and development of diabetes mellitus.
# h. Assessment Stratification
The patient can be classified as low, intermediate, or high risk for CVD based on the risk assessment. Any patient that is considered very high risk or is symptomatic (defined as secondary prevention -out of the scope of this guideline) should be treated accordingly. The FRS defines low risk as <10%, intermediate risk as 10 -19% and high risk as ≥20%. These groupings are an arbitrary convenience, not a scientifically validated stratification.
A patient in the intermediate risk group may warrant a secondary assessment to raise or lower their risk stratification. However, further investigations may not be appropriate if the results would not influence the decision of how to manage the risk or treat the patient.
Secondary assessment should be done on patients for whom treatment decisions are uncertain. These assessments may include carotid ultrasound, hsCRP, or coronary artery calcium (CAC) scoring. Updated guidance on the use of CAC is recommended by the CCS 2021 guidelines. 2 Conduct a shared decision-making conversation regarding healthy behaviour modifications and if necessary pharmacological interventions. Consider using cardiovascular age during the discussion. Cardiovascular (CV) age using the Cardiovascular Life Expectancy Model (CLEM) is calculated as the patient's age minus the difference between his or her estimated remaining life expectancy (adjusted for coronary and stroke risk) and the average remaining life expectancy of Canadians of the same age and sex (chiprehab.com/index.html). 4,48
# Management of Risk Healthy Behaviour
Healthy behaviour modifications need to be strongly advocated as the first-line intervention for all risk groups. Adequate explanations and support should be provided to patients, so they clearly understand the nature and significance of CVD, and that they have the primary responsibility for adopting the healthy behaviour changes required for reducing their risk.
# Use the prevention visit code -14066 for discussions related to management of modifiable risks. Diagnostics codes that require a prevention focused advice include smoking (786), unhealthy eating and medical obesity (783), physically inactive (785).
a. Smoking: Promote smoking cessation and avoidance of second-hand smoke. Behavioral and pharmacotherapy interventions, alone or in combination, have been shown to improve rates of smoking cessation among the general adult population. 49,50 Use a Screening, Brief Intervention and Referral to Treatment (SBIRT) approach. 51 When talking to a patient about smoking: 1) Screen for use 2) Conduct a Brief Intervention by providing risks of behaviour 3) Assess for willingness to quit 4) Support behaviour change by connecting to resources or treatment.
• For support to quit, refer patients to: QuitNow at www.quitnow.ca/ HealthLinkBC Quitting Smoking -Patients can call 8-1-1 or visit the website www.healthlinkbc.ca/mental-healthsubstance-use/quitting-smoking. BC Smoking Cessation Program at www.gov.bc.ca/bcsmokingcessation Smokers' Helpline at 1-866-366-3667 or online at SmokersHelpline.ca • For more information on effective pharmacological aids for smoking cessation, refer to BC Smoking Cessation program.
• Electronic cigarettes, also known as e-cigarettes, vaping (available with or without nicotine), may play a role as an aid in smoking cessation. At present time, their risk and benefits have not been clearly established [51][52][53][54] and are not included as a pharmacological aid.
b. Physical Activity: Support patient working towards 30 minutes or more of moderate to vigorous intensity physical activity on most days of the week (weekly total ≥150 minutes). 25,55 Behavioural interventions for healthful diet and physical activity have been shown to generally improve participants' dietary intake and physical activity levels at 6 to 12 months of followup. 56 Techniques such as motivational interviewing and brief action planning, that promote collaborative engagement with the patient, are more effective than exercise prescription alone for patients to achieve their physical activity goals.
• Exercise stress test may be warranted for previously sedentary people with additional risk factors for CVD who wish to undertake exercise more vigorous than brisk walking. 4 • For patients who are sedentary, consider a graduated exercise program using Brief Action Planning (BAP).
• Engage the patients in completing a Physical Activity Readiness Questionnaire for Everyone (PAR-Q+) and electronic Physical Activity Readiness Medical Examination (ePARmed-X+) to help them determine their readiness. Refer them to an accessible exercise program (such as healthy heart programs). • For assistance with personalized physical activity advice, refer patient to a physical activity expert at HealthLinkBC or by telephone at 8-1-1.
c. Diet: Encourage a well-balanced diet. There are many dietary pathways to achieve CV risk reduction such as the Mediterranean diet (which emphasizes fruits, vegetables, legumes, whole grains and olive oil, with moderate consumption of fish, dairy products, poultry and minimizing meats and sweets) or the Dietary Approaches to Stop Hypertension (DASH) diet. 4 • For assistance with personalized diet advice, refer patient to a dietitian at HealthLinkBC by telephone 8-1-1 or website: www.healthlinkbc.ca.
# d. Alcohol Consumption:
Screen for alcohol abuse. Use a Screening, Brief Intervention, and Referral for Treatment (SBIRT) approach.
# Follow-up to Healthy Behaviour Modifications
• Assess success of healthy behaviour intervention change at first follow-up.
• Assess cardiovascular risk using lipid profile (non-fasting)
• For those with elevated lipids from their initial risk assessment, they may be followed up with a lipid profile in 3 -6 months. If elevated lipids are still a concern, consider pharmaceutical management. • Studies consistently demonstrate a 20-22% relative risk reduction for each 1 mmol/L reduction in low-density lipoprotein cholesterol (LDL-C). 9 The absolute risk reduction is thus dependent upon the baseline risk and the baseline LDL-C, as statin treatment will provide a greater absolute LDL-C lowering in those with higher baseline values. 2 Both non-HDL-C and ApoB appear to be stronger predictors than LDL-C for major future cardiovascular events. 2,57,58 Non-HDL-C may also be a better indicator of residual risk after statin therapy than LDL-C. 59 ApoB is not available with lipid profiles unless diagnosis of complex dyslipidemia is indicated.
# Pharmaceutical Management
Acetylsalicylic Acid (ASA) Therapy ASA therapy in Primary Prevention: Evidence does not support the use of aspirin in low and intermediate risk patients. The evidence for use of aspirin in high risk patients is currently uncertain. 5,60 Use of aspirin in people >75 may further heighten the risk of clinical significant bleeding. 61
# Statin Therapy
For those patients with DM, CKD, or Familial Hyperdyslipidemia, statin therapy is indicated along with healthy behaviour interventions. Prior to the initiation of statin therapy:
• inform the patient of adverse effects [63][64][65] -effects may include muscle pain/myopathy/weakness, rhabdomyolysis, cataracts, elevated blood glucose and diabetes, acute renal failure, and liver injury; • educate the patient about any possible drug interactions with other prescribed medication, over-the-counter remedies and non-pharmaceuticals -consult a pharmacist or product monograph for a complete list; and • emphasize the importance of long-term compliance -it is estimated that 75% of primary prevention patients aged >65 years old started on statins stop their therapy within 2 years. 66 Follow-up to Statin Therapy Within 3 -6 months of the initiation of statin therapy, follow-up with the patient. This may include:
• Measure lipids with a non-HDL-C or an ApoB to assess patient adherence to statin therapy and any response to statin therapy (see Controversies in Care). A full lipid profile is not indicated. If both healthy behaviour intervention and a statin intervention have not been successful and lipids are still above target in the follow-up investigation, consider any other causes of elevated lipids (e.g., hypothyroidism, non-adherence). • Inquire about any adverse effects. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is ≈0.001%. 65 If muscle pain or weakness is reported in patients, measure CK. In asymptomatic patients, CK is not necessary. CK elevation is of concern only when it is significantly elevated (i.e., >5X). 63 • Measure liver transaminase enzyme (alanine aminotransferase (ALT)) only once within the first 3 months of starting statin. If a patient has elevated liver transaminase enzymes, (greater than 3X the normal) consider secondary causes. 65 Further follow-ups as clinically needed. After the initial follow-up, routine monitoring of CK and ALT is not indicated for asymptomatic patients. More frequent routine monitoring with a full lipid profile, non-HDL-C or an ApoB is not considered necessary for the sole purpose of treat-to-target.
# When to Refer Patients to a Specialist
Consider referral to a specialist when there is:
• Difficulty reaching treatment targets despite maximum-tolerated lipid-lowering therapy.
• Intolerance to or adverse effects of statin treatment. Statin intolerance needs to be well documented prior to referral. 63
# Controversies in Care Statin Therapy in Primary Prevention
Both the Canadian Cardiovascular Society (CCS) 4 and the American Heart Association (ACC/AHA)5 acknowledge that there is high interindividual variability in LDL-C levels attained with statin therapy. They agree that recent studies have demonstrated lower CVD event rates with moderate-intensity and high-intensity statin therapy that outweighed the observable risks. 4,5,67 The 2016 USPSTF systematic review of statin therapy in primary prevention showed a reduced risk of all-cause and cardiovascular mortality and ASCVD events and noted greater absolute benefits in those at greater baseline risk. 68 both the CCS and ACC/AHA have recommended a more aggressive approach for statin use (see
# CKD or high risk HTN Treat with statins.
No specific recommendation.
# Statin Use for Primary Prevention in the Elderly Population
The CCS and the ACC/AHA guidelines both recommend discussion of statin use with elderly patients who are believed to be at higher risk. 2,4,5,69 There are randomized controlled trials currently underway specifically assessing statins in primary prevention in this population.
# Treatment Goals
• Both the CCS 4 and the ACC/AHA 5 acknowledge there is controversy regarding the use of lipid treatment targets. This guideline is aligned with the current CCS (2021) recommendations in that treatment with maximally tolerated statins is recommended. If thresholds are not achieved, add-on therapy should be considered.
# Management of Other Clinical Conditions §
A number of clinical conditions contribute significantly to the risk of developing CVD.
# Blood Pressure Control
Support healthy behaviour modifications, followed by the use of antihypertensive medications when appropriate, with consideration for the presence of other CVD risk factors.
# For more information, refer to BCGuidelines.ca -Hypertension -Diagnosis and Management.
Diabetes Care Support healthy behaviour modifications followed by the use of medications when appropriate to control blood glucose. DM is a major risk factor for CVD, but a patient with DM does not need to be automatically considered high risk for CVD. CCS defines a patient with DM high risk for CVD with age ≥40 years, >15-year duration for age ≥30 years (type 1 diabetes mellitus), or with the presence of microvascular disease. While the current FRS now includes diabetic status to individualize a type 2 DM patient's risk, use the United Kingdom Prospective Diabetes (UKPDS) risk calculator or table, website: www.dtu.ox.ac.uk/riskengine. For more information, refer to BCGuidelines.ca -Diabetes Care.
# CKD Management
In patients with CKD, the combination of simvastatin plus ezetimibe has shown benefit in reducing major atherosclerotic events when compared to placebo; however, no benefit on all-cause mortality has been demonstrated. 70 For more information, refer to BCGuidelines.ca -Chronic Kidney Disease -Identification, Evaluation and Management of Adult Patients.
# Methodology
These guideline recommendations are tailored to support practice in British Columbia and are based on guidance by the Canadian Cardiovascular Society (CCS) 2,4 , American Cardiology/American Heart Association (ACC/AHA) 5 , and the European of Cardiology 6 . The guideline development working group used the AGREE II tool to assess the 6 domains and the overall guideline assessment. The working group looked at the three guidelines mentioned above carefully to identify the Scope of Purpose, Stakeholder Involvement, Rigor of Development, Clarity of Presentation, Applicability, Editorial Independence and made an assessment of the overall guideline quality. The AGREE II scores of the guidelines from the working group members showed some variation in domain scoring by individual members but overall agreement of the variation in the quality of these guidelines. The team gained a significant appreciation of both the methodology behind the three guidelines as well as the content and were able to use information from all of them in the GPAC guideline development. The working group started with the draft of the previous version of the GPAC guideline and studied the recommendations from the other three groups to inform this updated version. Where available, key references are provided. In situations where there is a lack of rigorous evidence, we provide best clinical opinion to support decision making and high-quality patient care. The guideline development process included significant engagement and consultation with primary care providers, specialists and key stakeholders, including the Provincial Laboratory Medicine Services. For more information about GPAC guideline development processes, refer to the GPAC handbook available at BCGuidelines.ca.
# Resources
# Health Data Coalition -hdcbc.ca
An online, physician-led data sharing platform that can assist you in assessing your own practice in areas such as chronic disease management or medication prescribing. HDC data can graphically represent patients in your practice with chronic kidney disease in a clear and simple fashion, allowing for reflection on practice and tracking improvements over time.
HealthLinkBC -healthlinkbc.ca HealthLinkBC provides reliable non-emergency health information and advice to patients in BC. Information and advice on managing Diabetes in several languages is available by telephone, website, a mobile app and a collection of print resources.
People can speak to a health services navigator, registered dietitian, registered nurse, qualified exercise professional, or a pharmacist by calling 8-1-1 toll-free in B.C, or 7-1-1 for the deaf and hard of hearing.
# Diagnostic Codes
Prevention visit code -14066
# Smoking -786
Unhealthy eating and medical obesity -783
Physically inactive -785
# Appendices
Undertake a patient-specific discussion regarding the potential risks and benefits of statin use Confirm adherence and barriers to use Follow-up 3-6 months: LDL-C < 2.0mmol/L or > 50% reduction or ApoB < 0.8 g/L or non-HDL-C < 2.6mmol/L
# Consider Statin Treatment
Evaluate CVD risk vs. additional side effects and cost
# Discuss add-on therapy
# Target achieved on maximally tolerated dose
Calculate risk in all adults ≥ 40 using the Framingham risk Score (FRS) or another tool of choice. Statins are associated with a dose-dependent risk of elevated liver enzymes (NNH of 96).4 Investigations are warranted if ALT >3 times the upper limit of normal.
Statin therapy was not associated with cognitive impairment in a meta-analysis of RCTs involving cognitively normal and cognitively impaired patients. 10 Management options for the above adverse effects include statin discontinuation, switching to an alternative statin, dose decreases, and alternate day dosing. 4,5 Data on efficacy of these management options is limited or missing.
Abbreviations: BID = twice daily; CrCl = creatinine clearance in milliliters per minute; G = generics available; mg = milligram; RDP = reference drug program; Tabs = tablets;
Footnotes: a Not an exhaustive list; b Consult product monograph for detailed dosing instructions, dose adjustments for unique patient populations, and drug interactions. Product monographs available from Government of Canada: Drug Product Database, Health Canada advisories, warnings and recalls available from Government of Canada: Recalls and Safety Alerts, and drug interaction software such a Lexicomp. c For normal renal and hepatic function. Consult product monograph for detailed dosing instructions and dose adjustments for unique patient populations. d Pricing is approximate as of Dec 2021 and does not include dispensing fees or additional markups. Note: Information on which products PharmaCare covers can be obtained using the B.C. PharmaCare Formulary Search *Reimbursement is subject to the rules of a patient's PharmaCare plan, including any deductibles. In all cases, coverage is subject to drug price limits set by PharmaCare: Drug Coverage.
PharmaCare
# Associated Documents
Resource Guide for Physicians -Tools for Primary Prevention of Cardiovascular Disease
The principles of the Guidelines and Protocols Advisory Committee are to:
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This guideline is based on scientific evidence current as of effective date.
This guideline was developed by the Guidelines and Protocols Advisory Committee in collaboration with the Provincial Laboratory Medicine Services, and adopted under the Medical Services Act and the Laboratory Services Act.
For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook.
# Appendix B: Framingham 10-year Risk Estimation
Step 1: Calculate the patient's total points using Table 1.
Step 2: Determine the patient's 10-year CVD risk using Table 2. Double risk percentage if there is a history of premature CVD (men<55 and women<65) in patient's first-degree relatives.
Step 3: Determine the patient's 10-year CVD risk level using Table 3.
# Appendix C: Lipid Testing in Primary Prevention of Cardiovascular Disease
# Full Lipid Profile Testing in CVD Primary Prevention
Indications for a full lipid profile include:
• CVD Risk Assessment Consider to assess CVD risk in: all asymptomatic men and women ≥40 to establish a baseline; all patients with pre-existing risk-related conditions (e.g., HTN, DM, CKD); and all patients with a known family history of premature CVD (defined as men aged <55 years and women aged <65 years in first degree relatives). • Reassessment of CVD Risk A patient may be reassessed in 1 to 5 years depending on their initial risk assessment or if their risk factors change significantly. ApoB is the primary protein for all atherogenic lipoproteins, and each atherogenic particle contains one molecule of ApoB. Therefore, the concentration of ApoB directly reflects the number of atherogenic particles.
Both non-HDL-C and ApoB appear to be stronger predictors than LDL-C for major future cardiovascular events. Non-HDL-C may also be a better indicator of residual risk after statin therapy than LDL-C. ApoB is not available with lipid profiles unless diagnosis of complex dyslipidemia is indicated.
# Indications for a non-HDL-C or ApoB include:
• Men and women with elevated lipids from their initial risk assessment may be followed up with a non-HDL-C or an ApoB after 3 -6 months to assess the impact of healthy behaviour modifications. • Follow-up within 3 -6 months of the initiation of statin therapy to assess patient adherence and response from statin therapy.
More frequent routine monitoring with a full lipid profile, non-HDL-C or an ApoB is considered not necessary for the sole purpose of treat-to-target.
# Adverse Effects of Statins
The most common adverse events in patients treated with a statin include headache, GI disturbances, and myalgia. 6 Meta-analyses of RCTs show no significant difference in the rate of adverse events, or in the rate of discontinuation due to adverse events between those taking a statin vs placebo. 5,6 There continued to be no significant difference when looking at subgroups such as primary vs secondary prevention, the statin used or discontinuation specifically due to myalgia, muscle pain or myopathy. 6,7 There is increasing awareness and concern about rare but serious adverse effects of statins.
The development of diabetes is associated with an NNH of 255 over 4 years. 4,7 While the risk of myalgia is common (2-11%), the risk of more serious adverse events such as rhabdomyolysis is low (<0.1%; NNH 22,727 over 1 year) 9 and is seen in patients with additional risk factors such as comorbidities (i.e. hypothyroid, renal/hepatic impairment), age (>80), genetic factors (i.e. SLCO1B1), or concurrent drug therapy (i.e. CYP3A4 inhibitors or inducers, gemfibrozil, protease inhibitors, cyclosporine). 5,9 Advise patients to report muscle pain and/ or weakness. CK elevation is of concern only when it is significantly elevated (i.e., >5X). 4 Resource Guide for Physicians -Tools for Primary Prevention of Cardiovascular Disease
# Risk Assessment Resources
There are a number of tools to assist in determining a patient's risk to cardiovascular disease (CVD). Each tool varies in the risk factors, time frame and CVD outcomes. There are known limitations to each of the risk tools, and the risk categories are based on consensus rather than by scientific evidence.
Older risk tools used only hard endpoints (e.g., coronary heart disease (CHD) deaths) to calculate one's risk. Newer risk tools have expanded their endpoints to include more CVD outcomes. NOTE: The FRS, or any CVD risk assessment tool, is a risk estimation only of a patient's CVD risk. Since these scores are plus or minus several percentage points, it is important to consider modifying the risk estimation based on other known risk factors (e.g., family history, ethnicity) and a practitioner's clinical judgement. For example, the Canadian Cardiovascular Society (CCS) suggests that among individuals 30 -59 years of age without diabetes, the presence of a positive history of premature CVD in first degree relatives increases a patient's FRS by approximately 2-fold.
# Risk Assessment Tools
• Canadian Cardiovascular Society: estimates the 10-year risk of developing CVD, with paper-base and an online calculator, using FRS. https://ccs.ca/calculators-and-forms/ • Framingham Heart Study: FRS risk calculators (for patients age ≤74) for various CVD outcomes (e.g., CVD, CHD) and time frames (e.g., 10-year risk, 30-year risk | None | None |
013b94c25788986bfc8b3814a8160149cd777c18 | cma | None | # INTRODUCTION
Deaths due to opioid overdose have reached unprecedented levels in Canada; over 12,800 opioid-related deaths occurred between January 2016 and March 2019, and overdose death rates increased by approximately 50% from 2016 to 2018. 1 In 2016, Health Canada declared the opioid epidemic a national public health crisis, 2 and life expectancy increases have halted in Canada for the first time in decades. 3 Children are not exempt from this crisis, and the Chief Public Health Officer of Canada has recently prioritized the prevention of problematic substance use among Canadian youth. 4 In 2014, the overall health care costs of substance use in Canada were estimated to be $11.1 billion, of which 2.8% ($0.3 billion) were attributed to opioids. 5 Since then, health care use resulting from opioid use has increased dramatically. Opioid-related hospitalizations increased by 27% between 2013 and 2017. 6 From 2016 to 2017, emergency department (ED) visits due to opioids increased by 73% in Ontario, and 23% in Alberta. 6 Furthermore, youth aged 15 to 24 years have the highest and fastest-growing rates of ED visits related to opioids, tripling over the past 5 years. 6 EDs are often the main source of health care for patients with substance use disorders. 7 ED visits are crucial opportunities to identify and address the complex needs of patients who are socially and medically marginalized. 8 Those who visit the ED frequently are at significant risk of subsequent overdose. 9 People who overdose are more likely to have visited an ED in the preceding year, and are more likely than the average patient to have left without being seen or against medical advice. 10 In the context of a national opioid crisis, there is a professional imperative for emergency providers to take evidence-based steps to prevent future morbidity and mortality resulting from opioid use and from common presentations of opioid-related illness in ED settings. Nonfatal opioid overdose, rapid opioid tapering, and opioid withdrawal are significant risk factors for subsequent death due to opioid overdose. 11,12 In Canada, ED-based interventions for opioid use disorder have been shown to be effective and acceptable to patients. CAEP supports a broad and multi-faceted public health approach to addressing this complex health crisis and embraces an evidence-based harm reduction approach to substance use, which aims to reduce the harms of substance use without mandating abstinence. 17,18 This position statement offers recommendations designed to position emergency medicine, emergency health care providers, and EDs as key partners in a broad and intersectoral strategy to address Canada's opioid crisis for Canadians of all ages.
The scope of this position statement is limited to clinical practice in the ED. The recommendations in this position statement are applicable and adaptable across urban, suburban, and rural practice environments nationwide, although reasonable modifications may be required to suit local patient needs, demographics, and epidemiology. These recommendations were not developed according to systematic review or guideline methodologies and should not be interpreted as a clinical practice guideline. This position statement is intended to advance common practice, and not to establish a standard of care. c) Missed scheduled doses of opioid agonist therapy (e.g., methadone, buprenorphine/naloxone) should be provided in the ED to patients on stable treatment, after confirming the time of last dosing with the patient's community pharmacy. If patients have missed doses before the day of the ED visit, consider contacting their primary provider to discuss dose replacement as per provincial guidelines.
d) EDs should ensure that treatment is provided in a patient-centered and compassionate manner that is free from judgment, bias, and discrimination.
# GOING FORWARD
Substance use disorder education has been lacking across the spectrum of medical training. 19 This lack of education and training has been identified as a major barrier to providing appropriate care for patients with substance use disorders, and must be addressed to build capacity across EDs in the country. 15,20 There is evidence to suggest that physicians who have undergone training are more likely to provide treatment for opioid use disorder, such as buprenorphine/naloxone. 21 The College of Family Physicians of Canada certifies family physicians who have added competence in Addiction Medicine. 22 The Royal College of Physicians and Surgeons has also established an Area of Focused Competency in Addiction Medicine. 23 Within the Royal College's new competency-based residency curriculum, Canadian emergency medicine residents will need to develop proficiencies in addiction medicine, including those related to encounters with individuals with opioid use disorder. 24 CAEP will support educational initiatives and curriculum for areas of competency related to opioid use disorder for emergency physicians, and act as a platform for exchange of knowledge and best practices across the country.
Finally, further attention should be directed toward the challenges in assessing and monitoring the impact of the opioid crisis on EDs across the country. Inadequate ED data collection on opioid-related visits remains a significant barrier to public health planning. In 2018, Ontario, Alberta, and the Yukon were the only jurisdictions in which all EDs submitted sufficient data to the National Ambulatory Care Reporting System (NACRS) for analysis. 6 As such, the most recent Canadian Institute for Health Information (CIHI) report on opioid-related harms only provided analyses on ED data and trends in ED visits in these jurisdictions. 6 EDs across the country are encouraged to collaborate with public health organizations on data collection and surveillance, and improve monitoring of trends in ED visits due to opioids across the lifespan at the provincial and national levels.
# CONCLUSIONS
Emergency physicians are on the front lines of the opioid crisis and must act to address Canada's largest public health emergency to date. The recommendations outlined in this position statement are important steps to ensure that people of all ages with opioid use disorders are provided equitable, compassionate, and evidence-based care in the ED setting. These recommendations can be implemented across urban and rural practice environments nationwide and should be adapted to meet patient needs and availability of resources locally.
# Competing interests: None declared.
Supplementary Materials: To view supplementary material for this article, please visit . | # INTRODUCTION
Deaths due to opioid overdose have reached unprecedented levels in Canada; over 12,800 opioid-related deaths occurred between January 2016 and March 2019, and overdose death rates increased by approximately 50% from 2016 to 2018. 1 In 2016, Health Canada declared the opioid epidemic a national public health crisis, 2 and life expectancy increases have halted in Canada for the first time in decades. 3 Children are not exempt from this crisis, and the Chief Public Health Officer of Canada has recently prioritized the prevention of problematic substance use among Canadian youth. 4 In 2014, the overall health care costs of substance use in Canada were estimated to be $11.1 billion, of which 2.8% ($0.3 billion) were attributed to opioids. 5 Since then, health care use resulting from opioid use has increased dramatically. Opioid-related hospitalizations increased by 27% between 2013 and 2017. 6 From 2016 to 2017, emergency department (ED) visits due to opioids increased by 73% in Ontario, and 23% in Alberta. 6 Furthermore, youth aged 15 to 24 years have the highest and fastest-growing rates of ED visits related to opioids, tripling over the past 5 years. 6 EDs are often the main source of health care for patients with substance use disorders. 7 ED visits are crucial opportunities to identify and address the complex needs of patients who are socially and medically marginalized. 8 Those who visit the ED frequently are at significant risk of subsequent overdose. 9 People who overdose are more likely to have visited an ED in the preceding year, and are more likely than the average patient to have left without being seen or against medical advice. 10 In the context of a national opioid crisis, there is a professional imperative for emergency providers to take evidence-based steps to prevent future morbidity and mortality resulting from opioid use and from common presentations of opioid-related illness in ED settings. Nonfatal opioid overdose, rapid opioid tapering, and opioid withdrawal are significant risk factors for subsequent death due to opioid overdose. 11,12 In Canada, ED-based interventions for opioid use disorder have been shown to be effective and acceptable to patients. [13][14][15][16] CAEP supports a broad and multi-faceted public health approach to addressing this complex health crisis and embraces an evidence-based harm reduction approach to substance use, which aims to reduce the harms of substance use without mandating abstinence. 17,18 This position statement offers recommendations designed to position emergency medicine, emergency health care providers, and EDs as key partners in a broad and intersectoral strategy to address Canada's opioid crisis for Canadians of all ages.
The scope of this position statement is limited to clinical practice in the ED. The recommendations in this position statement are applicable and adaptable across urban, suburban, and rural practice environments nationwide, although reasonable modifications may be required to suit local patient needs, demographics, and epidemiology. These recommendations were not developed according to systematic review or guideline methodologies and should not be interpreted as a clinical practice guideline. This position statement is intended to advance common practice, and not to establish a standard of care. c) Missed scheduled doses of opioid agonist therapy (e.g., methadone, buprenorphine/naloxone) should be provided in the ED to patients on stable treatment, after confirming the time of last dosing with the patient's community pharmacy. If patients have missed doses before the day of the ED visit, consider contacting their primary provider to discuss dose replacement as per provincial guidelines.
d) EDs should ensure that treatment is provided in a patient-centered and compassionate manner that is free from judgment, bias, and discrimination.
# GOING FORWARD
Substance use disorder education has been lacking across the spectrum of medical training. 19 This lack of education and training has been identified as a major barrier to providing appropriate care for patients with substance use disorders, and must be addressed to build capacity across EDs in the country. 15,20 There is evidence to suggest that physicians who have undergone training are more likely to provide treatment for opioid use disorder, such as buprenorphine/naloxone. 21 The College of Family Physicians of Canada certifies family physicians who have added competence in Addiction Medicine. 22 The Royal College of Physicians and Surgeons has also established an Area of Focused Competency in Addiction Medicine. 23 Within the Royal College's new competency-based residency curriculum, Canadian emergency medicine residents will need to develop proficiencies in addiction medicine, including those related to encounters with individuals with opioid use disorder. 24 CAEP will support educational initiatives and curriculum for areas of competency related to opioid use disorder for emergency physicians, and act as a platform for exchange of knowledge and best practices across the country.
Finally, further attention should be directed toward the challenges in assessing and monitoring the impact of the opioid crisis on EDs across the country. Inadequate ED data collection on opioid-related visits remains a significant barrier to public health planning. In 2018, Ontario, Alberta, and the Yukon were the only jurisdictions in which all EDs submitted sufficient data to the National Ambulatory Care Reporting System (NACRS) for analysis. 6 As such, the most recent Canadian Institute for Health Information (CIHI) report on opioid-related harms only provided analyses on ED data and trends in ED visits in these jurisdictions. 6 EDs across the country are encouraged to collaborate with public health organizations on data collection and surveillance, and improve monitoring of trends in ED visits due to opioids across the lifespan at the provincial and national levels.
# CONCLUSIONS
Emergency physicians are on the front lines of the opioid crisis and must act to address Canada's largest public health emergency to date. The recommendations outlined in this position statement are important steps to ensure that people of all ages with opioid use disorders are provided equitable, compassionate, and evidence-based care in the ED setting. These recommendations can be implemented across urban and rural practice environments nationwide and should be adapted to meet patient needs and availability of resources locally.
# Competing interests: None declared.
Supplementary Materials: To view supplementary material for this article, please visit https://doi.org/10.1017/cem.2020.459. | None | None |
Subsets and Splits